title: High ubiquitous mitochondrial creatine kinase expression in hepatocellular carcinoma denotes a poor prognosis with highly malignant potential.
abstract: We previously reported the increased serum mitochondrial creatine kinase (MtCK) activity in patients with hepatocellular carcinoma (HCC), mostly due to the increase in ubiquitous MtCK (uMtCK), and high uMtCK mRNA expression in HCC cell lines. We explored the mechanism(s) and the relevance of high uMtCK expression in HCC. In hepatitis C virus core gene transgenic mice, known to lose mitochondrial integrity in liver and subsequently develop HCC, uMtCK mRNA and protein levels were increased in HCC tissues but not in non-tumorous liver tissues. Transient overexpression of ankyrin repeat and suppressor of cytokine signaling box protein 9 (ASB9) reduced uMtCK protein levels in HCC cells, suggesting that increased uMtCK levels in HCC cells may be caused by increased gene expression and decreased protein degradation due to reduced ASB9 expression. The reduction of uMtCK expression by siRNA led to increased cell death, and reduced proliferation, migration and invasion in HCC cell lines. Then, consecutive 105 HCC patients, who underwent radiofrequency ablation with curative intent, were enrolled to analyze their prognosis. The patients with serum MtCK activity >19.4 U/L prior to the treatment had significantly shorter survival time than those with serum MtCK activity ≤ 19.4 U/L, where higher serum MtCK activity was retained as an independent risk for HCC-related death on multivariate analysis. In conclusion, high uMtCK expression in HCC may be caused by hepatocarcinogenesis per se but not by loss of mitochondrial integrity, of which ASB9 could be a negative regulator, and associated with highly malignant potential to suggest a poor prognosis.
authors.affiliation: Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Baasanjav
authors.initials: B
authors.lastname: Uranbileg
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Enooku
authors.forename: Yoko
authors.initials: Y
authors.lastname: Soroida
authors.forename: Ryunosuke
authors.initials: R
authors.lastname: Ohkawa
authors.forename: Yotaro
authors.initials: Y
authors.lastname: Kudo
authors.forename: Hayato
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Tateishi
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Yoshida
authors.forename: Seiko
authors.initials: S
authors.lastname: Shinzawa
authors.forename: Kyoji
authors.initials: K
authors.lastname: Moriya
authors.forename: Natsuko
authors.initials: N
authors.lastname: Ohtomo
authors.forename: Takako
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Inoue
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tomiya
authors.forename: Soichi
authors.initials: S
authors.lastname: Kojima
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Matsuura
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yatomi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D052281:Creatine Kinase, Mitochondrial Form / Q000378:metabolism*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008113:Liver Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D011379:Prognosis; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: C540562:ASB9 protein, human; D034741:RNA, Small Interfering; D050826:Suppressor of Cytokine Signaling Proteins; D052281:Creatine Kinase, Mitochondrial Form
keywords: ankyrin repeat and suppressor of cytokine signaling box protein 9; hepatocellular carcinoma; prognostic factor; ubiquitous mitochondrial creatine kinase