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Herdenberg, Carl
Publications (3 of 3) Show all publications
Franklin, O., Billing, O., Öhlund, D., Berglund, A., Herdenberg, C., Wang, W., . . . Sund, M. (2019). Novel prognostic markers within the CD44-stromal ligand network in pancreatic cancer. Journal of Pathology, 5(2), 130-141
Open this publication in new window or tab >>Novel prognostic markers within the CD44-stromal ligand network in pancreatic cancer
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2019 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 5, no 2, p. 130-141Article in journal (Refereed) Published
Abstract [en]

The dense stroma in pancreatic cancer tumours is rich in secreted extracellular matrix proteins and proteoglycans. Secreted hyaluronan, osteopontin and type IV collagen sustain oncogenic signalling by interactions with CD44s and its variant isoform CD44v6 on cancer cell membranes. Although well established in animal and in vitro models, this oncogenic CD44-stromal ligand network is less explored in human cancer. Here, we use a pancreatic cancer tissue microarray from 69 primary tumours and 37 metastatic lymph nodes and demonstrate that high tumour cell expression of CD44s and, surprisingly, low stromal deposition of osteopontin correlate with poor survival independent of established prognostic factors for pancreatic cancer. High stromal expression of hyaluronan was a universal trait of both primary tumours and metastatic lymph nodes. However, hyaluronan species of different molecular mass are known to function differently in pancreatic cancer biology and immunohistochemistry cannot distinguish between them. Using gas-phase electrophoretic molecular mobility analysis, we uncover a shift towards high molecular mass hyaluronan in pancreatic cancer tissue compared to normal pancreas and at a transcriptional level, we find that hyaluronan synthesising HAS2 correlates positively with CD44. The resulting prediction that high molecular mass hyaluronan would then correlate with poor survival in pancreatic cancer was confirmed in serum samples, where we demonstrate that hyaluronan >27 kDa measured before surgery is an independent predictor of postoperative survival. Our findings confirm the prognostic value of CD44 tissue expression and highlight osteopontin tissue expression and serum high molecular mass hyaluronan as novel prognostic markers in pancreatic cancer.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
CD44, biomarkers, hyaluronan, osteopontin, pancreatic cancer, type IV collagen
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-154564 (URN)10.1002/cjp2.122 (DOI)000465218700006 ()30456933 (PubMedID)2-s2.0-85064472279 (Scopus ID)
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-05-20Bibliographically approved
Faraz, M., Herdenberg, C., Holmlund, C., Henriksson, R. & Hedman, H. (2018). A protein interaction network centered on leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) regulates growth factor receptors. Journal of Biological Chemistry, 293(9), 3421-3435
Open this publication in new window or tab >>A protein interaction network centered on leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) regulates growth factor receptors
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2018 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, no 9, p. 3421-3435Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
The American Society for Biochemistry and Molecular Biology, 2018
Keywords
LRIG1, PDGFRA, PON2, PTPRK, ZBTB16, platelet-derived growth factor-C (PDGF-C), protein expression, protein-protein interaction, receptor tyrosine kinase, yeast two-hybrid
National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-147386 (URN)10.1074/jbc.M117.807487 (DOI)000426562800032 ()29317492 (PubMedID)
Available from: 2018-05-02 Created: 2018-05-02 Last updated: 2018-06-09Bibliographically approved
Lindquist, D., Alsina, F. C., Herdenberg, C., Larsson, C., Höppener, J., Wang, N., . . . Hedman, H. (2018). LRIG1 negatively regulates RET mutants and is downregulated in thyroid cancer. International journal of oncology, 52(4), 1189-1197
Open this publication in new window or tab >>LRIG1 negatively regulates RET mutants and is downregulated in thyroid cancer
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2018 (English)In: International journal of oncology, ISSN 1791-2423, Vol. 52, no 4, p. 1189-1197Article in journal (Refereed) Published
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.

Keywords
thyroid cancer, LRIG1, RET, C634R, M918T, MEN2A, MEN2B
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-145641 (URN)10.3892/ijo.2018.4273 (DOI)000427164400013 ()29436694 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)
Available from: 2018-03-12 Created: 2018-03-12 Last updated: 2018-06-09Bibliographically approved
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