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Transforming growth factor-β promotes aggressiveness and invasion of clear cell renal cell carcinoma
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Medical Biosciences.
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.
2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 24, 35917-35931 p.Article in journal (Refereed) Published
Abstract [en]

The molecular mechanisms whereby transforming growth factor-β (TGF-β) promotes clear cell renal cell carcinoma (ccRCC) progression is elusive. The cell membrane bound TGF-β type I receptor (ALK5), was recently found to undergo proteolytic cleavage in aggressive prostate cancer cells, resulting in liberation and subsequent nuclear translocation of its intracellular domain (ICD), suggesting that ALK5-ICD might be a useful cancer biomarker. Herein, the possible correlation between ALK5 full length (ALK5-FL) and ALK5-ICD protein, phosphorylated Smad2/3 (pSmad2/3), and expression of TGF-β target gene PAI-1, was investigated in a clinical ccRCC material, in relation to tumor grade, stage, size and cancer specific survival. Expression of ALK5-FL, ALK5-ICD, pSmad2/3 and PAI-1 protein levels were significantly higher in higher stage and associated with adverse survival. ALK5-ICD, pSmad2/3 and PAI-1 correlated with higher grade, and ALK5-FL, pSmad2/3 and PAI-1 protein levels were significantly correlated with larger tumor size. Moreover, the functional role of the TGF-β - ALK5-ICD pathway were investigated in two ccRCC cell lines by treatment with ADAM/MMP2 inhibitor TAPI-2, which prevented TGF-β-induced ALK5-ICD generation, nuclear translocation, as well as cell invasion. The present study demonstrated that canonical TGF-β Smad2/3 pathway and generation of ALK5-ICD correlates with poor survival and invasion of ccRCC in vitro.

Place, publisher, year, edition, pages
2016. Vol. 7, no 24, 35917-35931 p.
Keyword [en]
ccRCC, ALK5, pSmad2/3, PAI-1, TGF-β signaling pathway
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-120254DOI: 10.18632/oncotarget.9177ISI: 000377756800034PubMedID: 27166254OAI: oai:DiVA.org:umu-120254DiVA: diva2:927569
Available from: 2016-05-12 Created: 2016-05-12 Last updated: 2016-11-22Bibliographically approved

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Tumkur Sitaram, RaviprakashMallikarjuna, PramodLandström, MaréneLjungberg, Börje
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