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

Raviprakash T Sitaram1, Pramod Mallikarjuna2, Maréne Landström2

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

Oncotarget
|May 12, 2016
PubMed

Insights

Transforming growth factor-β (TGF-β) and its receptor ALK5 intracellular domain (ALK5-ICD) correlate with clear cell renal cell carcinoma (ccRCC) progression. Higher levels of ALK5-ICD indicate poorer survival and increased invasion in ccRCC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The molecular mechanisms of transforming growth factor-β (TGF-β) in clear cell renal cell carcinoma (ccRCC) progression are not fully understood.
  • Proteolytic cleavage of TGF-β type I receptor (ALK5) releasing its intracellular domain (ALK5-ICD) has been observed in other cancers, suggesting potential as a biomarker.

Purpose of the Study:

  • To investigate the correlation between ALK5 full length (ALK5-FL), ALK5-ICD, phosphorylated Smad2/3 (pSmad2/3), and PAI-1 expression in ccRCC.
  • To assess the relationship of these markers with tumor grade, stage, size, and patient survival.
  • To explore the functional role of the TGF-β - ALK5-ICD pathway in ccRCC cell invasion.

Main Methods:

  • Analysis of ALK5-FL, ALK5-ICD, pSmad2/3, and PAI-1 protein levels in clinical ccRCC samples.
  • Correlation analysis with tumor characteristics (grade, stage, size) and cancer-specific survival.
  • In vitro experiments using ccRCC cell lines treated with an ADAM/MMP2 inhibitor (TAPI-2) to block ALK5-ICD generation and nuclear translocation.

Main Results:

  • Elevated expression of ALK5-FL, ALK5-ICD, pSmad2/3, and PAI-1 was observed in higher stage ccRCC and associated with adverse survival.
  • ALK5-ICD, pSmad2/3, and PAI-1 levels correlated with higher tumor grade.
  • ALK5-FL, pSmad2/3, and PAI-1 levels correlated with larger tumor size.
  • Inhibition of ALK5-ICD generation and nuclear translocation by TAPI-2 reduced TGF-β-induced ccRCC cell invasion.

Conclusions:

  • The canonical TGF-β Smad2/3 pathway and ALK5-ICD generation are linked to poorer survival and increased invasion in ccRCC.
  • ALK5-ICD may serve as a potential biomarker for ccRCC progression and patient outcomes.
Keywords:
ALK5PAI-1TGF-β signaling pathwayccRCCpSmad2/3

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