LncRNA lnc-TSI Inhibits Metastasis of Clear Cell Renal Cell Carcinoma by Suppressing TGF-β-induced Epithelial-mesenchymal Transition

Abstract Transforming growth factor-β (TGF-β)/Smads signal plays an important role in cancer metastasis by mediating epithelial-mesenchymal transition (EMT) in cancer cells. Lnc-TSI is a recently identified long noncoding RNA which negatively regulates TGF-β/Smads signal. The study was conducted to test the hypothesis that lnc-TSI inhibits metastasis in clear cell renal cell carcinoma (ccRCC) by regulating the TGF-β/Smad3 pathway. Here we show that lnc-TSI was upregulated in ccRCC cells and tissue and was associated with the activation of TGF-β/Smads signal. Depleting lnc-TSI enhanced tumor cell invasion and metastasis in vitro and ccRCC lung metastasis in vivo, whereas overexpressing lnc-TSI inhibited ccRCC cell invasion and tumor metastasis. Mechanistic studies indicated that lnc-TSI specifically inhibited the phosphorylation of Smad3 and subsequent EMT by binding with the MH2 domain of Smad3 to block the interaction between Smad3 and TGF-β receptor I in ccRCC cells. In a cohort of 150 patients with ccRCC, expression of lnc-TSI in tumors was negatively correlated with pSmad3 and activated EMT markers. Patients with expression of tumor lnc-TSI ≥median at radical nephrectomy had a higher survival rate compared to those with lnc-TSI