LncRNA-CCAT1经由miR-4295调控ROCK2促进EMT发生导致胆管癌厄洛替尼耐药的机制研究

厄洛替尼耐药是胆管癌治疗失败的主要原因，EMT在这过程中发挥关键作用，但机制尚不明确。我们前期研究证实长链非编码RNA CCAT1在胆管癌进展中起重要作用，深入研究发现：CCAT1在厄洛替尼耐药胆管癌细胞中表达显著升高；下调CCAT1可抑制ROCK2的表达和EMT发生，并增加耐药细胞对厄洛替尼的敏感性。进一步探索发现CCAT1可通过竞争性结合miR-4295促进ROCK2的表达。结合既往研究和我们已发表的研究均证实ROCK2与EMT密切相关，我们推测CCAT1通过吸附miR-4295上调ROCK2促进EMT发生，最终导致胆管癌细胞对厄洛替尼耐药。本研究拟在细胞、组织、动物实验等多层面明确CCAT1通过ROCK2促进EMT导致胆管癌细胞对厄洛替尼耐药，阐明其调控ROCK2的具体分子机制，分析胆管癌组织中CCAT1及ROCK2的表达与临床特征的关联,为寻找逆转胆管癌厄洛替尼耐药提供新的思路。

Erlotinib resistance is the main reason for the failure of cholangiocarcinoma treatment. EMT plays a key role in this process, but the mechanism is not clear. Our previous studies confirmed that long-chain noncoding RNA ccat1 plays an important role in the development of cholangiocarcinoma. In-depth studies found that ccat1 expression significantly increased in erlotinib resistant cholangiocarcinoma cells; down regulating ccat1 can inhibit the expression of Rock2 and EMT, and increase the sensitivity of resistant cells to erlotinib. It was found that ccat1 could promote the expression of Rock2 through competitive binding of mir-4295. In combination with previous studies and published studies, we have confirmed that Rock2 is closely related to EMT. We speculate that ccat1 can promote EMT by up regulating Rock2 by adsorbing mir-4295, and eventually lead to the resistance of cholangiocarcinoma cells to gierlotinib. The purpose of this study is to clarify the role of ccat1 in promoting EMT to induce erlotinib resistance in cholangiocarcinoma cells through Rock2 in cell, tissue and animal experiments, clarify the specific molecular mechanism of its regulation of Rock2, analyze the relationship between the expression of ccat1 and Rock2 in cholangiocarcinoma tissues and clinical characteristics, and provide a new idea for reversing erlotinib resistance in cholangiocarcinoma