“原癌基因”miR-17-92簇的新角色：抑制结直肠癌

　　

  2016年4月19日，韩家淮教授课题组在Cancer Letters 上发表题为:“ MicroRNA-17~92 inhibits colorectal cancer progression by targeting angiogenesis”的文章，揭示微小RNA抑制结肠癌新机制。

    一直以来，miR-17~92簇都被视为原癌基因，其在多种肿瘤组织中呈高表达，并和多种类型肿瘤的预后呈负相关。但是miR-17~92簇在结直肠癌发生发展中的作用如何尚无定论。

    为了回答这一问题，韩家淮课题组首先构建了在肠上皮细胞中特异性过表达miR-17~92簇的条件性转基因小鼠，然后通过AOM-DSS诱导结肠癌。通过对比miR-17~92簇转基因小鼠和野生型小鼠的肿瘤发生率、肿瘤直径等指标，发现过表达miR-17~92簇转基因小鼠的肿瘤直径明显小于野生型小鼠。

    并进一步通过体外实验揭示了相关的分子机制：miR-17~92簇通过抑制下游靶基因TGFBR2/HIF1α/VEGFA的表达，进而负调控肿瘤的血管生成，从而抑制肿瘤的生长速度。

    该研究发现了一个有趣的现象，所谓的“原癌基因”miR-17~92簇在结直癌的进展过程中并非真的起到促癌作用，反而抑制肿瘤生长。这也提示，如果临床上选择miR-17~92簇作为结肠癌的干预靶点需要更为审慎。

    该文章的第一作者为2013级博士生马华彬和博士后潘金水医生。
 
原文摘要：

MicroRNA-17~92 inhibits colorectal cancer progression by targeting angiogenesis

The miR-17~92 microRNA (miRNA) cluster host gene is upregulated in a broad spectrum of human cancers including colorectal cancer (CRC). Previous studies have shown that miR-17~92 promotes tumorigenesis and cancer angiogenesis in some tumor models. However, its role in the initiation and progression of CRC remains unknown. In this study, we found that transgenic mice overexpressing miR-17~92 specifically in epithelial cells of the small and large intestines exhibited decreased tumor size and tumor angiogenesis in azoxymethane and dextran sulfate sodium salt (AOM-DSS)-induced CRC model as compared to their littermates control. Further study showed that miR-17~92 inhibited the progression of CRC via suppressing tumor angiogenesis through targeting multiple tumor angiogenesis-inducing genes, TGFBR2, HIF1α, and VEGFA in vivo and in vitro. Collectively, we demonstrated that miR-17~92 suppressed tumor progression by inhibiting tumor angiogenesis in a genetically engineered mouse model, indicating the presence of cellular context-dependent pro- and anti-cancer effects of miR-17~92.