Lu Xu, Yang Chao, Hu Yuanchang, Xu Jian, Shi Chengyu, Rao Jianhua, Yu Weixin, Cheng Feng
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.
J Cancer. 2021 Jan 1;12(3):771-789. doi: 10.7150/jca.49680. eCollection 2021.
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.
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。
