CALR-SUV39H1调控轴通过EMT促进胃癌转移的分子机制研究

胃癌是我国高发病预后极差和高死亡的一类恶性肿瘤，转移是影响疗效与预后的主要原因。项目组在前期发现胃癌组织CALR显著高表达，敲低CALR后能有效抑制胃癌细胞转移侵袭能力，并降低EMT相关Snail、ZEB1及SUV39H1和升高E-cadherin、ZO-1表达水平的基础上，结合新近文献证实CALR可间接调控SUV39H1表达、SUV39H1与Snail结合调控E-cadherin表达等最新进展，提出“CALR通过上调SUV39H1，调控EMT进程，从而促进胃癌转移”的科学假说。为验证这一假说，本项目将从胃癌临床样本、细胞和裸鼠转移模型三个维度，通过抑制或过表达CALR，观察其对胃癌转移、SUV39H1及EMT相关分子表达的影响；明确CALR、SUV39H1、EMT三者之间的调控关系，阐明CALR促进胃癌转移的分子机制，为CALR高表达诱导的胃癌转移患者的精准靶向治疗提供新思路和理论依据。

Gastric cancer (GC) is a kind of malignant tumor with extremely poor prognosis and high incidence and mortality in China. Our previous findings demonstrated that the expression of CALR was significantly upregulated in the GC tissues and that inhibition of CALR effectively restrained GC cell metastasis ability and expression of Snail, ZEB1 and SUV39H1 and increased expression of E-cadherin and ZO-1. Notably, CALR has been demontrated to be capable of indirectly regulating SUV39H1 expression and SUV39H1 could bind to the important EMT molecule-Snail and mediate E-cadherin repression. Based on those results, we thus propose a novel hypothesis that CALR induces EMT and further promotes metastasis of GC cells through up-regulating the expression of SUV39H1. To verify this hypothesis, this project will employ GC clinical samples, cell models and nude mice metastasis models to clarify the correlation among CALR, SUV39H1 and EMT; assess the effects of CALR on GC cell metastasis and SUV39H1 expression and EMT molecules expression by interference or overexpression; and elucidate the underlying molecular mechanism of CALR promoting GC metastasis. This study will provide new ideas and experimental evidence for the targeted and accurate treatment of GC patients with metastasis induced by high CALR expression.