CD147调控TRPM7促进胃癌转移的分子机制研究

Distant metastasis is a major cause of death in patients of gastric cancer, it is important to find the key genes and regulatory mechanisms for prevention of gastric cancer metastasis and prolong survival. We previously found that: "CD147 and TRPM7 can predict the prognosis and metastasis of patients with gastric cancer, and there is a positive correlation between them. The expression of CD147 may interfere with the expression of TRPM7 down while significantly inhibit migration, adhesion and invasion of gastric cancer cells. We have published that TRPM7 may prove mediated calcium influx through the regulation of cell migration and invasion.Therefore, CD147 may by regulation within TRPM7-mediated calcium influx and other downstream pathways, thus promoting metastasis of gastric cancer. The current project will focus on the following: 1. By migration, adhesion, invasion and in vivo experiments to detect the role of TRPM7 in the regulation of gastric metastasis; 2. To identify the target role of CD147 by in vitro and clinical data, and to study its downstream pathways related with TRPM7 during metastasis of gastric cancer. This project will elucidate the molecular mechanism of CD147-TRPM7- downstream pathways regulating gastric cancer metastasis and provide a theoretical basis for the targeted treatment of gastric cancer.

远处转移是胃癌患者的主要死因，故发现转移关键基因及其调控机制对防治胃癌转移及延长患者生存具有重要意义。我们前期发现：“CD147及TRPM7均可预测胃癌患者的预后和转移，且两者表达存在正相关。而干扰CD147可下调TRPM7表达同时显著抑制胃癌细胞的迁移、粘附和侵袭能力，结合我们已证明的TRPM7可通过介导钙内流调控鼻咽癌细胞迁移和侵袭的已发表结果，据此推测：“CD147可能通过调控TRPM7介导的钙内流等下游通路，从而促进胃癌转移”。因此，本项目将在前期基础上，1）通过迁移、粘附、侵袭及体内实验，研究TRPM7在调控胃癌转移中的关键作用；2）结合体外实验和临床病理资料对CD147作用于靶基因TRPM7加以验证，并研究CD147作用于TRPM7及其下游通路进而调控胃癌转移的意义。本项目将阐明CD147-TRPM7-下游通路调控胃癌转移的分子机制，为胃癌的靶向治疗提供理论依据。

胃癌细胞的侵袭转移是患者预后不良的主要因素，其机制尚不明确。本组前期发现多量长链非编码RNA（lncRNA）在胃癌（GC）组织中差异表达。与OPA相互作用的蛋白5反义转录本1（OIP5-AS1）在各种类型的癌症中起着重要的调节作用,但是OIP5-AS1在胃癌（GC）中的功能作用和调节机制仍然未知。在这项研究中，我们发现与相邻的非癌性组织相比，GC组织中OIP5-AS1的表达增加，这与患者总体生存时间的缩短显着相关。生物信息学分析筛选验证和胃癌组织、细胞表达检测提示OIP5-AS1可以抑制miR-140表达，发现两者存在多个结合位点，基于此我们提出OIP5-AS1通过miRNA海绵作用调控miR-140的理论假说。进一步的，生信分析发现miR-140与TRPM7之间存在多个结合位点，基于此我们也提出了miR140通过TPPM7海绵吸附调控TRPM7的理论假说。本项目拟通过荧光素酶报告基因进一步深入探讨OIP5-AS1调控miR-140以及miR-140调控TRPM7的机制,以期揭示 OIP5-AS1/miR-140/TRPM7 信号通路调控胃癌转移的具体机制，为胃癌转移的防治提供新思路。