Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India.
J Cell Biochem. 2018 Feb;119(2):2022-2035. doi: 10.1002/jcb.26365. Epub 2017 Sep 18.
microRNA-145 (miR-145) has been shown to act as a tumor suppressor in colorectal cancer but its role in the regulation of epithelial-mesenchymal transition (EMT) is unclear. Ectopic expression of miR-145 suppressed the proliferation, migration and invasion in SW480 but surprisingly enhanced these traits in its metastatic counterpart, SW620 cells, while, antimiR-145 reversed the effects of miR-145 in both of these human colorectal cancer cells. In SW480 and SW620 cells, SMAD-interacting protein 1 (SIP1), was identified as a target of miR-145, and its expression was suppressed both at mRNA and protein levels, and siRNA-SIP1 mimicked the effects of miR-145. Further, re-introduction of SIP1 alone or its co-expression with miR-145, rescued SW480 and SW620 cells from the effects of miR-145, indicating that the distinct functions of miR-145 might be mediated, in part, through SIP1. Since Wnt signaling plays an essential role in EMT in CRC progression, the effects of miR-145 on the expression of Wnt signaling intermediates and EMT markers were studied. Re-expression of miR-145 was found to downregulate the expression of CTNNB1, TCF4, CCND1, VIM, and SNAI, but, upregulated CDH1 expression in SW480 cells. On the other hand, miR-145 exhibited an oncogenic potential in SW620 cells by actuating Wnt signaling and the expression of EMT-relevant markers. These results strongly hint that the paradoxical functions of miR-145 in the regulation of proliferation, migration and invasion might be mediated through downregulation of SIP1, and differential tuning of Wnt signaling and EMT-mediators.
microRNA-145 (miR-145) 已被证明在结直肠癌中作为一种肿瘤抑制因子发挥作用，但它在调节上皮-间充质转化 (EMT) 中的作用尚不清楚。miR-145 的异位表达抑制了 SW480 的增殖、迁移和侵袭，但令人惊讶的是，它增强了其转移性对应物 SW620 细胞的这些特性，而 antimiR-145 则逆转了 miR-145 在这两种人结直肠癌细胞中的作用。在 SW480 和 SW620 细胞中，SMAD 相互作用蛋白 1 (SIP1) 被鉴定为 miR-145 的靶标，其表达在 mRNA 和蛋白水平均受到抑制，而 siRNA-SIP1 模拟了 miR-145 的作用。此外，单独引入 SIP1 或与 miR-145 共同表达，可使 SW480 和 SW620 细胞免受 miR-145 的影响，表明 miR-145 的不同功能可能部分通过 SIP1 介导。由于 Wnt 信号通路在结直肠癌进展中的 EMT 中起着至关重要的作用，因此研究了 miR-145 对 Wnt 信号通路中间产物和 EMT 标志物表达的影响。发现 miR-145 的重新表达可下调 CTNNB1、TCF4、CCND1、VIM 和 SNAI 的表达，但上调 SW480 细胞中 CDH1 的表达。另一方面，miR-145 通过激活 Wnt 信号通路和 EMT 相关标志物的表达，在 SW620 细胞中表现出致癌潜能。这些结果强烈暗示，miR-145 在调节增殖、迁移和侵袭中的矛盾功能可能是通过下调 SIP1 以及差异调节 Wnt 信号通路和 EMT 介质来介导的。
