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miR-1254的上调通过降低PAX5使Hippo-YAP信号通路失活,从而促进肝癌细胞的增殖、迁移和侵袭。

Upregulation of miR-1254 promotes Hepatocellular Carcinoma Cell Proliferation, Migration, and Invasion via Inactivation of the Hippo-YAP signaling pathway by decreasing PAX5.

作者信息

Lu Xu, Yang Chao, Hu Yuanchang, Xu Jian, Shi Chengyu, Rao Jianhua, Yu Weixin, Cheng Feng

机构信息

Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation; Nanjing 210029, Jiangsu Province, China.

Department of General Surgery, Changzhou Jintan District People's Hospital; Changzhou 213200, Jiangsu Province, China.

出版信息

J Cancer. 2021 Jan 1;12(3):771-789. doi: 10.7150/jca.49680. eCollection 2021.

Abstract

Increasing evidence suggests that microRNAs (miRNAs) affect the progression of hepatocellular carcinoma (HCC). However, the exact function and mechanism of miR-1254 in HCC remains unclear. This study explored the effects of miR-1254 on the biological behavior of HCC cells and determined the underlying mechanism. RT-qPCR was used to detect the expression of miR-1254. Gain- or loss-of-function assays determined if miR-1254 affected the biological function of HCC cells . Dual luciferase reporter assays confirmed the target gene of miR-1254. Tumor xenografts in mice were used to explore the effects of miR-1254 on tumorigenesis and metastasis of HCC. miR-1254 was upregulated in HCC tissues and cell lines and linked to larger tumor size, aggressive vascular invasion and higher Edmondson grade. Lentiviral-based overexpression and knockdown experiments indicated that miR-1254 promoted proliferation, migration, invasion, and the epithelial-mesenchymal transition of HCC cells. The paired box gene 5 (PAX5) was downregulated in HCC tissues, negatively correlated with miR-1254 expression, and confirmed to be a direct target of miR-1254. Restoration of PAX5 reversed the effects of miR-1254 on the biological behavior of HCC cells. Advanced mechanism studies suggested that PAX5 might mediate miR-1254 by regulating the Hippo signaling pathway. Tumor xenografts in mice confirmed that miR-1254 promoted tumorigenesis and metastasis, and led to poor survival. In conclusion, miR-1254 promoted proliferation, migration, and invasion of HCC cells via decreasing Hippo signaling through targeting PAX5 and . This miRNA might be a therapeutic target for HCC.

摘要

越来越多的证据表明,微小RNA(miRNA)会影响肝细胞癌(HCC)的进展。然而,miR-1254在HCC中的确切功能和机制仍不清楚。本研究探讨了miR-1254对HCC细胞生物学行为的影响,并确定了其潜在机制。采用RT-qPCR检测miR-1254的表达。功能获得或缺失实验确定miR-1254是否影响HCC细胞的生物学功能。双荧光素酶报告基因实验证实了miR-1254的靶基因。利用小鼠肿瘤异种移植模型探讨miR-1254对HCC肿瘤发生和转移的影响。miR-1254在HCC组织和细胞系中上调,且与更大的肿瘤大小、侵袭性血管侵犯和更高的Edmondson分级相关。基于慢病毒的过表达和敲低实验表明,miR-1254促进HCC细胞的增殖、迁移、侵袭以及上皮-间质转化。配对盒基因5(PAX5)在HCC组织中表达下调,与miR-1254表达呈负相关,并被证实是miR-1254的直接靶标。恢复PAX5可逆转miR-1254对HCC细胞生物学行为的影响。进一步的机制研究表明,PAX5可能通过调节Hippo信号通路介导miR-1254的作用。小鼠肿瘤异种移植模型证实,miR-1254促进肿瘤发生和转移,并导致生存率降低。总之,miR-1254通过靶向PAX5降低Hippo信号通路活性,从而促进HCC细胞的增殖、迁移和侵袭。这种miRNA可能是HCC的一个治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b7b7/7778534/d5336cbc01b8/jcav12p0771g001.jpg

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