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Mallikarjuna, P., Tumkur Sitaram, R., Aripaka, K., Ljungberg, B. & Landström, M. (2019). Interactions between TGF-β type I receptor and hypoxia-inducible factor-alpha mediates a synergistic crosstalk leading to poor prognosis for patients with clear cell renal cell carcinoma. Cell Cycle, 18(17), 2141-2156
Open this publication in new window or tab >>Interactions between TGF-β type I receptor and hypoxia-inducible factor-alpha mediates a synergistic crosstalk leading to poor prognosis for patients with clear cell renal cell carcinoma
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2019 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 18, no 17, p. 2141-2156Article in journal (Refereed) Published
Abstract [en]

To investigate the significance of expression of HIF-1 alpha, HIF-2 alpha, and SNAIL1 proteins; and TGF-beta signaling pathway proteins in ccRCC, their relation with clinicopathological parameters and patient's survival were examined. We also investigated potential crosstalk between HIF-alpha and TGF-beta signaling pathway, including the TGF-beta type 1 receptor (ALK5-FL) and the intracellular domain of ALK5 (ALK5-ICD). Tissue samples from 154 ccRCC patients and comparable adjacent kidney cortex samples from 38 patients were analyzed for HIF-1 alpha/2 alpha, TGF-beta signaling components, and SNAIL1 proteins by immunoblot. Protein expression of HIF-1 alpha and HIF-2 alpha were significantly higher, while SNAIL1 had similar expression levels in ccRCC compared with the kidney cortex. HIF-2 alpha associated with poor cancer-specific survival, while HIF-1 alpha and SNAIL1 did not associate with survival. Moreover, HIF-2 alpha positively correlated with ALK5-ICD, pSMAD2/3, and PAI-1; HIF-1 alpha positively correlated with pSMAD2/3; SNAIL1 positively correlated with ALK5-FL, ALK5-ICD, pSMAD2/3, PAI-1, and HIF-2 alpha. Intriguingly, in vitro experiments performed under normoxic conditions revealed that ALK5 interacts with HIF-1 alpha and HIF-2 alpha, and promotes their expression and the expression of their target genes GLUT1 and CA9, in a VHL dependent manner. We found that ALK5 induces expression of HIF-1 alpha and HIF-2 alpha, through its kinase activity. Under hypoxic conditions, HIF-alpha proteins correlated with the activated TGF-beta signaling pathway. In conclusion, we reveal that ALK5 plays a pivotal role in synergistic crosstalk between TGF-beta signaling and hypoxia pathway, and that the interaction between ALK5 and HIF-alpha contributes to tumor progression.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
ALK5, clear cell renal cell carcinoma, HIF-α, SNAIL1, transforming growth factor-β
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-162654 (URN)10.1080/15384101.2019.1642069 (DOI)000478075700011 ()31339433 (PubMedID)
Available from: 2019-09-05 Created: 2019-09-05 Last updated: 2019-09-05Bibliographically approved
Zang, G., Mu, Y., Gao, L., Bergh, A. & Landström, M. (2019). PKC sigma facilitates lymphatic metastatic spread of prostate cancer cells in a mice xenograft model. Oncogene, 38(22), 4215-4231
Open this publication in new window or tab >>PKC sigma facilitates lymphatic metastatic spread of prostate cancer cells in a mice xenograft model
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2019 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 38, no 22, p. 4215-4231Article in journal (Refereed) Published
Abstract [en]

Prostate cancer disseminates primarily into the adjacent lymph nodes, which is related to a poor outcome. Atypical protein kinase C ζ (PKCζ) is highly expressed in aggressive prostate cancer and correlates with Gleason score, clinical stage, and poor prognosis. Here, we report the molecular mechanisms of PKCζ in lymphatic metastasis during prostate cancer progression. Using zinc-finger nuclease technology or PKCζ shRNA lentiviral particles, and orthotopic mouse xenografts, we show that PKCζ-knockout or knockdown from aggressive prostate cancer (PC3 and PC3U) cells, decreasesd tumor growth and lymphatic metastasis in vivo. Intriguingly, PKCζ-knockout or knockdown impaired the activation of AKT, ERK, and NF-κB signaling in prostate cancer cells, thereby impairing the expression of lymphangiogenic factors and macrophage recruitment, resulting in aberrant lymphangiogenesis. Moreover, PKCζ regulated the expression of hyaluronan synthase enzymes, which is important for hyaluronan-mediated lymphatic drainage and tumor dissemination. Thus, PKCζ plays a crucial oncogenic role in the lymphatic metastasis of prostate cancer and is predicted to be a novel therapeutic target for prostate cancer.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-160292 (URN)10.1038/s41388-019-0722-9 (DOI)000469339100002 ()30705401 (PubMedID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Research CouncilSwedish Cancer Society, CAN 2017/544Swedish Cancer Society, 2016/387Knut and Alice Wallenberg Foundation, 2012.0090
Available from: 2019-06-17 Created: 2019-06-17 Last updated: 2019-06-17Bibliographically approved
Aripaka, K., Gudey, S. K., Zang, G., Schmidt, A., Åhrling, S. S., Österman, L., . . . Landström, M. (2019). TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer. EBioMedicine, 45, 192-207
Open this publication in new window or tab >>TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 45, p. 192-207Article in journal (Refereed) Published
Abstract [en]

Background: Tumour necrosis factor receptor associated factor 6 (TRAF6) promotes inflammation in response to various cytokines. Aberrant Wnt3a signals promotes cancer progression through accumulation of β-Catenin. Here we investigated a potential role for TRAF6 in Wnt signaling.

Methods: TRAF6 expression was silenced by siRNA in human prostate cancer (PC3U) and human colorectal SW480 cells and by CRISPR/Cas9 in zebrafish. Several biochemical methods and analyses of mutant phenotype in zebrafish were used to analyse the function of TRAF6 in Wnt signaling.

Findings: Wnt3a-treatment promoted binding of TRAF6 to the Wnt co-receptors LRP5/LRP6 in PC3U and LNCaP cells in vitro. TRAF6 positively regulated mRNA expression of β-Catenin and subsequent activation of Wnt target genes in PC3U cells. Wnt3a-induced invasion of PC3U and SW480 cells were significantly reduced when TRAF6 was silenced by siRNA. Database analysis revealed a correlation between TRAF6 mRNA and Wnt target genes in patients with prostate cancer, and high expression of LRP5, TRAF6 and c-Myc correlated with poor prognosis. By using CRISPR/Cas9 to silence TRAF6 in zebrafish, we confirm TRAF6 as a key molecule in Wnt3a signaling for expression of Wnt target genes.

Interpretation: We identify TRAF6 as an important component in Wnt3a signaling to promote activation of Wnt target genes, a finding important for understanding mechanisms driving prostate cancer progression.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
beta-Catenin, LRP5, Prostate cancer, TRAF6, Wnt3a, Zebrafish
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-161915 (URN)10.1016/j.ebiom.2019.06.046 (DOI)000475860000026 ()31262711 (PubMedID)2-s2.0-85067957867 (Scopus ID)
Available from: 2019-08-06 Created: 2019-08-06 Last updated: 2019-08-06Bibliographically approved
Mallikarjuna, P., Tumkur Sitaram, R., Landström, M. & Ljungberg, B. (2018). VHL status regulates transforming growth factor-β signaling pathways in renal cell carcinoma. OncoTarget, 9(23), 16297-16310
Open this publication in new window or tab >>VHL status regulates transforming growth factor-β signaling pathways in renal cell carcinoma
2018 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, no 23, p. 16297-16310Article in journal (Refereed) Published
Abstract [en]

To evaluate the role of pVHL in the regulation of TGF-β signaling pathways in clear cell renal cell carcinoma (ccRCC) as well as in non-ccRCC; the expression of pVHL, and the TGF-β pathway components and their association with clinicopathological parameters and patient’s survival were explored. Tissue samples from 143 ccRCC and 58 non-ccRCC patients were examined by immunoblot. ccRCC cell lines were utilized for mechanistic in-vitro studies. Expression levels of pVHL were significantly lower in ccRCC compared with non-ccRCC. Non-ccRCC and ccRCC pVHL-High expressed similar levels of pVHL. Expression of the TGF-β type I receptor (ALK5) and intra-cellular domain were significantly higher in ccRCC compared with non-ccRCC. In non-ccRCC, expressions of ALK5-FL, ALK5-ICD, pSMAD2/3, and PAI-1 had no association with clinicopathological parameters and survival. In ccRCC pVHL-Low, ALK5-FL, ALK5-ICD, pSMAD2/3, and PAI-1 were significantly related with tumor stage, size, and survival. In ccRCC pVHL-High, the expression of PAI-1 was associated with stage and survival. In-vitro studies revealed that pVHL interacted with ALK5 to downregulate its expression through K48-linked poly-ubiquitination and proteasomal degradation, thus negatively controlling TGF-β induced cancer cell invasiveness. The pVHL status controls the ALK5 and can thereby regulate the TGF-β pathway, aggressiveness of tumors, and survival of the ccRCC and non-ccRCC patients.

Place, publisher, year, edition, pages
Impact Journals, LLC, 2018
Keywords
ccRCC, non-ccRCC, ALK5, pVHL, TGF-β signaling
National Category
Cancer and Oncology Cell and Molecular Biology
Research subject
Molecular Cellbiology; Cancer Epidemiology
Identifiers
urn:nbn:se:umu:diva-146504 (URN)10.18632/oncotarget.24631 (DOI)2-s2.0-85044474424 (Scopus ID)
Available from: 2018-04-11 Created: 2018-04-11 Last updated: 2018-06-09Bibliographically approved
Holst, M. R., Vidal-Quadras, M., Larsson, E., Song, J., Hubert, M., Blomberg, J., . . . Lundmark, R. (2017). Clathrin-Independent Endocytosis Suppresses Cancer Cell Blebbing and Invasion. Cell reports, 20(8), 1893-1905
Open this publication in new window or tab >>Clathrin-Independent Endocytosis Suppresses Cancer Cell Blebbing and Invasion
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2017 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 20, no 8, p. 1893-1905Article in journal (Refereed) Published
Abstract [en]

Cellular blebbing, caused by local alterations in cellsurface tension, has been shown to increase the invasiveness of cancer cells. However, the regulatory mechanisms balancing cell-surface dynamics and bleb formation remain elusive. Here, we show that an acute reduction in cell volume activates clathrinindependent endocytosis. Hence, a decrease in surface tension is buffered by the internalization of the plasma membrane (PM) lipid bilayer. Membrane invagination and endocytosis are driven by the tension- mediated recruitment of the membrane sculpting and GTPase-activating protein GRAF1 (GTPase regulator associated with focal adhesion kinase-1) to the PM. Disruption of this regulation by depleting cells of GRAF1 or mutating key phosphatidylinositol- interacting amino acids in the protein results in increased cellular blebbing and promotes the 3D motility of cancer cells. Our data support a role for clathrin-independent endocytic machinery in balancing membrane tension, which clarifies the previously reported role of GRAF1 as a tumor suppressor.

Place, publisher, year, edition, pages
Cell Press, 2017
Keywords
Endocytosis, clathrin-independent endocytosis, membrane blebbing, membrane tension, GRAF1, cancer invasion, cell migration, ARHGAP26, cell surface dynamics, GRAF1-dependent endocytosis
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-139144 (URN)10.1016/j.celrep.2017.08.006 (DOI)000408154300014 ()28834752 (PubMedID)
Available from: 2017-09-15 Created: 2017-09-15 Last updated: 2019-05-10Bibliographically approved
Bugaytsova, J. A., Björnham, O., Chernov, Y. A., Gideonsson, P., Henriksson, S., Mendez, M., . . . Boren, T. (2017). Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence. Cell Host and Microbe, 21(3), 376-389
Open this publication in new window or tab >>Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence
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2017 (English)In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 21, no 3, p. 376-389Article in journal (Refereed) Published
Abstract [en]

The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.

Place, publisher, year, edition, pages
CELL PRESS, 2017
National Category
Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-132788 (URN)10.1016/j.chom.2017.02.013 (DOI)000396375600023 ()28279347 (PubMedID)
Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2019-05-24Bibliographically approved
Gudey, S. K., Sundar, R., Heldin, C.-H., Bergh, A. & Landström, M. (2017). Pro-invasive properties of Snail1 are regulated by sumoylation in response to TGFβ stimulation in cancer. OncoTarget, 8(58), 97703-97726
Open this publication in new window or tab >>Pro-invasive properties of Snail1 are regulated by sumoylation in response to TGFβ stimulation in cancer
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 58, p. 97703-97726Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor beta (TGF beta) is a key regulator of epithelial-tomesenchymal transition (EMT) during embryogenesis and in tumors. The effect of TGF beta, on EMT, is conveyed by induction of the pro-invasive transcription factor Snail1. In this study, we report that TGF beta stimulates Snail1 sumoylation in aggressive prostate, breast and lung cancer cells. Sumoylation of Snail1 lysine residue 234 confers its transcriptional activity, inducing the expression of classical EMT genes, as well as TGF beta receptor I (T beta RI) and the transcriptional repressor Hes1. Mutation of Snail1 lysine residue 234 to arginine (K234R) abolished sumoylation of Snail1, as well as its migratory and invasive properties in human prostate cancer cells. An increased immunohistochemical expression of Snail1, Sumo1, T beta RI, Hes1, and c-Jun was observed in aggressive prostate cancer tissues, consistent with their functional roles in tumorigenesis.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keywords
signal transduction, tumor biology, Snail1, sumoylation, prostate cancer
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-144979 (URN)10.18632/oncotarget.20097 (DOI)000419392300002 ()29228645 (PubMedID)
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2019-05-09Bibliographically approved
Song, J. & Landström, M. (2017). TGFβ activates PI3K-AKT signaling via TRAF6. OncoTarget, 8(59), 99205-99206
Open this publication in new window or tab >>TGFβ activates PI3K-AKT signaling via TRAF6
2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 59, p. 99205-99206Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keywords
AKT, PI3K, p85, TGF beta, TRAF6
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-144978 (URN)10.18632/oncotarget.22275 (DOI)000419561600002 ()29245887 (PubMedID)
Available from: 2018-02-21 Created: 2018-02-21 Last updated: 2018-06-09Bibliographically approved
Hamidi, A., Song, J., Thakur, N., Itoh, S., Marcusson, A., Bergh, A., . . . Landström, M. (2017). TGF-β promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85α. Science Signaling, 10(486), Article ID eaal4186.
Open this publication in new window or tab >>TGF-β promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85α
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2017 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 10, no 486, article id eaal4186Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor–β (TGF-β) is a pluripotent cytokine that regulates cell fate and plasticity in normal tissues and tumors. The multifunctional cellular responses evoked by TGF-β are mediated by the canonical SMAD pathway and by noncanonical pathways, including mitogen-activated protein kinase (MAPK) pathways and the phosphatidylinositol 3′-kinase (PI3K)–protein kinase B (AKT) pathway. We found that TGF-β activated PI3K in a manner dependent on the activity of the E3 ubiquitin ligase tumor necrosis factor receptor–associated factor 6 (TRAF6). TRAF6 polyubiquitylated the PI3K regulatory subunit p85α and promoted the formation of a complex between the TGF-β type I receptor (TβRI) and p85α, which led to the activation of PI3K and AKT. Lys63-linked polyubiquitylation of p85α on Lys513 and Lys519 in the iSH2 (inter–Src homology 2) domain was required for TGF-β–induced activation of PI3K-AKT signaling and cell motility in prostate cancer cells and activated macrophages. Unlike the activation of SMAD pathways, the TRAF6-mediated activation of PI3K and AKT was not dependent on the kinase activity of TβRI. In situ proximity ligation assays revealed that polyubiquitylation of p85α was evident in aggressive prostate cancer tissues. Thus, our data reveal a molecular mechanism by which TGF-β activates the PI3K-AKT pathway to drive cell migration.

Place, publisher, year, edition, pages
American Association for the Advancement of Science, 2017
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-137787 (URN)10.1126/scisignal.aal4186 (DOI)000404615300002 ()28676490 (PubMedID)
Note

TGF-beta promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85 alpha

Available from: 2017-07-27 Created: 2017-07-27 Last updated: 2018-06-09Bibliographically approved
Song, J., Mu, Y., Li, C., Bergh, A., Miaczynska, M., Heldin, C.-H. & Landström, M. (2016). APPL proteins promote TGF beta-induced nuclear transport of the TGF beta type I receptor intracellular domain. OncoTarget, 7(1), 279-292
Open this publication in new window or tab >>APPL proteins promote TGF beta-induced nuclear transport of the TGF beta type I receptor intracellular domain
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 1, p. 279-292Article in journal (Refereed) Published
Abstract [en]

The multifunctional cytokine transforming growth factor-beta (TGF beta) is produced by several types of cancers, including prostate cancer, and promote tumour progression in autocrine and paracrine manners. In response to ligand binding, the TGF beta type I receptor (T beta RI) activates Smad and non-Smad signalling pathways. The ubiquitin-ligase tumour necrosis factor receptor-associated factor 6 (TRAF6) was recently linked to regulate intramembrane proteolytic cleavage of the T beta RI in cancer cells. Subsequently, the intracellular domain (ICD) of T beta RI enters in an unknown manner into the nucleus, where it promotes the transcription of pro-invasive genes, such as MMP2 and MMP9. Here we show that the endocytic adaptor molecules APPL1 and APPL2 are required for TGF beta-induced nuclear translocation of T beta RI-ICD and for cancer cell invasiveness of human prostate and breast cancer cell lines. Moreover, APPL proteins were found to be expressed at high levels in aggressive prostate cancer tissues, and to be associated with T beta RI in a TRAF6-dependent manner. Our results suggest that the APPL-T beta RI complex promotes prostate tumour progression, and may serve as a prognostic marker.

Keywords
APPL proteins, prostate cancer, signal transduction, tumour necrosis factor receptor-associated factor 6, transforming growth factor beta
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-117841 (URN)10.18632/oncotarget.6346 (DOI)000369950300023 ()26583432 (PubMedID)
Available from: 2016-03-30 Created: 2016-03-04 Last updated: 2019-05-10Bibliographically approved
Projects
Molecular mechanisms for migration and invasion of prostate cancer cells [2009-04405_VR]; Umeå UniversityIDENTIFICATION OF NOVEL MOLECULAR SIGNALING PATHWAYS WHICH PROMOTES INVASIVE CANCER REGULATED BY TRANSFORMING GROWTH FACTOR BETA AND THE UBIQUITIN LIGASE TRAF6 [2012-02781_VR]; Umeå UniversityEXPLORING SIGNALING PATHWAYS IN PROSTATE CANCER REGULATED BY TRANSFORMING GROWTH FACTOR BETA AND TRAF6 [2016-02513_VR]; Umeå UniversityEVALUATION OF NOVEL CANCER SPECIFIC DRUGS [2016-06125_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-6737-7230

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