Loss of TINCR expression promotes proliferation, metastasis through activating EpCAM cleavage in colorectal cancer.

Zuo-Yang Zhang,Yu-Han Hu,Li Yuan,Wen-Juan Zhang,Zhe-Ying Zhang,Lin Zheng,Yan-Xia Lu,Ya-Ya Chang,Xue-Nong Li,Fan Zhang

doi:10.18632/oncotarget.8141

Zuo-Yang Zhang, Yu-Han Hu + Show 8 more

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https://doi.org/10.18632/oncotarget.8141

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Abstract

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.

Highlights

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females worldwide [1]
We relied on Oncomine, a cancer microarray database and web-based data-mining platform [15, 16], to identify the expression level of Terminal differentiation-induced lncRNA (TINCR) in colorectal cancer tissues, and the result indicated that TINCR was significantly downregulated in colorectal cancer tissues comparing with adjacent tissues. (Supplementary, Figure S1A, S1B)
These results suggest that the decreased TINCR expression is clinically relevant to the metastasis of CRC

Summary

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females worldwide [1]. LncRNAs, a subgroup of non-protein coding transcripts, ranging in length from 200 bp to tens of kilobases (kb), and accumulating evidences have shown that lncRNAs may promote the formation and progression of colorectal cancer [4,5,6]. Several lncRNAs function as transcriptional activators or repressors in CRC. LncRNACCAT1 promotes long-range chromatin interactions at the MYC locus and dramatically increases the expression of MYC [9]. The fact that overexpression of lncRNA-ROR in wild HCT116 cells could significantly decrease the expression of p53 indicates that ROR is a strong repressor of p53 [10]. The ability of lncRNA to interact with signal transduction pathways allows them to regulate the function of cancer cells. Colorectal cancer-associated lncRNA (CCAL) promotes CRC progression by targeting AP-2α, and activated the Wnt/β-catenin pathway [11]. LncRNA-PVT-1 decrease the proliferation and invasion capabilities by acting the TGF-β signal pathway and the apoptotic signals in CRC cells [12]

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