title: MEK1 signaling promotes self-renewal and tumorigenicity of liver cancer stem cells via maintaining SIRT1 protein stabilization.
abstract: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death. This high mortality has been commonly attributed to the presence of residual cancer stem cells (CSCs). Meanwhile, MEK1 signaling is regarded as a key molecular in HCC maintenance and development. However, nobody has figured out the particular mechanisms that how MEK1 signaling regulates liver CSCs self-renewal. In this study, we show that inhibition or depletion of MEK1 can significantly decrease liver CSCs self-renewal and tumor growth both in vitro and vivo conditions. Furthermore, we demonstrate that MEK1 signaling promotes liver CSCs self-renewal and tumorigenicity by maintaining SIRT1 level. Mechanistically, MEK1 signaling keeps SIRT1 protein stabilization through activating SIRT1 ubiquitination, which inhibits proteasomal degradation. Clinical analysis shows that patients co-expression of MEK1 and SIRT1 are associated with poor survival. Our finding indicates that MEK1-SIRT1 can act as a novel diagnostic biomarker and inhibition of MEK1 may be a viable therapeutic option for targeting liver CSCs treatment.
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Jiamin
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Chungang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Limei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Shan
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Shen
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D000066673:Cell Self Renewal; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D055550:Protein Stability; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000737:chemistry* / Q000378:metabolism; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: MEK1 signaling; SIRT1; cancer stem cells (CSCs); hepatocellular carcinoma (HCC); proteasome degradation