title: Mus81 knockdown improves chemosensitivity of hepatocellular carcinoma cells by inducing S-phase arrest and promoting apoptosis through CHK1 pathway.
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.
authors.affiliation: Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital /Fourth Affiliated Hospital of Jinan University, Tongfu Roud 396, Guangzhou, 510220, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital /Fourth Affiliated Hospital of Jinan University, Tongfu Roud 396, Guangzhou, 510220, China.
authors.forename: Wei-Jia
authors.initials: WJ
authors.lastname: Chen
authors.affiliation: Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital /Fourth Affiliated Hospital of Jinan University, Tongfu Roud 396, Guangzhou, 510220, China.
authors.forename: Lun
authors.initials: L
authors.lastname: Yan
authors.affiliation: Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital /Fourth Affiliated Hospital of Jinan University, Tongfu Roud 396, Guangzhou, 510220, China.
authors.forename: Guo-Qian
authors.initials: GQ
authors.lastname: Tan
authors.affiliation: Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital /Fourth Affiliated Hospital of Jinan University, Tongfu Roud 396, Guangzhou, 510220, China.
authors.forename: Wei-Tao
authors.initials: WT
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital /Fourth Affiliated Hospital of Jinan University, Tongfu Roud 396, Guangzhou, 510220, China.
authors.forename: Xuan-Jin
authors.initials: XJ
authors.lastname: Zhu
authors.affiliation: Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital /Fourth Affiliated Hospital of Jinan University, Tongfu Roud 396, Guangzhou, 510220, China.
authors.forename: Xiao-Chuan
authors.initials: XC
authors.lastname: Ge
authors.affiliation: Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital /Fourth Affiliated Hospital of Jinan University, Tongfu Roud 396, Guangzhou, 510220, China.
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, Guangzhou Red Cross Hospital /Fourth Affiliated Hospital of Jinan University, Tongfu Roud 396, Guangzhou, 510220, China.
authors.forename: Bai-Lin
authors.initials: BL
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004720:Endonucleases / Q000235:genetics*; D015251:Epirubicin / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics*; D015398:Signal Transduction; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D015251:Epirubicin; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D004720:Endonucleases; C498773:Mus81 protein, mouse
keywords: Apoptosis; CHK1; Mus81; cell cycle arrest; chemosensitivity; hepatocellular carcinoma