Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Mol Ther. 2018 May 2;26(5):1287-1298. doi: 10.1016/j.ymthe.2018.02.024. Epub 2018 Mar 6.
We previously demonstrated that long non-coding RNA cytoskeleton regulator RNA (CYTOR), also known as Linc00152, was significantly overexpressed in colon cancer and conferred resistance to oxaliplatin-induced apoptosis. At the same time, elevated CYTOR expression was also reported in gastric cancer and exerted influences on epithelial-mesenchymal transition (EMT) markers. However, the precise mechanism by which CYTOR promotes the EMT phenotype and cancer metastasis remains poorly understood. Here, we showed that loss of epithelial characteristics and simultaneous gain of mesenchymal features correlated with CYTOR expression. Knockdown of CYTOR attenuated colon cancer cell migration and invasion. Conversely, ectopic expression of CYTOR induced an EMT program and enhanced metastatic properties of colon cancer cells. Mechanistically, the binding of CYTOR to cytoplasmic β-catenin impeded casein kinase 1 (CK1)-induced β-catenin phosphorylation that enabled it to accumulate and translocate to the nucleus. Reciprocally, β-catenin/TCF complex enhanced the transcription activity of CYTOR in nucleus, thus forming a positive feed-forward circuit. Moreover, elevated CYTOR, alone or combined with overexpression of nuclear β-catenin, was predictive of poor prognosis. Our findings suggest that CYTOR promotes colon cancer EMT and metastasis by interacting with β-catenin, and the positive feed-forward circuit of CYTOR-β-catenin might be a useful therapeutic target in antimetastatic strategy.
我们之前的研究表明，长链非编码 RNA 细胞骨架调节 RNA（也称为 Linc00152）在结肠癌中显著过表达，并赋予其对奥沙利铂诱导的细胞凋亡的抗性。同时，在胃癌中也报道了升高的 CYTOR 表达，并对上皮-间充质转化（EMT）标志物产生影响。然而，CYTOR 促进 EMT 表型和癌症转移的确切机制仍知之甚少。在这里，我们表明上皮特征的丧失和同时获得间充质特征与 CYTOR 表达相关。敲低 CYTOR 减弱了结肠癌细胞的迁移和侵袭。相反，CYTOR 的异位表达诱导 EMT 程序并增强结肠癌细胞的转移特性。从机制上讲，CYTOR 与细胞质 β-连环蛋白结合，阻碍了酪蛋白激酶 1（CK1）诱导的 β-连环蛋白磷酸化，使其能够积累并易位到细胞核。反过来，β-连环蛋白/TCF 复合物增强了 CYTOR 在核内的转录活性，从而形成正反馈回路。此外，升高的 CYTOR，单独或与核 β-连环蛋白的过表达一起，预示着预后不良。我们的研究结果表明，CYTOR 通过与 β-连环蛋白相互作用促进结肠癌细胞 EMT 和转移，并且 CYTOR-β-连环蛋白的正反馈回路可能是抗转移策略中的一个有用的治疗靶点。
