Liu Zhifang, Chen Long, Zhang Xinchao, Xu Xia, Xing Huaixin, Zhang Yingjie, Li Wenjuan, Yu Han, Zeng Jiping, Jia Jihui
Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, China.
J Cell Mol Med. 2014 Apr;18(4):610-23. doi: 10.1111/jcmm.12209. Epub 2014 Jan 22.
Runt-related transcription factor 3 (RUNX3) is a putative tumour suppressor via regulating the expression of a series of target genes. Clinical studies demonstrated that loss of RUNX3 expression is associated with gastric cancer progression and poor prognosis, but the underlying mechanism is not entirely clear. Accumulating evidence shows that the epithelial-mesenchymal transition (EMT) plays an important role in cancer relapse and metastasis. Therefore, we addressed whether RUNX3 has a role in the EMT in gastric cancer. Knockdown of RUNX3 promoted cell invasion and increased the protein expression of the mesenchymal marker vimentin in human gastric cancer cells. Overexpression of RUNX3 suppressed cell invasion and decreased the protein expression of vimentin in the cells and inhibited gastric cancer cells colonization in nude mice. Furthermore, overexpression of RUNX3 increased the expression of microRNA-30a (miR-30a), and miR-30a directly targeted the 3' untranslated region of vimentin and decreased its protein level. miR-30a inhibitor abrogated RUNX3-mediated inhibition of cell invasion and downregulation of vimentin. Thus, RUNX3 suppressed gastric cancer cell invasion and vimentin expression by activating miR-30a. In gastric cancer patients, levels of RUNX3 were positively correlated with miR-30a and negatively associated with the levels of vimentin. Collectively, our data suggest a novel molecular mechanism for the tumour suppressor activity of RUNX3. Effective therapy targeting the RUNX3 pathway may help control gastric cancer cell invasion and metastasis by inhibiting the EMT.
runt相关转录因子3（RUNX3）是一种通过调节一系列靶基因表达发挥潜在抑癌作用的因子。临床研究表明，RUNX3表达缺失与胃癌进展及不良预后相关，但其潜在机制尚不完全清楚。越来越多的证据表明，上皮-间质转化（EMT）在癌症复发和转移中起重要作用。因此，我们探讨了RUNX3在胃癌EMT过程中是否发挥作用。敲低RUNX3可促进人胃癌细胞的侵袭，并增加间质标志物波形蛋白的蛋白表达。过表达RUNX3可抑制细胞侵袭，降低细胞中波形蛋白的蛋白表达，并抑制胃癌细胞在裸鼠体内的定植。此外，过表达RUNX3可增加微小RNA-30a（miR-30a）的表达，且miR-30a直接靶向波形蛋白的3'非翻译区并降低其蛋白水平。miR-30a抑制剂可消除RUNX3介导的对细胞侵袭的抑制作用以及波形蛋白的下调。因此，RUNX3通过激活miR-30a抑制胃癌细胞侵袭和波形蛋白表达。在胃癌患者中，RUNX3水平与miR-30a呈正相关，与波形蛋白水平呈负相关。总体而言，我们的数据揭示了RUNX3抑癌活性的一种新的分子机制。靶向RUNX3通路的有效治疗可能通过抑制EMT来帮助控制胃癌细胞的侵袭和转移。
