Li Bo, Xie Zhongshi, Li Bai
Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, People's Republic of China.
Department of Colorectal and Anal Surgery, the First Hospital of Jilin University, Changchun, 130021, People's Republic of China.
Tumour Biol. 2016 Aug;37(8):10075-84. doi: 10.1007/s13277-016-4888-2. Epub 2016 Jan 28.
Accumulating evidence showed that microRNA-152 (miR-152) was frequently downregulated, and functioned as tumor suppressor in many cancers, but little is known about its biological role and intrinsic regulatory mechanisms in colorectal cancer (CRC). Here, we explored the potential role of miR-152 in CRC and the possible molecular mechanisms. Our results proved that miR-152 expression was downregulated in CRC cell lines and tissue samples, and its expression was inversely correlated with advanced tumor-node-metastasis (TNM) stage (P < 0.01) and lymph node metastasis (P < 0.01). Function assays demonstrated that restoring the expression of miR-152 in CRC cells dramatically reduced the cell proliferation and cell migration and invasion and promoted apoptosis and caspase-3 activity in vitro, as well as suppressed tumor growth in vivo. Mechanistic investigations defined phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) as a direct and functional downstream target of miR-152. In addition, we also found that PIK3R3 expression was upregulated and was inversely correlated with miR-152 expression in clinical CRC tissues. Downregulation of PIK3R3 mimicked the tumor-suppressive effects of miR-152 overexpression in CRC cells. Taken together, these results elucidated the function of miR-152 in CRC progression and suggested that miR-152 might function as tumor suppressor in CRC by targeting PIK3R3.
越来越多的证据表明，微小RNA-152（miR-152）经常下调，并在许多癌症中发挥肿瘤抑制作用，但关于其在结直肠癌（CRC）中的生物学作用和内在调控机制知之甚少。在此，我们探讨了miR-152在CRC中的潜在作用及其可能的分子机制。我们的结果证明，miR-152在CRC细胞系和组织样本中的表达下调，其表达与晚期肿瘤-淋巴结-转移（TNM）分期（P<0.01）和淋巴结转移（P<0.01）呈负相关。功能分析表明，恢复CRC细胞中miR-152的表达可显著降低细胞增殖、细胞迁移和侵袭，并促进体外细胞凋亡和半胱天冬酶-3活性，以及抑制体内肿瘤生长。机制研究确定磷酸肌醇-3-激酶调节亚基3（PIK3R3）是miR-152的直接和功能性下游靶点。此外，我们还发现PIK3R3在临床CRC组织中的表达上调，且与miR-152表达呈负相关。PIK3R3的下调模拟了miR-152过表达对CRC细胞的肿瘤抑制作用。综上所述，这些结果阐明了miR-152在CRC进展中的作用，并表明miR-152可能通过靶向PIK3R3在CRC中发挥肿瘤抑制作用。
