Maoa Rurong, Zou Fangyuan, Yang Liyan, Lin Shengchao, Li Yueqi, Ma Mingxing, Yin Peihao, Liang Xin, Liu Jianwen
Int J Biochem Cell Biol. 2015 Dec;69:153-61. doi: 10.1016/j.biocel.2015.10.008.
MiR-139-5p down-regulation has frequently been implicated in colorectal carcinoma. However, there is little known about its biological function between inflammation and cancer in vivo. Here, a transgenic murine model of colorectal carcinoma was used to investigate pathogenetic role of miR-139-5p in colitis and colitis-associated tumorigenesis. We showed that miR-139-5p knockout mice were higher sensitive to DSS-induced colitis and enhanced formation of intestinal neoplasia was observed when mice were exposed to AOM/DSS treatment. MiR-139-5p knockout mice exhibited an increased expression of genes involved in Wnt pathway. Such genes are closely associated with cell proliferation and differentiation, promoting the β-catenin nuclear accumulation. Furthermore, biochemical studies in HCT-116 cells revealed that the over-expression of miR-139-5p inhibited the crosstalk between PI3K/AKT and Wnt pathway mediated by IGF-1R. Collectively, these findings indicate that miR-139-5p plays a crucial role in the development and progression of colitis-associated tumorigenesis and suggest that miR-139-5p may serve as a potential therapeutic target for the treatment of colitis-associated cancer in the future.
MiR-139-5p表达下调常与结直肠癌相关。然而，其在体内炎症与癌症之间的生物学功能却鲜为人知。在此，利用一种结直肠癌转基因小鼠模型来研究miR-139-5p在结肠炎及结肠炎相关肿瘤发生中的致病作用。我们发现，miR-139-5p基因敲除小鼠对右旋葡聚糖硫酸钠（DSS）诱导的结肠炎更为敏感，且当小鼠接受氧化偶氮甲烷（AOM）/DSS处理时，肠道肿瘤形成增加。miR-139-5p基因敲除小鼠中参与Wnt信号通路的基因表达增加。这些基因与细胞增殖和分化密切相关，促进β-连环蛋白核内积累。此外，对HCT-116细胞的生化研究表明，miR-139-5p的过表达抑制了由胰岛素样生长因子-1受体（IGF-1R）介导的PI3K/AKT与Wnt信号通路之间的相互作用。总体而言，这些发现表明miR-139-5p在结肠炎相关肿瘤发生的发展和进程中起关键作用，并提示miR-139-5p未来可能成为治疗结肠炎相关癌症的潜在治疗靶点。
