1. Mus81 knockdown improves chemosensitivity of hepatocellular carcinoma cells by inducing S-phase arrest and promoting apoptosis through CHK1 pathway
- Author
-
Jian-Wei Liu, Lun Yan, Xuan‐Jin Zhu, Guo-Qian Tan, Xiao‐Chuan Ge, Wei‐Tao Li, Wei-Jia Chen, Bai-Lin Wang, and Fan Wu
- Subjects
0301 basic medicine ,Cancer Research ,Apoptosis ,Small hairpin RNA ,Mice ,0302 clinical medicine ,Gene Knockdown Techniques ,RNA, Small Interfering ,Original Research ,Cancer Biology ,Mice, Knockout ,Gene knockdown ,Liver Neoplasms ,hepatocellular carcinoma ,Cell cycle ,Tumor Burden ,DNA-Binding Proteins ,chemosensitivity ,Oncology ,cell cycle arrest ,030220 oncology & carcinogenesis ,S Phase Cell Cycle Checkpoints ,Signal Transduction ,Carcinoma, Hepatocellular ,CHK1 ,Genetic Vectors ,Antineoplastic Agents ,Biology ,03 medical and health sciences ,Cell Line, Tumor ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,MTT assay ,Mus81 ,CHEK1 ,Protein Kinase Inhibitors ,Epirubicin ,Dose-Response Relationship, Drug ,Lentivirus ,Endonucleases ,Xenograft Model Antitumor Assays ,digestive system diseases ,Disease Models, Animal ,030104 developmental biology ,Cell culture ,Drug Resistance, Neoplasm ,Immunology ,Checkpoint Kinase 1 ,Cancer research ,Protein Kinases - Abstract
As a critical endonuclease in DNA repair, Mus81 is traditionally regarded as a tumor suppressor, but recently correlated with the sensitivity of mitomycin C and 5‐fluorouracil in colon cancer and breast cancer cells. However, its role in chemosensitivity of other human malignancies still remains unknown. This study therefore aims to investigate the effects of Mus81 knockdown on the chemosensitivity of hepatocellular carcinoma (HCC), a usually chemorefractory tumor, and explore the underlying mechanisms. Mus81 expression in HepG2 and Bel‐7402 HCC cell lines was depleted by lentivirus‐mediated short hairpin RNA and the elevated sensitivity of these Mus81‐inhibited HCC cells to therapeutic agents, especially to epirubicin (EPI), was evidenced by MTT assay and an HCC chemotherapy mouse model. Flow cytometric analysis also showed that Mus81 knockdown lead to an obvious S‐phase arrest and an elevated apoptosis in EPI‐treated HepG2 and Bel‐7402 cells, which could be rescued by CHK1 inhibition. The activation of CHK1/CDC25A/CDK2 pathway was also demonstrated in Mus81‐inhibited HepG2 cells and xenograft mouse tumors under EPI treatment. Meanwhile, the apoptosis of HepG2 cells in response to EPI was remarkably promoted by Mus81 knockdown through activating p53/Bax/Caspase‐3 pathway under the controlling of CHK1. In addition, CHK2 inhibition slightly raised CHK1 activity, thereby enhancing the S‐phase arrest and apoptosis induced by EPI in Mus81‐suppressed HCC cells. In conclusion, Mus81 knockdown improves the chemosensitivity of HCC cells by inducing S‐phase arrest and promoting apoptosis through CHK1 pathway, suggesting Mus81 as a novel therapeutic target for HCC.
- Published
- 2015