miRNA调控胃癌特异性腹膜转移的机制研究

Peritoneal dissemination is the overwhelming cause of mortality in patients with gastric cancer. The absence of specific markers for peritoneal metastasis in gastric cancer has made the successful early diagnosis and target therapy for advanced gastric cancer very difficult. Therefore, it's very important to search specific molecular markers and signal pathway for gastric cancer peritoneal metastasis. Our previous study found that miR-181b, miR-223 and miR-136 were differentially expressed in specific peritoneal metastasis of gastric cancer cell lines, and then screened and verified its downstream target gene ADAM11, EPB41L3, ALCAM and H0XC10. This project intends to observe the three miRNA how to regulate gastric cancer peritoneal metastasis, and further validation their early diagnosis and prognosis function with clinical samples. This project wants to find new targets and warning marker for gastric cancer peritoneal metastasis, and further lay a wealth of clinical and theoretical basis to eliminate or reverse specificity of peritoneal metastasis.

由于胃癌特异性腹膜转移缺乏有效的诊疗手段，目前已成为进展期胃癌患者死亡的主要原因。因此，寻找胃癌腹膜转移的特异性分子标记物对进展期胃癌诊断和靶向治疗具有重要临床意义。我们前期研究发现miR-181b、miR-223和miR-136在特异性腹膜转移胃癌细胞系中差异表达，进而筛选并验证了其下游靶基因ADAM11、EPB41L3、ALCAM 和H0XC10。本项目拟在前期工作基础上，观察通过体内外实验观察目标miRNA调控胃癌腹膜转移恶性生物学表型的内在机制，以期找到胃癌特异性腹膜转移的逆转分子靶标；同时利用临床胃癌组织标本验证目标miRNA对胃癌腹膜转移的分子标志物作用。本项目从调控基因的上游分子miRNA的角度，探讨胃癌特异性腹膜转移的分子机制，为找到新的预警标志物及调控靶点，进一步提高胃癌腹膜转移的早期诊断率，并为消除或逆转胃癌特异性腹膜转移奠定丰富的临床和理论基础。

由于胃癌特异性腹膜转移缺乏有效的诊疗手段，目前已成为进展期胃癌患者死亡的主要原因。因此，寻找胃癌腹膜转移的特异性分子标记物对进展期胃癌诊断和靶向治疗具有重要临床意义。MicroRNA在胚胎发育、生理学和肿瘤发生过程中发挥重要作用，但microRNA在调控胃癌转移中的机制研究尚未完全阐明。我们通过体外和体内筛选、芯片分析及和生物信息学预测，并采用功能验证和临床验证，发现miR-181b、miR-223和miR-136在胃癌特异性腹膜转移中发挥重要作用，3个miRNA的分子簇可有效预测胃癌患者术后腹膜转移。MIR-181B通过抑制Adam金属蛋白酶结构域11抑制胃癌腹膜转移。MIR-223通过抑制红细胞膜蛋白带4.1样3和激活的白细胞粘附分子调控胃癌腹膜转移，而miR-136通过抑制同源盒C10促进胃癌腹膜转移。3个miRNA调控的下游靶转移相关基因，与器官特异性转移行为的相关性以前未见报道，为首次发现。该研究从调控基因的上游分子miRNA的角度，探讨了胃癌特异性腹膜转移的分子机制，为提高胃癌腹膜转移的早期诊断率，消除或逆转胃癌特异性腹膜转移奠定了丰富的临床和理论基础。