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Theranostics 2020; 10(12):5322-5340. doi:10.7150/thno.42371 This issue Cite

Research Paper

PEX5, a novel target of microRNA-31-5p, increases radioresistance in hepatocellular carcinoma by activating Wnt/β-catenin signaling and homologous recombination

Jie Wen¹, Kai Xiong¹, Abudureyimujiang Aili¹, Hao Wang¹, Yuequan Zhu², Zhengquan Yu³, Xueyan Yao⁴, Ping Jiang¹, Lixiang Xue^1✉, Junjie Wang^1✉

1. Peking University Third Hospital, Beijing 100191, China.
2. Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China.
3. College of Biological Sciences, China Agricultural University, Beijing 100193, China.
4. Peking University People's Hospital, Beijing 100044, China.

✉ Corresponding authors: Lixiang Xue, Center of Basic Medical Research, Department of Radiation Oncology, Peking University Third Hospital, Beijing 100191, China. Email: lixiangxuepku.edu.cn. Junjie Wang, Department of Radiation Oncology, Peking University Third Hospital, Beijing 100191, China. Email: junjiewang_educn More

Abstract

Rationale: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, with high recurrence and metastasis rates. Although radiation is an effective treatment for tumors, it is often limited by intrinsic radioresistance in HCC. The contributions of dysregulated microRNAs, including miR-31-5p, to HCC progression have been recently reported. However, the role of miR-31-5p in the radiation response of HCC is unknown. In this study, we aimed to investigate the impact of miR-31-5p on HCC radiosensitivity.

Methods: miR-31-5p expression in HCC tissues, paired adjacent tissues, and HCC cell lines was measured using quantitative real-time polymerase chain reaction and in situ hybridization. Bioinformatic analyses, gain- and loss-of-function experiments, and luciferase reporter assays were performed to validate peroxisomal biogenesis factor 5 (PEX5) as a direct target of miR-31-5p. The biofunctions of PEX5 and miR-31-5p in HCC were determined by Transwell, wound-healing, and Cell Counting Kit-8 (CCK8) assays. A colony formation assay was used to evaluate the radiosensitivity of HCC cells. The interaction among PEX5, β-catenin, Rac1, and JNK-2 was confirmed by coimmunoprecipitation. A xenograft tumor model was established to validate the effects of miR-31-5p and PEX5 on HCC progression and radiosensitivity in vivo.

Results: Low expression of miR-31-5p in HCC specimens, as observed in this study, predicted a poor clinical outcome. However, the expression pattern of PEX5, as a direct target of miR-31-5p, was opposite that of miR-31-5p, and high PEX5 expression indicated poor prognosis in HCC patients. Ectopic expression of PEX5 increased the proliferation, migration, and invasion abilities and enhanced the radioresistance of HCC cells in vitro and in vivo; however, these phenotypes were inhibited by miR-31-5p. Mechanistically, PEX5 stabilized cytoplasmic β-catenin and facilitated β-catenin nuclear translocation to activate Wnt/β-catenin signaling. Moreover, upon radiation exposure, PEX5 reduced excessive reactive oxygen species (ROS) accumulation and activated the homologous recombination (HR) pathway, which protected HCC cells from radiation-induced damage.

Conclusions: Our findings demonstrated a novel role for PEX5 as a miR-31-5p target and a mediator of the Wnt/β-catenin signaling and HR pathways, providing new insights into studying HCC radiation responses and implicating PEX5 and miR-31-5p as potential therapeutic targets in HCC.

Keywords: miR-31-5p, PEX5, β-catenin, Homologous Recombination, Radiosensitivity

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