title: CD44 variant 9 is a potential biomarker of tumor initiating cells predicting survival outcome in hepatitis C virus-positive patients with resected hepatocellular carcinoma.
abstract: This study investigated whether the expression of CD44 variant 9 (CD44v9) might be a functional marker of tumor-initiating stem-like cells in primary hepatocellular carcinomas (HCCs) of hepatitis C virus (HCV)(+) patients and provide an indicator of patient survival, as well as associated mechanisms. A total of 90 HCV(+) HCC patients who underwent surgery from 2006 to 2011 were enrolled and monitored for 2-8 years. Expression of CD44v9 was validated immunohistochemically in all HCCs, followed by comparative proteome, survival, and clinicopathological analyses. CD44 variant 8--10 was further evaluated in diethylnitrosamine-induced HCCs of C57Bl/6J mice. Focally localized CD44v(+) cells with a membranous staining pattern were detected in human HCV(+) and mouse HCCs. CD44v9(+) cells of HCCs were predominantly negative for Ki67 and P-p38, indicating decrease of cell proliferation in the CD44v9(+) tumor cell population, likely to be related to suppression of intracellular oxidative stress due to activation of Nrf2-mediated signaling, DNA repair, and inhibition of xenobiotic metabolism. CD44v9 IHC evaluation in 90 HCV(+) HCC cases revealed that positive expression was significantly associated with poor overall and recurrence-free survival, a younger age, poor histological differentiation of HCCs, and high alkaline phosphatase levels compared with patients with negative expression. CD44v9 is concluded to be a potential biomarker of tumor-initiating stem-like cells and a prognostic marker in HCV(+) HCC patients associated with Nrf2-mediated resistance to oxidative stress.
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Anna
authors.initials: A
authors.lastname: Kakehashi
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Sugihara
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Min
authors.initials: M
authors.lastname: Gi
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Wanibuchi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000601:surgery* / Q000821:virology*; D049109:Cell Proliferation; D004052:Diethylnitrosamine; D005260:Female; D016174:Hepacivirus / Q000302:isolation & purification*; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis / Q000378:metabolism*; D007150:Immunohistochemistry; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000601:surgery / Q000821:virology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D020543:Proteome / Q000032:analysis / Q000378:metabolism; D040901:Proteomics; D000071456:Sequestosome-1 Protein / Q000378:metabolism; D015398:Signal Transduction; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; C497483:CD44 protein, human; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D000072019:Kelch-Like ECH-Associated Protein 1; D019394:Ki-67 Antigen; D051267:NF-E2-Related Factor 2; D020543:Proteome; D000071456:Sequestosome-1 Protein; D004052:Diethylnitrosamine
keywords: Biomarker; CD44v9; TISC; hepatocellular carcinoma; oxidative stress