MiR-148b参与胃癌细胞周期调控的分子机制研究

胃癌是我国最常见的恶性肿瘤之一，预后差，寻找可用于早期诊断的基因标志，发现新的分子治疗靶点，意义重大。近年来，miRNAs作为癌基因或抑癌基因参与肿瘤发生的研究颇受关注。申请者在前期工作中率先发现miR-148b在胃癌组织中显著低表达，并通过负性调控胆囊收缩素B受体（CCKBR）表达，影响胃癌细胞增殖。然而，我们在过表达miR-148b的胃癌细胞系中发现细胞周期的改变，但沉默CCKBR的表达却不能观察到类似的细胞周期变化。进一步的芯片筛查发现CDK6 mRNA的表达水平在过表达miR-148b的胃癌细胞中明显降低，real-time PCR结果也与之一致。在此基础上，本项目拟深入探寻miR-148b参与胃癌细胞周期调控的可能分子机制，试图证明miR-148b通过负性调节CDK6的表达影响细胞周期，进一步探寻二者作用后触发的下游信号通路，将可能为胃癌的早诊或治疗提供新的靶点。

Gastric cancer is one of the most common cancers with a heavy mortality in China. It's of great significance to find attractive biomarkers for early diagnosis and new molecular targets for gastric cancer. Recently, it has been demonstrated that miRNAs which act as tumor suppressor genes or oncogenes play a significant role in tumorigenesis. In our previous work, we have already found significant down-regulation of miR-148b in gastric cancer tissues. Moreover, subsequent experiments confirmed that miR-148b inhibited cell proliferation in gastric cancer, depending on negative regulation of the expression of cholecystokinin-B receptor (CCKBR). However,we also found overexpression of miR-148b could induce the alteration of cell cycle in gastric cancer which did not related to CCKBR. Using bioinformatics methods, microarray analysis and real-time PCR, we found significant down-regulation of CDK6 on mRNA level in cells which were overexpression of miR-148b. Conclusively, we try to demonstrate that miR-148b has an effect on cell cycle depending on negative regulation of CDK6 in gastric cancer.Furthermore, we will clarify the downstream signaling pathways in this process. Maybe our research would provide potential biomarkers and therapeutic targets for eraly diagnosis and treatment against gastric cancer.