Wang Tao, Hou Jingjing, Jian Shuo, Luo Qicong, Wei Jie, Li Zengpeng, Wang Xuegang, Bai Peide, Duan Bo, Xing Jinchun, Cai Jianchun
The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, 361003, China.
Department of Gastrointestinal Surgery, Zhongshan Hospital affiliated to Xiamen University, Xiamen, China 361004.
J Cancer. 2018 Oct 1;9(20):3776-3786. doi: 10.7150/jca.26263. eCollection 2018.
MicroRNAs (miRNAs) are important regulators and associated with the development of many different types of cancer, including gastric cancer. However, their pathophysiologic role and their relevance to tumorigenesis, invasion and metastasis are still unknown. In our current study, we performed microRNA array and found that 28 of miRNAs were differentially expressed in INF type of gastric cancer. Among 28 miRNAs, miR-29b was one of the most significantly down-regulated miRNA. Further bioinformatics analysis showed that MMP2 was a potential target of miR-29b. Interestingly, luciferase analysis showed that miR-29b negatively regulates MMP2 by binding with the miRNA response element (MRE) on the 3'UTR of MMP2. In addition, overexpression of miR-29b significantly decreased the mRNA and protein level of MMP2 and the activity of MMP2 to suppress gastric cancer cell migration. Moreover, lentivirus mediated overexpression of miR-29b dramatically suppressed the ability of BGC823 cells to form colonies and their ability to develop tumor in nude mice. Finally, our qPCR and western blot analysis showed that miR-29b was significantly reduced in clinical gastric cancer tissue, whereas MMP2 protein was significantly up-regulated, suggesting that this aberrant down-regulation of miR-29b might be associated with the abnormal regulation of MMP2 and the development of gastric cancer. Significant apparent was also found between miR-29b expression and TNM staging, lymph node status, tumor differentiation and Ming classification. Together, our data suggest an important regulatory role of miR-29b in the development of gastric cancer. Thus, miR-29b and MMP2 might be important diagnostic or therapeutic targets for human tumor diseases.
微小RNA（miRNA）是重要的调节因子，与包括胃癌在内的多种不同类型癌症的发生发展相关。然而，它们的病理生理作用及其与肿瘤发生、侵袭和转移的相关性仍不清楚。在我们当前的研究中，我们进行了miRNA芯片分析，发现28种miRNA在胃癌的INF类型中差异表达。在这28种miRNA中，miR-29b是下调最显著的miRNA之一。进一步的生物信息学分析表明，基质金属蛋白酶2（MMP2）是miR-29b的潜在靶点。有趣的是，荧光素酶分析表明，miR-29b通过与MMP2 3'非翻译区（UTR）上的miRNA反应元件（MRE）结合来负向调节MMP2。此外，miR-29b的过表达显著降低了MMP2的mRNA和蛋白水平以及MMP2的活性，从而抑制胃癌细胞迁移。此外，慢病毒介导的miR-29b过表达显著抑制了BGC823细胞形成集落的能力及其在裸鼠体内形成肿瘤的能力。最后，我们的定量聚合酶链反应（qPCR）和蛋白质印迹分析表明，临床胃癌组织中miR-29b显著降低，而MMP2蛋白显著上调，这表明miR-29b的这种异常下调可能与MMP2的异常调节和胃癌的发生发展有关。在miR-29b表达与TNM分期、淋巴结状态、肿瘤分化和明氏分类之间也发现了显著关联。总之，我们的数据表明miR-29b在胃癌发生发展中具有重要的调节作用。因此，miR-29b和MMP2可能是人类肿瘤疾病重要的诊断或治疗靶点。
