Li Qingguo, Liang Xin, Wang Yuwei, Meng Xianke, Xu Ye, Cai Sanjun, Wang Zhimin, Liu Jianwen, Cai Guoxiang
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Sci Rep. 2016 May 31;6:27157. doi: 10.1038/srep27157.
MicroRNAs (miRNAs) are important regulators involved in various cancers, including colorectal cancer (CRC). The functions and mechanisms of the miRNAs involved in CRC progress and metastasis are largely unknown. In this study, miRNA microarray analysis was performed to screen crucial miRNAs involved in CRC progress, and miR-139-5p was chosen for further study. The functional roles of miR-139-5p in colon cancer were demonstrated by CCK-8 proliferation assay, cell invasion and migration, cell apoptosis and in a KO mouse study. miR-139-5p expression was significantly decreased in cancer tissues compared to normal tissues. The miR-139-5p expression level was associated with tumour stage (P < 0.01). Function studies revealed that miR-139-5p was significantly correlated with the metastasis potential and drug resistance of colon cancer cells by affecting the epithelial-mesenchymal transition (EMT). Then, we identified BCL2 as a direct target of miR-139-5p cells in vitro. The patient samples and KO mice model showed that BCL2 expression was inversely correlated with the expression of miR-139-5p. In conclusion, we found that miR-139-5p targeted the BCL2 pathway to reduce tumour metastasis and drug sensitivity in CRC. This axis provided insight into the mechanism underlying miRNA regulation of CRC metastasis and a novel therapeutic target for CRC therapy.
微小RNA(miRNA)是参与包括结直肠癌(CRC)在内的各种癌症的重要调节因子。参与CRC进展和转移的miRNA的功能和机制在很大程度上尚不清楚。在本研究中,进行了miRNA微阵列分析以筛选参与CRC进展的关键miRNA,并选择miR-139-5p进行进一步研究。通过CCK-8增殖试验、细胞侵袭和迁移、细胞凋亡以及敲除小鼠研究,证明了miR-139-5p在结肠癌中的功能作用。与正常组织相比,癌组织中miR-139-5p表达显著降低。miR-139-5p表达水平与肿瘤分期相关(P < 0.01)。功能研究表明,miR-139-5p通过影响上皮-间质转化(EMT)与结肠癌细胞的转移潜能和耐药性显著相关。然后,我们在体外鉴定出BCL2是miR-139-5p细胞的直接靶点。患者样本和敲除小鼠模型表明,BCL2表达与miR-139-5p表达呈负相关。总之,我们发现miR-139-5p靶向BCL2通路以降低CRC中的肿瘤转移和药物敏感性。该轴为miRNA调节CRC转移的机制提供了见解,并为CRC治疗提供了新的治疗靶点。