title: Mitogen-activated protein kinase kinase 3 induces cell cycle arrest via p38 activation mediated Bmi-1 downregulation in hepatocellular carcinoma.
abstract: The underlying molecular pathogenesis of hepatocellular carcinoma (HCC) remains poorly understood. Mitogen-activated protein kinase kinase 3 (MKK3), has been reported as a novel tumor suppressor in breast cancer. However, its potential suppressive role in HCC has not been evaluated. In the current study, the biologic functions of MKK3 in HCC were investigated and a previously unreported cell cycle regulation mechanism was observed. MKK3 overexpression suppressed HepG2 and PLC‑PRF‑5 cell proliferation and induced cell cycle arrest in the two cell lines. In addition, MKK3 overexpression upregulated the cyclin-dependent kinase inhibitors, p16 INK4A and p15 INK4B in HCC cells. Their negative regulator, Bim‑1, was downregulated following MKK3 overexpression. Moreover, MKK3 activated p38 in HCC cells and SB203580, a p38 inhibitor, reversed the tumor suppressive effect of MKK3. In conclusion, the results identify MKK3 as a tumor suppressor and highlighted the significance of p38 pathway aberration in HCC.
authors.affiliation: Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin 300052, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin 300052, P.R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin 300052, P.R. China.
authors.forename: Shuzhi
authors.initials: S
authors.lastname: Feng
authors.affiliation: Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin 300052, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Lei
authors.affiliation: Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin 300052, P.R. China.
authors.forename: Jianli
authors.initials: J
authors.lastname: Tian
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000473:pathology*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology; D048371:MAP Kinase Kinase 3 / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C069077:BMI1 protein, human; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D063150:Polycomb Repressive Complex 1; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human