Decreased TGFBR3/betaglycan expression enhances the metastatic abilities of renal cell carcinoma cells through TGF-β-dependent and -independent mechanisms

Oncogene. 2018 Apr;37(16):2197-2212. doi: 10.1038/s41388-017-0084-0. Epub 2018 Feb 2.

Abstract

TGF-β regulates both the tumor-forming and migratory abilities of various types of cancer cells. However, it is unclear how the loss of TGF-β signaling components affects these abilities in clear-cell renal cell carcinoma (ccRCC). In this study, we investigated the role of TGFBR3 (TGF-β type III receptor, also known as betaglycan) in ccRCC. Database analysis revealed decreased expression of TGFBR3 in ccRCC tissues, which correlated with poor prognosis in patients. Orthotopic inoculation experiments using immunocompromised mice indicated that low TGFBR3 expression in ccRCC cells enhanced primary tumor formation and lung metastasis. In the presence of TGFBR3, TGF-β2 decreased the aldehyde dehydrogenase (ALDH)-positive ccRCC cell population, in which renal cancer-initiating cells are enriched. Loss of TGFBR3 also enhanced cell migration in cell culture and induced expression of several mesenchymal markers in a TGF-β-independent manner. Increased lamellipodium formation by FAK-PI3K signaling was observed with TGFBR3 downregulation, and this contributed to TGF-β-independent cell migration in ccRCC cells. Taken together, our findings reveal that loss of TGFBR3 endows ccRCC cells with multiple metastatic abilities through TGF-β-dependent and independent pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / pathology*
  • Cell Movement / drug effects
  • Cell Movement / genetics*
  • Cells, Cultured
  • Down-Regulation / genetics
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor
  • HEK293 Cells
  • Humans
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / pathology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Metastasis
  • Proteoglycans / genetics*
  • Receptors, Transforming Growth Factor beta / genetics*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology
  • Transforming Growth Factor beta / physiology*

Substances

  • Proteoglycans
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • betaglycan