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  • 1.
    Andersson, Ulrika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Bergenheim, A. Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Behnam-Motlagh, Parviz
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Rapid induction of long-lasting drug efflux activity in brain vascular endothelial cells but not malignant glioma following irradiation2002Ingår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 19, nr 1, s. 1-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The influence of radiotherapy on malignant glioma multidrug resistance to chemotherapy was evaluated because patients with glioma often are treated with a combination of radiotherapy and chemotherapy. Multidrug resistance gene (MDR1, mdr1a, and mdr1b) transcripts were found in human and rat glioma cell lines. P-Glycoprotein (Pgp) was immunohistochemically detected in glioma cell lines and in the rat brain vascular endothelial cell line (RBE4). A multidrug resistance pump efflux activity assay demonstrated increased calcein efflux of RBE4 endothelial cells, but not glioma cells, 2 h after irradiation and still increased 14 d after irradiation. The increased efflux was equally inhibited by verapamil with or without irradiation. In the rat intracranial glioma model (BT4C), Pgp was demonstrated in capillary endothelial cells of the tumor tissue and surrounding normal brain, but not in tumor cells. The expression of gene transcripts or Pgp was not affected by irradiation. The results indicate that long-lasting verapamil-resistant drug efflux mechanisms are activated in brain endothelial cells after irradiation. The results might explain the poor efficacy of chemotherapy following radiotherapy and contribute to consideration of new treatment strategies in the management of malignant glioma.

  • 2.
    Andersson, Ulrika
    et al.
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Guo, Dongsheng
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Malmer, Beatrice
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Bergenheim, A Tommy
    Umeå universitet, Medicinsk fakultet, Farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Brännström, Thomas
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Hedman, Håkan
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Epidermal growth factor receptor family (EGFR, ErbB2-4) in gliomas and meningiomas2004Ingår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 108, nr 2, s. 135-142Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Overexpression of epidermal growth factor receptor (EGFR, ErbB1) correlates with enhanced malignant potential of many human tumor types including glioblastoma multiforme. The significance of EGFR expression in meningiomas is, however, unclear. Reports regarding the other EGFR family members, ErbB2-4, in brain tumors are sparse. In this study, the expression of the EGFR family members was analyzed in relation to various parameters for the clinical importance of these receptors in 44 gliomas and 26 meningiomas. In gliomas, quantitative real-time reverse transcription (RT)-PCR revealed the highest EGFR mRNA expression in high-grade gliomas, while ErbB2 and ErbB3 mRNA were detected only in a few high-grade gliomas. In contrast, ErbB4 expression was most pronounced in low-grade gliomas. Immunohistochemistry showed significantly higher EGFR protein expression in high-grade gliomas compared to low-grade gliomas (P= 0.004). ErbB2 protein expression was mainly seen in high-grade gliomas. ErbB3 protein expression was low in all gliomas analyzed. ErbB4 protein expression was significantly higher in low-grade gliomas than in high-grade gliomas (P= 0.007). In meningiomas, quantitative real-time RT-PCR revealed expression of EGFR, ErbB2, and ErbB4 mRNA in the majority of the tumors. ErbB3 was detected in only one of the meningiomas analyzed. Immunohistochemistry demonstrated high ErbB2 protein expression in meningiomas. An intriguing observation in astrocytomas and oligodendrogliomas grade II, was a significantly decreased overall survival for patients with high EGFR protein expression (P= 0.04). The high ErbB4 expression in low-grade compared to high-grade gliomas might suggest that ErbB4 acts as a suppressor of malignant transformation in brain tumors, which is in line with previous studies in other tumor types.

  • 3.
    Asklund, Thomas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Kvarnbrink, Samuel
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Holmlund, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wibom, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergenheim, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Synergistic Killing of Glioblastoma Stem-like Cells by Bortezomib and HADC Inhibitors.2012Ingår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 32, nr 7, s. 2407-2413Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The malignant brain tumour glioblastoma is a devastating disease that remains a therapeutic challenge. Materials and Methods: Effects of combinations of the US Food and Drug Administation (FDA) approved proteasome inhibitor bortezomib and the histone deacetylase (HDAC) inhibitors vorinostat, valproic acid and sodium phenylbutyrate were studied on primary glioblastoma stem cell lines and conventional glioblastoma cell lines. Cell survival, proliferation and death were analyzed by fluorometric microculture cytotoxicity assay (FMCA), propidium iodide labeling and flow cytometry, and cell cloning through limiting dilution and live-cell bright-field microscopy. Results: Bortezomib and the HDAC inhibitors showed synergistic cell killing at clinically relevant drug concentrations, while the conventional cell lines cultured in serum-containing medium were relatively resistant to the same treatments. Conclusion: These findings of synergistic glioblastoma stem cell killing by bortezomib and three different FDA-approved HDAC inhibitors confirm and expand previous observations on co-operative effects between these classes of drugs.

  • 4.
    Asklund, Thomas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Kvarnbrink, Samuel
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Holmlund, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wibom, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergenheim, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Synergistic killing of Glioblastoma Stem-like cells by Bortezomib and HDAC Inhibitors2012Ingår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 32, nr 7 ; Special Issue, s. 2407-2413Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The malignant brain tumour glioblastoma is a devastating disease that remains a therapeutic challenge. Materials and Methods: Effects of combinations of the US Food and Drug Administation (FDA) approved proteasome inhibitor bortezomib and the histone deacetylase (HDAC) inhibitors vorinostat, valproic acid and sodium phenylbutyrate were studied on primary glioblastoma stem cell lines and conventional glioblastoma cell lines. Cell survival, proliferation and death were analyzed by fluorometric microculture cytotoxicity assay (FMCA), propidium iodide labeling and flow cytometry, and cell cloning through limiting dilution and live-cell bright-field microscopy. Results: Bortezomib and the HDAC inhibitors showed synergistic cell killing at clinically relevant drug concentrations, while the conventional cell lines cultured in serum-containing medium were relatively resistant to the same treatments. Conclusion: These findings of synergistic glioblastoma stem cell killing by bortezomib and three different FDA-approved HDAC inhibitors confirm and expand previous observations on co-operative effects between these classes of drugs.

  • 5. Cruz Alsina, Fernando
    et al.
    Javier Hita, Francisco
    Aldana Fontanet, Paula
    Irala, Dolores
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Ledda, Fernanda
    Paratcha, Gustavo
    Lrig1 is a cell-intrinsic modulator of hippocampal dendrite complexity and BDNF signaling2016Ingår i: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 17, nr 4, s. 601-616Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Even though many extracellular factors have been identified as promoters of general dendritic growth and branching, little is known about the cell-intrinsic modulators that allow neurons to sculpt distinctive patterns of dendrite arborization. Here, we identify Lrig1, a nervous system-enriched LRR protein, as a key physiological regulator of dendrite complexity of hippocampal pyramidal neurons. Lrig1-deficient mice display morphological changes in proximal dendrite arborization and defects in social interaction. Specifically, knockdown of Lrig1 enhances both primary dendrite formation and proximal dendritic branching of hippocampal neurons, two phenotypes that resemble the effect of BDNF on these neurons. In addition, we show that Lrig1 physically interacts with TrkB and attenuates BDNF signaling. Gain and loss of function assays indicate that Lrig1 restricts BDNF-induced dendrite morphology. Together, our findings reveal a novel and essential role of Lrig1 in regulating morphogenic events that shape the hippocampal circuits and establish that the assembly of TrkB with Lrig1 represents a key mechanism for understanding how specific neuronal populations expand the repertoire of responses to BDNF during brain development.

  • 6.
    Faraz, Mahmood
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Herdenberg, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Holmlund, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    A protein interaction network centered on leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) regulates growth factor receptors2018Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, nr 9, s. 3421-3435Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a tumor suppressor and a negative regulator of several receptor tyrosine kinases. The molecular mechanisms by which LRIG1 mediates its tumor suppressor effects and regulates receptor tyrosine kinases remain incompletely understood. Here, we performed a yeast two-hybrid screen to identify novel LRIG1-interacting proteins and mined data from the BioPlex (biophysical interactions of ORFeome-based complexes) protein interaction data repository. The putative LRIG1 interactors identified in the screen were functionally evaluated using a triple co-transfection system in which HEK293 cells were co-transfected with platelet-derived growth factor receptor α, LRIG1, and shRNAs against the identified LRIG1 interactors. The effects of the shRNAs on the ability of LRIG1 to down-regulate platelet-derived growth factor receptor α expression were evaluated. On the basis of these results, we present an LRIG1 protein interaction network with many newly identified components. The network contains the apparently functionally important LRIG1-interacting proteins RAB4A, PON2, GAL3ST1, ZBTB16, LRIG2, CNPY3, HLA-DRA, GML, CNPY4, LRRC40, and LRIG3, together with GLRX3, PTPRK, and other proteins. In silico analyses of The Cancer Genome Atlas data sets revealed consistent correlations between the expression of the transcripts encoding LRIG1 and its interactors ZBTB16 and PTPRK and inverse correlations between the transcripts encoding LRIG1 and GLRX3. We further studied the LRIG1 function–promoting paraoxonase PON2 and found that it co-localized with LRIG1 in LRIG1-transfected cells. The proposed LRIG1 protein interaction network will provide leads for future studies aiming to understand the molecular functions of LRIG1 and the regulation of growth factor signaling.

  • 7.
    Ghasimi, Soma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Haapasalo, H.
    Eray, M.
    Korhonen, K.
    Brannstrom, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Immunohistochemical analysis of LRIG proteins in meningiomas: correlation between estrogen receptor status and LRIG expression2012Ingår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 14, nr Suppl 3, s. 69-69Artikel i tidskrift (Övrigt vetenskapligt)
  • 8.
    Ghasimi, Soma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Haapasalo, Hannu
    Department of Pathology, Center of Laboratory Medicine, Tampere University .
    Eray, Mine
    Department of Pathology, Center of Laboratory Medicine, Tampere University .
    Korhonen, Katariina
    Department of Neurosurgery, Turku University Hospital, Turku, Finland.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Immunohistochemical analysis of LRIG proteins in meningiomas: correlation between estrogen receptor status and LRIG expression2012Ingår i: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 108, nr 3, s. 435-441Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family is comprised of three integral membrane proteins: LRIG1, LRIG2, and LRIG3. LRIG1 is a negative regulator of growth factor signaling. The expression and subcellular localization of LRIG proteins have prognostic implications in primary brain tumors, such as oligodendrogliomas and astrocytomas. The expression of LRIG proteins has not previously been studied in meningiomas. In this study, the expression of LRIG1, LRIG2, and LRIG3 was analyzed in 409 meningiomas by immunohistochemistry, and potential associations between LRIG protein expression and tumor grade, gender, progesterone receptor status, and estrogen receptor (ER) status were investigated. The LRIG proteins were most often expressed in the cytoplasm, though LRIG1 also showed prominent nuclear expression. Cytoplasmic expression of LRIG1 and LRIG2 correlated with histological subtypes of meningiomas (p = 0.038 and 0.013, respectively). Nuclear and cytoplasmic expression of LRIG1 was correlated with ER status (p = 0.003 and 0.004, respectively), as was cytoplasmic expression of LRIG2 (p = 0.006). This study is the first to examine the expression of LRIG proteins in meningiomas, and it shows a correlation between ER status and the expression of LRIG1 and LRIG2, which suggests a possible role for LRIG proteins in meningioma pathogenesis.

  • 9.
    Guo, Dongsheng
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Holmlund, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in ascidiacea2004Ingår i: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 84, nr 1, s. 157-165Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human LRIG1 (formerly LIG1), human LRIG2, and mouse Lrig1 (also known as Lig-1) encode integral membrane proteins. The human genes are located at chromosomes 3p14 and 1p13, which are regions frequently deleted in human cancers. We have searched for additional members of the LRIG family and by molecular cloning identified human LRIG3 and its mouse ortholog Lrig3. Human LRIG3 is located at chromosome 12q13. In silico analysis of public databases revealed a mouse Lrig2 mRNA, three LRIG homologs in the puffer fish Fugu rubripes, and one LRIG homolog in the ascidian tunicate Ciona intestinalis. The human and mouse LRIG polypeptides have the same predicted domain organization: a signal peptide, 15 tandem leucine-rich repeats with cysteine-rich N- and C-flanking domains, three immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tail. The extracellular part—especially the IgC2.2 domain, the transmembrane domain, and the membrane-proximal part of the cytoplasmic tail—are the most conserved regions. Northern blot analysis and real-time RT-PCR revealed that the three LRIG paralogs are widely expressed in human and mouse tissues. In conclusion, the LRIG gene family was found to have three widely expressed mammalian paralogs, corresponding orthologs in fish, and a homolog in Ascidiacea.

  • 10.
    Guo, Dongsheng
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nilsson, Jonas
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Haapasalo, Hannu
    Raheem, Olayinka
    Bergenheim, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Perinuclear leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1-3) as prognostic indicators in astrocytic tumors2006Ingår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 111, nr 3, s. 238-346Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have previously characterized three human leucine-rich repeats and immunoglobulin-like domains (LRIG) genes and proteins, named LRIG1-3 and proposed that they may act as suppressors of tumor growth. The LRIG1 transmembrane protein antagonizes the activity of epidermal growth factor receptor family receptor tyrosine kinases. In this study, we evaluated the mRNA expression level of LRIG1-3 in human glioma cell lines and control-matched glioma tissues, characterized the sub-cellular localization of an LRIG3–GFP fusion protein, and analyzed the relationship between sub-cellular localization of LRIG1-3 and clinical parameters in 404 astrocytic tumors by immunohistochemistry. LRIG1-3 mRNA was detected in all human glioma cell lines and matched glioma samples, with large differences in the expression levels. Ectopically expressed LRIG3–GFP localized to perinuclear and cytoplasmic compartments, and to the cell surface of transfected glioma cells. Perinuclear staining of LRIG1-3 was associated with low WHO grade and better survival of the patients. Perinuclear staining of LRIG3 was associated with a lower proliferation index and was in addition to tumor grade, an independent prognostic factor. Furthermore, within the groups of grade III and grade IV tumors, perinuclear staining of LRIG3 significantly correlated with better survival. These results indicate that expression and sub-cellular localization of LRIG1-3 might be of importance in the pathogenesis and prognosis of astrocytic tumors.

  • 11. Gur, Gal
    et al.
    Rubin, Chanan
    Katz, Menachem
    Amit, Ido
    Citri, Ami
    Nilsson, Jonas
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Amariglio, Ninette
    Henriksson, Roger
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Rechavi, Gideon
    Hedman, Håkan
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Wides, Ron
    Yarden, Yosef
    LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation2004Ingår i: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 23, nr 16, s. 3270-3281Artikel i tidskrift (Refereegranskat)
  • 12.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Regulation of leukocyte integrin adhesiveness1995Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
  • 13.
    Hedman, Håkan
    et al.
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    LRIG inhibitors of growth factor signalling - double-edged swords in human cancer?2007Ingår i: Eur J Cancer, ISSN 0959-8049, Vol. 43, nr 4, s. 676-682Artikel i tidskrift (Refereegranskat)
  • 14.
    Hedman, Håkan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lindström, Annika K
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Tot, Tibor
    Stendahl, Ulf
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hellberg, Dan
    LRIG2 in contrast to LRIG1 predicts poor survival in early-stage squamous cell carcinoma of the uterine cervix2010Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 49, nr 6, s. 812-815Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The human leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family comprises LRIG1, 2, and 3. LRIG1 negatively regulates growth factor signaling and is a proposed tumor suppressor. In early stage uterine cervical carcinoma, expression of LRIG1 is associated with good survival. Less is known about the function and expression of LRIG2; it has not been studied in cervical carcinoma, previously. MATERIALS AND METHODS: LRIG2 expression was studied by immunohistochemistry in 129 uterine cervical squamous cell carcinomas and 36 uterine cervical adenocarcinomas. Possible associations between LRIG2 immunoreactivity and patient survival were evaluated. RESULTS: In early-stage squamous cell carcinoma (stages IB-IIB), high expression of LRIG2 was associated with poor survival (Kaplan-Meier, log-rank, p=0.02). The 10-year survival rate for patients with high expression of LRIG2 was 60%, compared to 87% in patients with low expression (odds ratio 0.22, 95% CI 0.07-0.64). In multivariate analysis including the previously studied tumor suppressor LRIG1 and clinical stage, LRIG2 emerged as an independent prognostic factor (odds ratio 0.22, 95% CI 0.09-0.50). For patients with both high expression of LRIG2 and low expression of LRIG1, the 10-year survival rate was only 26% compared to 66% for the remaining study population. There was no correlation between LRIG2 expression and prognosis in the limited adenocarcinoma series. DISCUSSION AND CONCLUSION: LRIG2 appears to be a significant predictor of poor prognosis in early-stage squamous cell carcinoma of the uterine cervix. A combination of high LRIG2 expression and low LRIG1 expression identified women with a very poor prognosis.

  • 15.
    Hedman, Håkan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nilsson, Jonas
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Guo, Dongsheng
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Is LRIG1 a tumour suppressor gene at chromosome 3p14.3?2002Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 41, nr 4, s. 352-354Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The LRIG1 gene (formerly LIG-1), recently cloned by us, displays structural similarities to the Drosophila Kek I gene. Kek I encodes a cell surface protein, Kekkon-1, which inhibits epidermal growth factor receptor-mediated signalling. We localized the LRIG1 gene to chromosome band 3p14.3, a region known to be deleted in various human cancers. In the present study LRIG1 gene expression was examined in different tumour cell lines and corresponding normal tissues by real-time RT-PCR. In many tumour cell lines, LRIG1 expression appeared absent or was down regulated compared to corresponding normal tissues. The results are consistent with LRIG1 being a tumour suppressor gene in humans. However, further studies are justified to elucidate the explicit role of LRIG1 as a negative regulator of oncogenesis.

  • 16.
    Hellström, Martin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Ericsson, Madelene
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Johansson, Bengt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Faraz, Mahmood
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Anderson, Fredrick
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Regional Cancer Center Stockholm/Gotland, Stockholm, Sweden.
    Nilsson, Stefan K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Cardiac hypertrophy and decreased high-density lipoprotein cholesterol in Lrig3-deficient mice2016Ingår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 310, nr 11, s. R1045-R1052Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genetic factors confer risk for cardiovascular disease. Recently, large genome-wide population studies have shown associations between genomic loci close to LRIG3 and heart failure and plasma high-density lipoprotein (HDL) cholesterol level. Here, we ablated Lrig3 in mice and investigated the importance of Lrig3 for heart function and plasma lipid levels. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze Lrig3 expression in the hearts of wild-type and Lrig3-deficient mice. In addition, molecular, physiological, and functional parameters such as organ weights, heart rate, blood pressure, heart structure and function, gene expression in the heart, and plasma insulin, glucose, and lipid levels were evaluated. The Lrig3-deficient mice were smaller than the wild-type mice but otherwise appeared grossly normal. Lrig3 was expressed at detectable but relatively low levels in adult mouse hearts. At 9 mo of age, ad libitum-fed Lrig3-deficient mice had lower insulin levels than wildtype mice. At 12 mo of age, Lrig3-deficient mice exhibited increased blood pressure, and the Lrig3-deficient female mice displayed signs of cardiac hypertrophy as assessed by echocardiography, heart-to-body weight ratio, and expression of the cardiac hypertrophy marker gene Nppa. Additionally, Lrig3-deficient mice had reduced plasma HDL cholesterol and free glycerol. These findings in mice complement the human epidemiological results and suggest that Lrig3 may influence heart function and plasma lipid levels in mice and humans.

  • 17.
    Holmlund, Camilla
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Haapasalo, Hannu
    Yi, Wei
    Raheem, Olayinka
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bragge, Helena
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Cytoplasmic LRIG2 expression is associated with poor oligodendroglioma patient survival.2009Ingår i: Neuropathology (Kyoto. 1993), ISSN 0919-6544, E-ISSN 1440-1789, Vol. 29, nr 3, s. 242-247Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The three leucine-rich repeats and immunoglobulin-like domains (LRIG) genes encode integral membrane proteins. Of these, LRIG1 negatively regulates growth factor signaling and is implicated as a tumor suppressor in certain malignancies. In astrocytic tumors, the subcellular distribution of LRIG proteins is associated with specific clinicopathological features and patient survival. The role of LRIG proteins in oligodendroglioma has not previously been studied. Here we used immunohistochemistry to analyze the expression of the LRIG proteins in 63 oligodendroglial tumors, and evaluated possible associations between LRIG protein expression and clinicopathological parameters. Notably, cytoplasmic LRIG2 expression was found to be an independent prognostic factor associated with poor oligodendroglioma patient survival. This is the first report of an LRIG protein showing a negative effect on survival, suggesting that LRIG2 might have a function different from that of LRIG1, and possibly contributing to the etiology of oligodendroglioma.

  • 18.
    Holmlund, Camilla
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nilsson, Jonas
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Guo, Dongsheng
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Starefeldt, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Characterization and tissue-specific expression of human LRIG22004Ingår i: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 332, s. 35-43Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have recently identified and cloned the human LRIG1 gene (formerly LIG1). LRIG1 is a predicted integral membrane protein with a domain organization reminiscent of the Drosophila epidermal growth factor (EGF)-receptor antagonist Kekkon-1. We have searched for additional members of the human LRIG family and identified LRIG2 (KIAA0806). The LRIG2 gene was localized to chromosome 1p13 and had an open reading frame of 1065 amino acids. The LRIG2 protein was predicted to have the same domain organization as LRIG1 with a signal peptide, an extracellular part containing15 leucine-rich repeats and three immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tail. The LRIG2 amino acid sequence was 47% identical to human LRIG1 and mouse Lrig1 (also known as Lig-1). Northern blotting and RT-PCR revealed LRIG2 transcripts in all tissues analyzed. Quantitative real-time RT-PCR showed the most prominent RNA expression in skin, uterus, ovary, kidney, brain, small intestine, adrenal gland, and stomach. Immunoblotting of COS-7 cell lysates demonstrated that heterologously expressed human LRIG2 had an apparent molecular weight of 132 kDa under reducing gel-running conditions. N-glycosidase F treatment resulted in a reduction of the apparent molecular weight to 107 kDa, showing that LRIG2 was a glycoprotein carrying N-linked oligosaccharides. Cell surface biotinylation experiments and confocal fluorescence laser microscopy demonstrated expression of LRIG2 both at the cell surface and in the cytoplasm. LRIG2 was detected in tissue lysates from stomach, prostate, lung, and fetal brain by immunoblotting. In conclusion, LRIG2 was found to be a glycoprotein which was encoded by a gene on human chromosome 1p13 and its mRNA was present in all tissues analyzed.

  • 19.
    Johansson, Mikael
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    Oudin, Anaïs
    NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    Tiemann, Katja
    NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    Bernard, Amandine
    NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    Golebiewska, Anna
    NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    Keunen, Olivier
    NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    Fack, Fred
    NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    Stieber, Daniel
    NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    Wang, Baofeng
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Niclou, Simone P.
    NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    The soluble form of the tumor suppressor Lrig1 potently inhibits in vivo glioma growth irrespective of EGF receptor status2013Ingår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 15, nr 9, s. 1200-1211Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Deregulated growth factor signaling is a major driving force in the initiation and progression of glioblastoma. The tumor suppressor and stem cell marker Lrig1 is a negative regulator of the epidermal growth factor receptor (EGFR) family. Here, we addressed the therapeutic potential of the soluble form of Lrig1 (sLrig1) in glioblastoma treatment and the mechanism of sLrig1-induced growth inhibition. With use of encapsulated cells, recombinant sLrig1 was locally delivered in orthotopic glioblastoma xenografts generated from freshly isolated patient tumors. Tumor growth and mouse survival were evaluated. The efficacy of sLrig1 and the affected downstream signaling was studied in vitro and in vivo in glioma cells displaying variable expression of wild-type and/or a constitutively active EGFR mutant (EGFRvIII). Continuous interstitial delivery of sLrig1 in genetically diverse patient-derived glioma xenografts led to strong tumor growth inhibition. Glioma cell proliferation in vitro and tumor growth in vivo were potently inhibited by sLrig1, irrespective of EGFR expression levels. Of importance, tumor growth was also suppressed in EGFRvIII-driven glioma. sLrig1 induced cell cycle arrest without changing total receptor level or phosphorylation. Affected downstream effectors included MAP kinase but not AKT signaling. Of importance, local delivery of sLrig1 into established tumors led to a 32 survival advantage in treated mice. To our knowledge, this is the first report demonstrating that sLrig1 is a potent inhibitor of glioblastoma growth in clinically relevant experimental glioma models and that this effect is largely independent of EGFR status. The potent anti-tumor effect of sLrig1, in combination with cell encapsulation technology for in situ delivery, holds promise for future treatment of glioblastoma.

  • 20.
    Johansson, Mikael
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Oudin, Anaïs
    Tiemann, Katja
    Bernard, Amandine
    Keunen, Olivier
    Fack, Fred
    Golebiewska, Anna
    Stieber, Daniel
    Wang, Baofeng
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Niclou, Simone P.
    The soluble form of the tumor suppressor Lrig1 potently inhibits in vivo glioma growth irrespective of EGF receptor status2012Ingår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 14, nr Suppl. 3, s. 15-16Artikel i tidskrift (Övrigt vetenskapligt)
  • 21.
    Karlsson, Terese
    et al.
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Induction of apoptosis in resistant glioma cells by synthetic caspase-activation2004Ingår i: J Neurooncol, ISSN 0167-594X, Vol. 66, nr 1-2, s. 71-79Artikel i tidskrift (Refereegranskat)
  • 22.
    Karlsson, Terese
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Kvarnbrink, Samuel
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Botling, J
    Micke, P
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    LMO7 interacts with LRIG proteins, and is a negative prognostic marker in lung cancerManuskript (preprint) (Övrigt vetenskapligt)
  • 23.
    Karlsson, Terese
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Kvarnbrink, Samuel
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Holmlund, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Botling, Johan
    Micke, Patrick
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    LMO7 and LIMCH1 interact with LRIG proteins in lung cancer, with prognostic implications for early-stage disease2018Ingår i: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 125, s. 174-184Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: The human leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family comprises the integral membrane proteins LRIG1, LRIG2 and LRIG3. LRIG1 is frequently down-regulated in human cancer, and high levels of LRIG1 in tumor tissue are associated with favorable clinical outcomes in several tumor types including non-small cell lung cancer (NSCLC). Mechanistically, LRIG1 negatively regulates receptor tyrosine kinases and functions as a tumor suppressor. However, the details of the molecular mechanisms involved are poorly understood, and even less is known about the functions of LRIG2 and LRIG3. The aim of this study was to further elucidate the functions and molecular interactions of the LRIG proteins.

    Materials and methods: A yeast two-hybrid screen was performed using a cytosolic LRIG3 peptide as bait. In transfected human cells, co-immunoprecipitation and co-localization experiments were performed. Proximity ligation assay was performed to investigate interactions between endogenously expressed proteins. Expression levels of LMO7 and LIMCH1 in normal and malignant lung tissue were investigated using qRT-PCR and through in silico analyses of public data sets. Finally, a clinical cohort comprising 355 surgically treated NSCLC cases was immunostained for LMO7.

    Results: In the yeast two-hybrid screen, the two paralogous proteins LMO7 and LIMCH1 were identified as interaction partners to LRIG3. LMO7 and LIMCH1 co-localized and co-immunoprecipitated with both LRIG1 and LRIG3. Endogenously expressed LMO7 was in close proximity of both LRIG1 and LRIG3. LMO7 and LIMCH1 were highly expressed in normal lung tissue and down-regulated in malignant lung tissue. LMO7 immunoreactivity was shown to be a negative prognostic factor in LRIG1 positive tumors, predicting poor patient survival.

    Conclusion: These findings suggest that LMO7 and LIMCH1 physically interact with LRIG proteins and that expression of LMO7 is of clinical importance in NSCLC.

  • 24.
    Karlsson, Terese
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Kvarnbrink, Samuel
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Holmlund, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Botling, Johan
    Micke, Patrick
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Interactions between LRIG proteins and LMO7 and the expression of LMO7 in human lung cancer.2013Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, nr 8: suppl 1, s. 5315-Artikel i tidskrift (Refereegranskat)
  • 25.
    Karlsson, Terese
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Mark, Elisabeth B
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Redistribution of LRIG proteins in psoriasis2008Ingår i: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 128, nr 5, s. 1192-1195Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The human leucine-rich repeats and immunoglobulin-like domains (LRIG) family is composed of three members, LRIG1, -2, and -3, which are all expressed in human skin. LRIG1 negatively regulates growth factor signaling and is involved in the regulation of epidermal stem cell quiescence. Ablation of Lrig1 in mice results in psoriasiform epidermal hyperplasia. Hence, the LRIG proteins may be important for epidermal homeostasis and in psoriasis. Therefore, we analyzed the LRIG mRNA levels and the cellular and subcellular distribution of LRIG proteins in normal and psoriatic skin. The mRNA levels of LRIG1, -2, and -3 were not significantly different in psoriatic epidermis compared to clinically normal epidermis from the same patient. Immunohistochemistry showed that all three LRIG proteins were expressed in unique and specific patterns both in normal and psoriatic skin. Intriguingly, in psoriatic epidermis, the LRIG protein expression patterns were altered compared to normal skin. These results indicate that the LRIG proteins may have a role in epidermal homeostasis and psoriasis.

  • 26.
    Kvarnbrink, Samuel
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Karlsson, Terese
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Edlund, Karolina
    Botling, Johan
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Jirström, Karin
    Micke, Patrick
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    LRIG1 is a prognostic biomarker in non-small cell lung cancer2015Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, nr 8, s. 1113-1119Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The leucine-rich repeats and immunoglobulin-like domains (LRIG) family of transmembrane proteins are involved in the regulation of cellular signal transduction. LRIG1 is an endogenous inhibitor of receptor tyrosine kinases (RTKs) and an emerging tumor suppressor. In the lung epithelium, the expression of LRIG1 is downregulated by tobacco smoking, and further downregulated in lung squamous cell carcinoma. Material and methods: The expression of LRIG proteins were analyzed in 347 cases of non-small cell lung cancer (NSCLC) by immunohistochemistry, and LRIG1 mRNA expression was evaluated in 807 lung cancer samples in silico in the Oncomine database. Potential associations between the expression data and the clinical parameters, including patient survival, were investigated. Results: Expression of the LRIG1 protein was found to be an independent prognostic factor in NSCLC, whereas expression of LRIG2 or LRIG3 did not correlate with patient survival. The levels of LRIG1 mRNA also correlated with the survival of NSCLC patients. Conclusion: These findings demonstrate that LRIG1 is an independent prognostic factor in patients with NSCLC that could be important in future decision-making algorithms for adjuvant lung cancer treatment.

  • 27.
    Kvarnbrink, Samuel
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Karlsson, Terese
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Forssell, Joakim
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Edlund, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Holmlund, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Faraz, Mahmood
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Botling, J
    Feng, Mao
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Micke, P
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    LRIG1 is a prognostic biomarker and tumor suppressor in non-small cell lung cancerManuskript (preprint) (Övrigt vetenskapligt)
  • 28.
    Lindquist, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Alsina, Fernando C.
    Herdenberg, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Larsson, Catharina
    Höppener, Jo
    Wang, Na
    Paratcha, Gustavo
    Tarján, Miklós
    Tot, Tibor
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    LRIG1 negatively regulates RET mutants and is downregulated in thyroid cancer2018Ingår i: International journal of oncology, ISSN 1791-2423, Vol. 52, nr 4, s. 1189-1197Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) are characterized by genomic rearrangements and point mutations in the proto-oncogene RET. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a suppressor of various receptor tyrosine kinases, including RET. LRIG1 expression levels are associated with patient survival in many cancer types. In the present study, we investigated whether the oncogenic RET mutants RET2A (C634R) and RET2B (M918T) were regulated by LRIG1, and the possible effects of LRIG1 expression in thyroid cancer were investigated in three different clinical cohorts and in a RET2B-driven mouse model of MTC. LRIG1 was shown to physically interact with both RET2A and RET2B and to restrict their ligand-independent activation. LRIG1 mRNA levels were downregulated in PTC and MTC compared to normal thyroid gland tissue. There was no apparent association between LRIG1 RNA or protein expression levels and patient survival in the studied cohorts. The transgenic RET2B mice developed pre-cancerous medullary thyroid lesions at a high frequency (36%); however, no overt cancers were observed. There was no significant difference in the incidence of pre-cancerous lesions between Lrig1 wild-type and Lrig1-deficient RET2B mice. In conclusion, the findings that LRIG1 is a negative regulator of RET2A and RET2B and is also downregulated in PTC and MTC may suggest that LRIG1 functions as a thyroid tumor suppressor.

  • 29.
    Lindquist, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Hakan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Expression of the human LRIG genes and proteins as prognostic markers in human cancer2012Ingår i: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 30, nr Suppl 1, s. S42-S42Artikel i tidskrift (Övrigt vetenskapligt)
  • 30.
    Lindquist, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    LRIG1 Was Down-Regulated in Medullary Thyroid Cancer but No Significant Effect of LRIG1 Was Found in RET2B Transgenic Mice and Human Differentiated Thyroid Cancer2017Ingår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, s. 152-152Artikel i tidskrift (Övrigt vetenskapligt)
  • 31.
    Lindquist, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Kvarnbrink, Samuel
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    LRIG and cancer prognosis2014Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, nr 9, s. 1135-1142Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    BACKGROUND: Optimal treatment decisions for cancer patients require reliable prognostic and predictive information. However, this information is inadequate in many cases. Several recent studies suggest that the leucine-rich repeats and immunoglobulin-like domains (LRIG) genes, transcripts, and proteins have prognostic implications in various cancer types. MATERIAL AND METHODS: Relevant literature was identified on PubMed using the key words lrig1, lrig2, and lrig3. LRIG mRNA expression in cancer versus normal tissues was investigated using the Oncomine database. RESULTS: The three human LRIG genes, LRIG1, LRIG2, and LRIG3, encode single-pass transmembrane proteins. LRIG1 is a negative regulator of growth factor signaling that has been shown to function as a tumor suppressor in vitro and in vivo in mice. The functions of LRIG2 and LRIG3 are less well defined. LRIG gene and protein expression are commonly dysregulated in human cancer. In early stage breast cancer, LRIG1 copy number was recently shown to predict early and late relapse in addition to overall survival; in nasopharyngeal carcinoma, loss of LRIG1 is also associated with poor survival. LRIG gene and protein expression have prognostic value in breast cancer, uterine cervical cancer, head-and-neck cancer, glioma, non-small cell lung cancer, prostate cancer, and cutaneous squamous cell carcinoma. In general, expression of LRIG1 and LRIG3 is associated with good survival, whereas expression of LRIG2 is associated with poor survival. Additionally, LRIG1 regulates cellular sensitivity to anti-cancer drugs, which indicates a possible role as a predictive marker. CONCLUSIONS: LRIG gene statuses and mRNA and protein expression are clinically relevant prognostic indicators in several types of human cancer. We propose that LRIG analyses could become important when making informed and individualized clinical decisions regarding the management of cancer patients.

  • 32.
    Lindquist, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Näsman, A.
    Department of Oncology-Pathology, Karolinska Institute, SE-171 76, Stockholm, Sweden.
    Tarján, M.
    Department of Pathology and Clinical Cytology, Central Hospital Falun, SE-791 29, Falun, Sweden.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Tot, T.
    Department of Pathology and Clinical Cytology, Central Hospital Falun, SE-791 29, Falun, Sweden.
    Dalianis, T.
    Department of Oncology-Pathology, Karolinska Institute, SE-171 76, Stockholm, Sweden.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Expression of LRIG1 is associated with good prognosis and human papillomavirus status in oropharyngeal cancer2014Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 110, nr 7, s. 1793-1800Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background:The incidence of human papillomavirus (HPV)-associated oropharyngeal cancer has increased rapidly during the past decades. HPV is typically associated with a favourable outcome; however, a need exists for new and more effective prognostic and predictive markers for this disease. Leucine-rich repeats and immunoglobulin-like domains (LRIG)-1 is a tumour suppressor protein that belongs to the LRIG family. LRIG1 expression has prognostic significance in various human cancers, including cervical cancer, where HPV is a key aetiological agent.Methods:The prognostic value of LRIG1 and LRIG2 immunoreactivity was investigated in tumour specimens from a Swedish cohort of patients with tonsillar and base of tongue oropharyngeal cancers, including 278 patients.Results:LRIG1 immunoreactivity correlated with disease-free survival and overall survival in univariate and multivariate analyses. Notably, patients with HPV-positive tumours with high LRIG1 staining intensity or a high percentage of LRIG1-positive cells showed a very good prognosis. Furthermore, LRIG1 expression correlated with HPV status, whereas LRIG2 expression inversely correlated with HPV status.Conclusions:Taken together, the results suggest that LRIG1 immunoreactivity could be a clinically important prognostic marker in HPV-associated oropharyngeal cancer.

  • 33.
    Lindström, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Ekman, K
    Stendahl, Ulf
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Tot, Tibor
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hellberg, Dan
    LRIG1 and squamous epithelial uterine cervical cancer: correlation to prognosis, other tumor markers, sex steroid hormones, and smoking2008Ingår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 18, nr 2, s. 312-317Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim is to evaluate LRIG1 as a prognosis predictor and correlations to cofactors in squamous cell cervical cancer. LRIG1 expression was studied in 128 cervical carcinomas and was compared with expression of nine other tumor markers. Smoking history was registered and pretreatment serum estradiol and progesterone levels were evaluated in 79 women. At clinical stage IB, 58% of the tumors showed LRIG1 expression, but there was a decline by increasing stage (33% in stage IV). Ninety percent of women with stage IB cancer and LRIG1 positivity survived, as compared to 64% without expression (P = 0.02). LRIG1 expression did not predict prognosis in advanced stages, but in stage IIA there was a marked relative difference, with 75% survival in tumors expressing LRIG1, as compared to 43% in those without. No correlation was found between LRIG1 and the other nine tumor markers studied. A high serum progesterone and smoking correlated to absent LRIG1 expression. We conclude that LRIG1 appears to be a significant prognosis predictor in early-stage cervical cancer, independent of the other tumor markers that were studied. Diminished expression in advanced stages and the inverse correlation to serum progesterone and smoking indicates that LRIG1 is a tumor suppressor in cervix.

  • 34.
    Ljuslinder, Ingrid
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Malmer, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Co-incidental increase in gene copy number of ERBB2 and LRIG1 in breast cancer2009Ingår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 11, nr 3, s. 403-Artikel i tidskrift (Refereegranskat)
  • 35.
    Ljuslinder, Ingrid
    et al.
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Golovleva, Irina
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Palmqvist, Richard
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Öberg, Åke
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Kirurgi.
    Stenling, Roger
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Jonsson, Yvonne
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Malmer, Beatrice
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    LRIG1 expression in colorectal cancer2007Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 46, nr 8, s. 1118-1122Artikel i tidskrift (Refereegranskat)
  • 36.
    Ljuslinder, Ingrid
    et al.
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Malmer, Beatrice
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Golovleva, Irina
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Thomasson, Marcus
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Grankvist, Kjell
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi.
    Höckenström, Thomas
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Emdin, Stefan
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Kirurgi.
    Jonsson, Yvonne
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Increased copy number at 3p14 in breast cancer2005Ingår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 7, nr 5, s. R719-R727Artikel i tidskrift (Refereegranskat)
  • 37.
    Mao, Feng
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Holmlund, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Faraz, Mahmood
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wang, Wanzhong
    Bergenheim, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Kvarnbrink, Samuel
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Regionalt Cancercentrum Stockholm Gotland, Karolinska, Stockholm, Sweden.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lrig1 is a haploinsufficient tumor suppressor gene in malignant glioma2018Ingår i: Oncogenesis, E-ISSN 2157-9024, Vol. 7, artikel-id 13Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recently, a genome-wide association study showed that a single nucleotide polymorphism (SNP) —rs11706832—in intron 2 of the human LRIG1 (Leucine-rich repeats and immunoglobulin-like domains 1) gene is associated with susceptibility to glioma. However, the mechanism by which rs11706832 affects glioma risk remains unknown; additionally, it is unknown whether the expression levels of LRIG1 are a relevant determinant of gliomagenesis. Here, we investigated the role of Lrig1 in platelet-derived growth factor (PDGF)-induced experimental glioma in mice by introducing mono-allelic and bi-allelic deletions of Lrig1 followed by inducing gliomagenesis via intracranial retroviral transduction of PDGFB in neural progenitor cells. Lrig1 was expressed in PDGFB-induced gliomas in wild-type mice as assessed using in situ hybridization. Intriguingly, Lrig1-heterozygous mice developed higher grade gliomas than did wild-type mice (grade IV vs. grade II/III, p = 0.002). Reciprocally, the ectopic expression of LRIG1 in the TB107 high-grade human glioma (glioblastoma, grade IV) cell line decreased the invasion of orthotopic tumors in immunocompromised mice in vivo and reduced cell migration in vitro. Concomitantly, the activity of the receptor tyrosine kinase MET was downregulated, which partially explained the reduction in cell migration. In summary, Lrig1 is a haploinsufficient suppressor of PDGFB-driven glioma, possibly in part via negative regulation of MET-driven cell migration and invasion. Thus, for the first time, changes in physiological Lrig1 expression have been linked to gliomagenesis, whereby the SNP rs11706832 may affect glioma risk by regulating LRIG1 expression.

  • 38. Muller, Susanne
    et al.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Kanter, Lena
    Flores-Staino, Carmen
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Andersson, Sonia
    Expression of LRIG1 and LRIG3 correlates with human papillomavirus status and patient survival in cervical adenocarcinoma2013Ingår i: International Journal of Oncology, ISSN 1019-6439, Vol. 42, nr 1, s. 247-252Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The incidence of cervical adenocarcinoma, which accounts for 10-20% of all cervical cancers, has increased continuously in developed countries during the last two decades, unlike squamous cell cervical carcinoma. This increasing trend, noted particularly among women under the age of 40 years, has occurred despite extensive cytological Pap smear screening. A deeper understanding of the etiology of cervical adenocarcinoma, better preventive measures and reliable prognostic markers are urgently needed. The human leucine-rich repeats and immunoglobulin-like domains (LRIG) gene family includes: LRIG1, LRIG2 and LRIG3. LRIG expression has proven to be of prognostic value in different types of human cancers, including breast cancer, early stage invasive squamous cervical cancer, cutaneous squamous cell carcinoma, oligodendroglioma and astrocytoma. LRIG1 functions as a tumor suppressor, while less is known about the functions of LRIG2 and LRIG3. This study evaluated the expression of the three LRIG proteins in tumor specimens from 86 women with pure cervical adenocarcinoma by immunohistochemistry. Possible correlations between LRIG expression and known prognostic factors, including human papillomavirus (HPV) status, FIGO stage and histology were investigated. Patient survival data were collected retrospectively and the possible prognostic value of LRIG protein expression was investigated. High staining intensity of LRIG1 and high fraction of LRIG3-positive cells were significantly associated with patient survival, and positive correlations were found between LRIG1 and LRIG3 staining intensity and HPV status. Thus, the LRIG proteins may be important determinants of cervical adenocarcinoma progression and their diagnostic and prognostic potential should be studied further.

  • 39. Neirinckx, Virginie
    et al.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Niclou, Simone P.
    Harnessing LRIG1-mediated inhibition of receptor tyrosine kinases for cancer therapy2017Ingår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1868, nr 1, s. 109-116Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Leucine-rich repeats and immunoglobulin-like domains containing protein 1 (LRIG1) is an endogenous feedback regulator of receptor tyrosine kinases (RTKs) and was recently shown to inhibit growth of different types of malignancies. Additionally, this multifaceted RTK inhibitor was reported to be a tumor suppressor, a stem cell regulator, and a modulator of different cellular phenotypes. This mini-review provides a concise and up-to-date summary about the known functions of LRIG1 and its related family members, with a special emphasis on underlying molecular mechanisms and the opportunities for harnessing its therapeutic potential against cancer. 

  • 40. Niclou, S. P.
    et al.
    Johansson, M.
    Tiemann, K.
    Oudin, A.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Local delivery of the soluble form of the tumor suppressor and stem cell regulator LRIG1 potently inhibits in vivo growth of glioblastomas with either wildtype or mutant EGFR expression2013Ingår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, nr Supplement 2, s. S777-S777, Meeting Abstract: 3307Artikel i tidskrift (Övrigt vetenskapligt)
  • 41.
    Nilsson, Jonas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Starefeldt, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    LRIG1 protein in human cells and tissues2003Ingår i: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 312, nr 1, s. 65-71Artikel i tidskrift (Refereegranskat)
  • 42.
    Nilsson, Jonas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Vallbo, Christina
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Guo, Dongsheng
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Hallberg, Bengt
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Cloning, characterization and expression of human LIG12001Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 284, nr 5, s. 1155-1161Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Growth factor receptors are frequently amplified and over-expressed in various human cancers. Recently, a Drosophila cell surface protein, Kekkon-1, was found to participate in an epidermal growth factor (EGF) driven negative feedback loop. Kekkon-1 is induced by EGF, binds to the EGF-receptor, and inhibits receptor-mediated signaling. Here, we have searched for human genes with homologies to Kekkon-1 and identified human LIG1. The gene is the human homologue of mouse Lig-1 and is located on chromosome band 3p14, a region frequently deleted in various human cancers. It is predicted to encode a transmembrane cell-surface protein with extracellular leucine-rich repeats and immunoglobulin-like domains. LIG1 mRNA was detected in all tissues analyzed. The highest and lowest relative expression levels were found in brain and spleen, respectively, and differed by more than 200-fold. Taken together, our data are compatible with a role for LIG1 as a growth and tumor suppressor in human tissues.

  • 43. Ranhem, Cecilia
    et al.
    Larsson, Gabriella Lillsunde
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Karlsson, Mats G.
    Hellstrom, Ann-Cathrin
    Ostensson, Ellinor
    Sorbe, Bengt
    Hellman, Kristina
    Andersson, Sonia
    Expression of LRIG proteins as possible prognostic factors in primary vaginal carcinoma2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 8, artikel-id e0183816Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Primary vaginal carcinoma (PVC) is a rare malignancy. Established prognostic factors include tumour stage and age at diagnosis. The leucine-rich repeats and immunoglobuline-like domains (LRIG)-1 protein functions as a tumour suppressor, but less is known about the functions of LRIG2 and LRIG3. The present study aimed to evaluate the expression of LRIG proteins and analyse their possible associations with clinical characteristics and survival in a cohort of PVC patients.

    Methods: We used immunohistochemistry to investigate LRIG1, LRIG2, and LRIG3 expression in tumour samples from a consecutive cohort of 70 PVC patients. The association between LRIG protein expression and clinical characteristics and cancer-specific survival was investigated using univariate and multivariate analyses.

    Results: The majority of PVC patients (72%) had >50% LRIG1- and LRIG2-positive cells, and no or low LRIG3-positive cells. HPV status was significantly correlated with LRIG1 expression (p = 0.0047). Having high LRIG1 expression was significantly correlated with superior cancer-specific survival in univariate and multivariate analyses. LRIG2 and LRIG3 expression did not significantly correlate with clinical characteristics or survival.

    Conclusion: LRIG1 expression might be of interest as a prognostic marker in PVC patients, whereas the role of LRIG2 and LRIG3 expression remains to be clarified.

  • 44. Roberts, Neil A.
    et al.
    Hilton, Emma N.
    Lopes, Filipa M.
    Singh, Subir
    Randles, Michael J.
    Gardiner, Natalie J.
    Chopra, Karl
    Coletta, Riccardo
    Bajwa, Zunera
    Ha, Robert J.
    Yue, Wyatt W.
    Schaefer, Franz
    Weber, Stefanie
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Stuart, Helen M.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Newman, William G.
    Woolf, Adrian S.
    Lrig2 and Hpse2, mutated in urofacial syndrome, pattern nerves in the urinary bladder2019Ingår i: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 95, nr 5, s. 1138-1152Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mutations in leucine-rich-repeats and immunoglobulin-likedomains 2 (LRIG2) or in heparanase 2 (HPSE2) cause urofacial syndrome, a devastating autosomal recessive disease of functional bladder outlet obstruction. It has been speculated that urofacial syndrome has a neural basis, but it is unknown whether defects in urinary bladder innervation are present. We hypothesized that urofacial syndrome features a peripheral neuropathy of the bladder. Mice with homozygous targeted Lrig2 mutations had urinary defects resembling those found in urofacial syndrome. There was no anatomical blockage of the outflow tract, consistent with a functional bladder outlet obstruction. Transcriptome analysis revealed differential expression of 12 known transcripts in addition to Lrig2, including 8 with established roles in neurobiology. Mice with homozygous mutations in either Lrig2 or Hpse2 had increased nerve density within the body of the urinary bladder and decreased nerve density around the urinary outflow tract. In a sample of 155 children with chronic kidney disease and urinary symptoms, we discovered novel homozygous missense LRIG2 variants that were predicted to be pathogenic in 2 individuals with non-syndromic bladder outlet obstruction. These observations provide evidence that a peripheral neuropathy is central to the pathobiology of functional bladder outlet obstruction in urofacial syndrome, and emphasize the importance of LRIG2 and heparanase 2 for nerve patterning in the urinary tract.

  • 45.
    Rondahl, Veronica
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Holmlund, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Karlsson, Terese
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wang, Baofeng
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Faraz, Mahmood
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Regionalt Cancercentrum Stockholm, Karolinska Universitetssjukhuset Solna, Stockholm, Sweden.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lrig2-deficient mice are protected against PDGFB-induced glioma2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 9, s. e73635-Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Background: The leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins constitute an integral membrane protein family that has three members: LRIG1, LRIG2, and LRIG3. LRIG1 negatively regulates growth factor signaling, but little is known regarding the functions of LRIG2 and LRIG3. In oligodendroglial brain tumors, high expression of LRIG2 correlates with poor patient survival. Lrig1 and Lrig3 knockout mice are viable, but there have been no reports on Lrig2-deficient mice to date. Methodology/Principal Findings: Lrig2-deficient mice were generated by the ablation of Lrig2 exon 12 (Lrig2E12). The Lrig2E12-/- mice showed a transiently reduced growth rate and an increased spontaneous mortality rate; 20-25% of these mice died before 130 days of age, with the majority of the deaths occurring before 50 days. Ntv-a transgenic mice with different Lrig2 genotypes were transduced by intracranial injection with platelet-derived growth factor (PDGF) B-encoding replication-competent avian retrovirus (RCAS)-producing DF-1 cells. All injected Lrig2E12+/+ mice developed Lrig2 expressing oligodendroglial brain tumors of lower grade (82%) or glioblastoma-like tumors of higher grade (18%). Lrig2E12-/- mice, in contrast, only developed lower grade tumors (77%) or had no detectable tumors (23%). Lrig2E12-/- mouse embryonic fibroblasts (MEF) showed altered induction-kinetics of immediate-early genes Fos and Egr2 in response to PDGF-BB stimulation. However, Lrig2E12-/- MEFs showed no changes in Pdgfr alpha or Pdgfr beta levels or in levels of PDGF-BB-induced phosphorylation of Pdgfr alpha, Pdgfr beta, Akt, or extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). Overexpression of LRIG1, but not of LRIG2, downregulated PDGFR alpha levels in HEK-293T cells. Conclusions: The phenotype of Lrig2E12-/- mice showed that Lrig2 was a promoter of PDGFB-induced glioma, and Lrig2 appeared to have important molecular and developmental functions that were distinct from those of Lrig1 and Lrig3.

  • 46.
    Sjödin, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Guo, Dongsheng
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hofer, Per-Åke
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Mammaglobin in normal human sweat glands and human sweat gland tumors2003Ingår i: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 121, nr 2, s. 428-429Artikel i tidskrift (Övrigt vetenskapligt)
  • 47.
    Sjödin, Anna
    et al.
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Guo, Dongsheng
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Lund-Johansen, Morten
    Krossnes, Bård Kronen
    Lilleng, Peer
    Henriksson, Roger
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Secretoglobins in the human pituitary: high expression of lipophilin B and its down-regulation in pituitary adenomas2005Ingår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 109, nr 4, s. 381-386Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Secretoglobins are small secreted proteins, the expression of which has mostly been associated with secretory mucosal epithelia. Several secretoglobins have been implicated in the development of various human cancers. Allelic deletions of chromosome 11q13 correlates with the invasiveness of pituitary tumors. Intriguingly, several secretoglobin genes are located on 11q13; however, for most of these genes the expression in the pituitary and pituitary tumors have not been investigated. Antibodies specific for the secretoglobin lipophilin B (SCGB1D2, BU101) were developed and used in an immunohistochemical analysis of a human normal tissue microarray. Prominent lipophilin B immunoreactivity was found in the secretory cells of the anterior pituitary. Eight of nine analyzed pituitary adenomas showed a reduction in lipophilin B immunoreactivity compared to normal pituitary. However, there was no apparent association between lipophilin B immunoreactivity and hormone production or tumor invasiveness. Expression of eight different secretoglobin mRNAs were analyzed in normal pituitary and the pituitary adenoma cell line HP75 by highly specific quantitative real-time reverse transcription-PCR assays. Lipophilins B and C (SCGB2A1, mammaglobin B) were the most prominently expressed secretoglobin mRNAs in the pituitary. No secretoglobin mRNA was detected in the HP75 cells. The present report demonstrates, for the first time, lipophilin B expression in the pituitary and its apparent down-regulation in pituitary adenomas.

  • 48.
    Sjödin, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Guo, Dongsheng
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Sørhaug, Sveinung
    Bjermer, Leif
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Dysregulated secretoglobin expression in human lung cancers2003Ingår i: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 41, nr 1, s. 49-56Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lipophilins A, B, C, mammaglobin, and uteroglobin are members of the secretoglobin family of small, secreted, proteins. The functions of these proteins are not well understood but uteroglobin has been implicated in the development of cancers. Uteroglobin is known to be highly expressed in normal lung and down-regulated in lung cancers but expression of the other secretoglobins in normal lung and lung neoplasms have not been investigated. Therefore, we developed quantitative real-time reverse transcription (RT-) PCR assays for the different secretoglobins and evaluated their expression in normal and neoplastic lung tissues. The secretoglobin transcript levels were quantitated by real-time RT-PCR in samples from three normal lungs, 24 lung tumors including six small cell lung carcinomas, seven adenocarcinomas, and five squamous cell carcinomas, and in cell lines from three small cell lung carcinomas and one mesothelioma. Uteroglobin was confirmed to be abundantly expressed in normal lung and the different lung tumors showed down-regulated uteroglobin expression. Of the other secretoglobins, only lipophilin C was detected in normal lung, albeit at low levels. The lung tumors, however, frequently showed neo- or up-regulation of lipophilins A, B, C, and mammaglobin. The results constitute the first quantitative evaluation of secretoglobin expression in normal and neoplastic human lung tissues and demonstrate dysregulation in various human lung cancers. These findings could have important biological and diagnostic implications.

  • 49.
    Sjödin, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Ljuslinder, Ingrid
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Mammaglobin and lipophilin B expression in breast tumors and their lack of effect on breast cancer cell proliferation.2008Ingår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 28, nr 3A, s. 1493-1498Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mammaglobin (SCGB2A2) and lipophilin B (SCGB1D2) are members of the secretoglobin polypeptide family. Mammaglobin has been shown to be overexpressed in breast tumor tissue, indicating that mammaglobin might confer a growth advantage to mammaglobin-expressing tumor cells. Materials and Methods: The mammaglobin and lipophilin B mRNA expression levels were investigated in seven breast tumors and matched non-neoplastic tissues from the same patients using quantitative real-time RT-PCR. The effect of mammaglobin and lipophilin B expression on breast cancer cell proliferation rates was investigated by analyzing retrovirally transduced Hs578T cell clones. Cell proliferation rates were determined during the exponential growth phase by analyzing the change in lactate dehydrogenase activity over time. Results: All analyzed breast cancer tumors had lower expression levels of mammaglobin and lipophilin B than the respective mean level of the non-neoplastic breast tissues; no prominent overexpression was evident. There was high variability in the expression of mammaglobin and lipophilin B among the non-neoplastic samples, showing that caution should be taken when evaluating their over- and underexpression in tumors. The expression levels of mammaglobin and lipophilin B correlated with each other in the analyzed samples (p=0.001). Ectopic overexpression of mammaglobin and lipophilin B did not affect the cell proliferation rate of Hs578T breast carcinoma cells in vitro. Conclusion: Our findings suggest that the overexpression of mammaglobin observed in certain breast tumors is an epiphenomenon not causally involved in breast carcinogenesis.

  • 50.
    Stefansson, Kristina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Oda, Husam
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Öfverman, Charlotte
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    LRIG protein expression and HPV prevalence in vulvar cancer patients in northern Sweden2015Ingår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 25, nr 9, s. 684-684Artikel i tidskrift (Övrigt vetenskapligt)
12 1 - 50 av 62
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