miR-424-5p represses the metastasis and invasion of intrahepatic cholangiocarcinoma by targeting ARK5
miR-424-5p represses the metastasis and invasion of intrahepatic cholangiocarcinoma by targeting ARK5
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miR-424-5p通过靶向ARK5抑制肝内胆管癌的转移和侵袭
DOI：
10.7150/ijbs.34113
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发表时间：
2019-01-01
影响因子：
9.2
通讯作者：
Zheng, Shusen
中科院分区：
文献类型：
--
作者：
Wu, Jingbang;Yang, Beng;Zheng, Shusen
MicroRNAs（miRNAs）在多种恶性肿瘤的发生、发展中发挥着重要作用。MiR-424- 5 p作为一种抑制因子参与多种肿瘤的增殖和转移。相反，miR-424- 5 p在某些肿瘤中会促进细胞增殖。然而，miR-424- 5 p在肝内胆管癌（intrahepatic cholangiocarcinoma，ICC）中的表达尚未见报道，其机制尚不清楚。在这里，我们发现miR-424- 5 p在ICC组织中与邻近的正常组织和ICC细胞相比经常下调。过表达miR-424- 5 p可显著抑制ICC细胞的侵袭和迁移。重要的是，发现miR-424- 5 p是ARK 5的抑制剂，通过结合ARK 5 mRNA的3 '-UTR，然后抑制mTOR磷酸化，从而解除ICC的上皮-间充质转化（EMT）。此外，发现ARK 5在ICC转移和调节EMT中起作用。ARK 5的敲低抑制ICC的侵袭和迁移，而过表达则产生相反的效果。此外，ARK 5的高表达也与不良预后相关。总之，我们的研究揭示了miR-424- 5 p在ICC细胞的侵袭、迁移和EMT进展中是至关重要的。靶向该通路可能是抑制ICC转移的新方法，恢复miR-424- 5 p表达可能是ICC治疗的有希望的策略。
MicroRNAs (miRNAs) have been validated to play prominent roles in the occurrence and development of many kinds of malignant cancer. MiR-424-5p has been reported to participate in various tumors proliferation and metastasis as a suppressor. On the contrary, miR-424-5p would promote cell proliferation in some tumors. However, the expression of miR-424-5p in intrahepatic cholangiocarcinoma (ICC) is rarely reported and its mechanism remains unclear. Here, we discover that miR-424-5p is frequently downregulated in ICC tissues compared with adjacent normal tissues and in ICC cells. Over-expression of miR-424-5p significantly inhibits the invasion and migration of ICC cells in vitro. Importantly, miR-424-5p is found to be a suppressor of ARK5, by binding to 3'-UTR of ARK5 mRNA and then inhibiting mTOR phosphorylated, thus deregulating epithelial-mesenchymal transition (EMT) of ICC. Furthermore, ARK5 is found to play a role in ICC metastasis and regulating EMT. Knockdown of ARK5 inhibits invasion and migration of ICC, while the over-expression gives an opposite effect. Besides, high-expression of ARK5 is also associated with poor prognosis. In conclusion, our study reveals that miR-424-5p is critical to the invasion, migration and EMT progression in ICC cells. Targeting the pathway described here may be a novel approach to inhibit metastasis of ICC and the restoration of miR-424-5p expression may be a promising strategy for ICC therapy.