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VHL status regulates transforming growth factor-β signaling pathways in renal cell carcinoma
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. (ML)ORCID iD: 0000-0002-2391-5903
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
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. Vol. 9, no 23, p. 16297-16310
Keywords [en]
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: urn:nbn:se:umu:diva-146504DOI: 10.18632/oncotarget.24631Scopus ID: 2-s2.0-85044474424OAI: oai:DiVA.org:umu-146504DiVA, id: diva2:1196867
Available from: 2018-04-11 Created: 2018-04-11 Last updated: 2018-06-09Bibliographically approved

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Mallikarjuna, PramodTumkur Sitaram, RaviprakashLandström, MaréneLjungberg, Börje

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