Research Papers:

Transforming growth factor-β promotes aggressiveness and invasion of clear cell renal cell carcinoma

Raviprakash T. Sitaram _, Pramod Mallikarjuna, Maréne Landström and Börje Ljungberg

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Oncotarget. 2016; 7:35917-35931. https://doi.org/10.18632/oncotarget.9177

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Raviprakash T. Sitaram1,*, Pramod Mallikarjuna2,*, Maréne Landström2,** and Börje Ljungberg1,**

1 Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden

2 Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden

* These authors have contributed equally to this work as first author

** These authors contributed equally to this work as last author

Correspondence to:

Raviprakash T. Sitaram, email:

Keywords: ccRCC, ALK5, pSmad2/3, PAI-1, TGF-β signaling pathway

Received: October 07, 2015 Accepted: April 19, 2016 Published: May 04, 2016


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.

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