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.
Highlights
Renal cell carcinoma (RCC) remains one of the most commonly diagnosed carcinomas in humans, with constantly rising mortality.[1,2] Clear cell RCC, which comprises 75%–80% of RCCs, is not sensitive to radiotherapy or chemotherapy.[3]
In this study, we identified a long noncoding RNA (lncRNA), lnc-TSI, which was expressed in clear cell renal cell carcinoma (ccRCC) cells and functioned as a negative regulator for tumor metastasis
In ccRCC cells, lnc-TSI inhibited the phosphorylation of Smad[3] and subsequent epithelial-mesenchymal transition (EMT) by binding with the MH2 domain of Smad[3] to block the interaction between Smad[3] and TbRI. lnc-TSI knockout promoted ccRCC metastasis whereas its overexpression drastically inhibited ccRCC metastasis
Summary
Renal cell carcinoma (RCC) remains one of the most commonly diagnosed carcinomas in humans, with constantly rising mortality.[1,2] Clear cell RCC (ccRCC), which comprises 75%–80% of RCCs, is not sensitive to radiotherapy or chemotherapy.[3]. The epithelial-mesenchymal transition (EMT), which is comprised of multiple dynamic transitional states between epithelial and mesenchymal phenotypes, plays a critical role in regulation of progression and metastasis in many types of tumors, including ccRCC.[6,7,8] Emerging evidence has shown that EMT was highly modulated by a number of transcription factors and regulators.[9,10,11] In particular, transforming growth factor-b (TGF-b)/Smads signaling, a crucial driver of EMT, plays a pivotal role in cancer progression, migration, invasion, and metastasis.[12,13,14] TGF-b initiates its molecular functions by binding with the TGF-b type II receptor, which phosphorylates the TGF-b type I receptor (TbRI), resulting in the phosphorylation of Smad[3] and Smad[2] and the following nucleus translocation of Smad[2], Smad[3], and Smad4.15,16 The phosphorylation of Smad[3] by TbRI was a key initial event in the activation of TGF-b/Smads signaling.[17,18,19] Despite the importance of the TGF-b-induced EMT, as a regulator of tumor metastasis, the molecular mechanisms underlying EMT in ccRCC have not been completely understood
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