Open AccessMus81 knockdown improves chemosensitivity of hepatocellular carcinoma cells by inducing S‐phase arrest and promoting apoptosis through CHK 1 pathway
Author(s) -
Wu Fan,
Chen WeiJia,
Yan Lun,
Tan GuoQian,
Li WeiTao,
Zhu XuanJin,
Ge XiaoChuan,
Liu JianWei,
Wang BaiLin
Publication year - 2016
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.588
Subject(s) - gene knockdown , apoptosis , cancer research , biology , cell cycle checkpoint , cell culture , small hairpin rna , cell cycle , microbiology and biotechnology , biochemistry , genetics
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 CHK 1 inhibition. The activation of CHK 1/ CDC 25A/ CDK 2 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 CHK 1. In addition, CHK 2 inhibition slightly raised CHK 1 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 CHK 1 pathway, suggesting Mus81 as a novel therapeutic target for HCC .