RETRACTED: lncRNA lnc-TSI Inhibits Metastasis of Clear Cell Renal Cell Carcinoma by Suppressing TGF-β-Induced Epithelial-Mesenchymal Transition

Abstract

The transforming growth factor-β (TGF-β)/Smads signal plays an important role in cancer metastasis by mediating the epithelial-mesenchymal transition (EMT) in cancer cells. lnc-TSI is a recently identified long noncoding RNA that negatively regulates the TGF-β/Smads signal. The present 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. Herein, we show that lnc-TSI was upregulated in ccRCC cells and tissue and was associated with activation of the 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 phosphorylated (p)Smad3 and activated EMT markers. Patients with expression of tumor lnc-TSI greater than or equal to the median at radical nephrectomy had a higher survival rate compared to those with lnc-TSI below the median during follow-up. These findings reveal a new regulatory mechanism of ccRCC metastasis and suggest a potential molecular target for the development of anti-cancer drugs.

Identification of Epithelial-Mesenchymal Transition- (EMT-) Related LncRNA for Prognostic Prediction and Risk Stratification in Esophageal Squamous Cell Carcinoma

“…Notably, the effect of lncRNA on the epithelial-mesenchymal transition (EMT) of tumor cells has also been confirmed in recent studies [ 15 , 16 ]. EMT is an essential step in the metastasis of malignant tumors, which can transform epithelial-like cells into a mesenchymal-like cell state.…”

Long noncoding RNAs: fine-tuners hidden in the cancer signaling network

“…Lnc-TSI impedes the phosphorylation of SMAD3 by blocking the interaction between SMAD3 and TGFBR1 at the MH2 domain. Consequently, the TGF-β/SMADs signaling pathway is inhibited, which suppresses epithelial–mesenchymal transition [ 78 ]. LncRNAs can also regulate the TGF-β signaling pathway by modulating its co-factors.…”

Regulation of TGFβ/SMAD signaling by long non-coding RNAs in different cancers: Dark Knight in the Castle of molecular oncology

“…lnc-TSI reduced invasive and metastasizing potential of ccRCC cells [ 23 ]. Mechanistically, it was shown that lnc-TSI interacted with the MH2 domain of SMAD3 and blocked the association between TGFβ receptor I and SMAD3 in ccRCC cells.…”

“…Mechanistically, it was shown that lnc-TSI interacted with the MH2 domain of SMAD3 and blocked the association between TGFβ receptor I and SMAD3 in ccRCC cells. Metastatic lesions were considerably enhanced in mice inoculated with lnc-TSI-silenced Caki-1 cells, whereas lnc-TSI overexpression markedly reduced the metastatic lesions in tumor bearing mice [ 23 ].…”