摘要
microRNA-374a (miR-374a) exhibits oncogenic functions in various tumor types. Here we report that miR-374a suppresses proliferation, invasion, migration and intrahepatic metastasis in colon adenocarcinoma cell lines HCT116 and SW620. Notably, we detected that PI3K/AKT signaling and its downstream cell cycle factors including c-Myc, cyclin D1 (CCND1), CDK4 and epithelial-mesenchymal transition (EMT)-related genes including ZEB1, N-cadherin, Vimentin, Slug, and Snail were all signifcantly downregulated after miR-374a overexpression. Conversely, cell cycle inhibitors p21 and p27 were upregulated. Expression of E-cadherin was only decreased in HCT116, without any obvious differences observed in SW620 cells. Furthermore, luciferase reporter assays confrmed that miR-374a could directly reduce CCND1. Interestingly, when CCND1 was silenced or overexpressed, levels of pPI3K, pAkt as well as cell cycle and EMT genes were respectively downregulated or upregulated. We examined miR-374a levels by in situ hybridization and its correlation with CCND1 expression in CRC tumor tissues. High miR-374a expression with low level of CCND1 was protective factor in CRC. Together these fndings indicate that miR-374a inactivates the PI3K/AKT axis by inhibiting CCND1, suppressing of colon cancer progression.
Keywords: miR-374a, CCND1, CRC, PI3K/AKT pathway, EMT
研究背景
结直肠癌是最常见的消化道肿瘤，其发生率和死亡率不断提高。研究发现，microRNA下调可能诱导结直肠癌的发病。miR-374a可以促进或抑制人癌症的发展，一些学者认为，miR-374a可以诱导乳腺癌的EMT过程，促进胃癌细胞的增殖，而在结直肠癌中miR-374a下调，且可减少患结直肠癌病人的死亡率。本文旨在深入探究中结直肠癌miR-374a的生物学功能和可能参与的通路以及其机制。
研究思路
主要研究结果
1. 体内和体外，过表达mir-374a均能抑制结直肠癌细胞的增殖、迁移、侵袭和肝内转移
2. mir-374a使PI3K/AKT通路失活且使影响下游的细胞周期和EMT因子
3. mir-374a直接结合在CCDN1的3’UTR上
4. CCND1可以反馈调节PI3K/AKT通路
5. 结肠癌组织中mir-374a与CCDN1间的关系及其临床意义
伯信合作技术：CCND1过表达载体构建
参考文献
Chen Y, Jiang J, Zhao M et al. microRNA-374a suppresses colon cancer progression by directly reducing CCND1 to inactivatethe PI3K/AKT pathway.
Oncotarget. 2016; 7(27):41306-41319.
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