Loss of TINCR expression promotes proliferation, metastasis through activating EpCAM cleavage in colorectal cancer.
Loss of TINCR expression promotes proliferation, metastasis through activating EpCAM cleavage in colorectal cancer.
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TINCR表达缺失通过激活结直肠癌EpCAM裂解促进增殖和转移
DOI：
10.18632/oncotarget.8141
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发表时间：
2016-04-19
期刊：
影响因子：
--
通讯作者：
Li XN
中科院分区：
文献类型：
--
作者：
Zhang ZY;Lu YX;Zhang ZY;Chang YY;Zheng L;Yuan L;Zhang F;Hu YH;Zhang WJ;Li XN
长非编码RNA(LncRNAs)与多种人类疾病有关，包括结直肠癌(CRC)。TINCR是一个3.7kb的非编码RNA，与角质形成细胞和胃癌细胞的分化有关。然而，人们对TINCR在调控结直肠癌进展中的作用知之甚少。在此，我们发现LncRNA TINCR与结直肠癌的增殖和转移有关。TINCR在结直肠癌组织和转移性结直肠癌细胞系中的表达与其对应的细胞系相比有统计学意义的下调。TINCR与结直肠癌的进展呈负相关，在体内和体外均促进肿瘤细胞生长、转移。而过表达TINCR则相反。此外，我们还通过RNA IP和RNA下拉实验发现TINCR与EpCAM特异性结合。TINCR的缺失促进了EPCAM的水解，进而释放了EPICD，进而激活了Wnt/β-catenin通路。进一步的研究表明，c-Myc通过抑制SP1的转录活性来抑制TINCR的表达，从而建立了控制c-Myc和TINCR表达的正反馈环。这些结果表明，TINCR的表达缺失促进了结直肠癌的增殖和转移，可能是一个潜在的抑癌基因。
Long non-coding RNAs (lncRNAs) are involved in kinds of human diseases, including colorectal cancer (CRC). TINCR, a 3.7 kb long non coding RNA, was associated with cell differentiation in keratinocyte and gastric cancer cells. However, little is known about the role of TINCR in regulation CRC progression. Here, we showed that lncRNA TINCR was associated with CRC proliferation and metastasis. TINCR was statistically downregulated in CRC tissues and metastatic CRC cell lines compared with their counterparts. TINCR was reversely correlated with CRC progression and promoted tumor cells growth, metastasis in vivo and in vitro. While overexpression of TINCR had opposite effect. In addition, we also found that TINCR specifically bound to EpCAM through RNA IP and RNA pull down assays. Loss of TINCR promoted hydrolysis of EpCAM and then released EpICD, subsequently, activated the Wnt/β-catenin pathway. Further studies shown that c-Myc repressed the expression of TINCR through repressing sp1 transcriptive activity, which established a positive feedback loop controlling c-Myc and TINCR expression. These findings elucidate that loss of TINCR expression promotes proliferation and metastasis in CRC and it could be considered as a potential cancer suppressor gene.
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