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

Research Paper

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

Xu Lu1*, Chao Yang1*, Yuanchang Hu1 *, Jian Xu2, Chengyu Shi1, Jianhua Rao1, Weixin Yu2✉, Feng Cheng1✉

1. 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.
2. Department of General Surgery, Changzhou Jintan District People's Hospital; Changzhou 213200, Jiangsu Province, China.
*These authors contributed equally to this work.

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Citation:
Lu X, Yang C, Hu Y, Xu J, Shi C, Rao J, Yu W, Cheng F. Upregulation of miR-1254 promotes Hepatocellular Carcinoma Cell Proliferation, Migration, and Invasion via Inactivation of the Hippo-YAP signaling pathway by decreasing PAX5. J Cancer 2021; 12(3):771-789. doi:10.7150/jca.49680. Available from https://www.jcancer.org/v12p0771.htm

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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 in vitro. 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 in vitro and in vivo. This miRNA might be a therapeutic target for HCC.

Keywords: miR-1254, PAX5, Hippo signaling pathway, Progression, Metastasis, HCC