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

It is unclear how the loss of TGF-b signaling components affects metastatic abilities in clear cell renal cell carcinoma (ccRCC). In this study, we identified that low TGFBR3 expression in ccRCC cells enhanced primary tumor formation and lung metastasis. In the presence of TGFBR3, TGF-b2 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-b-independent manner. Increased lamellipodium formation by FAK-PI3K signaling was observed with TGFBR3 downregulation, and this contributed to TGF-b-independent cell migration in ccRCC cells. Taken together, our findings reveal that loss of TGFBR3 endows ccRCC cells with multiple metastatic abilities through TGF-b-dependent and independent pathways. Overall design: Target genes for TGF-b2 and TGFBR3 in ccRCC cells were identified.