Open AccessCD 44 variant 9 is a potential biomarker of tumor initiating cells predicting survival outcome in hepatitis C virus‐positive patients with resected hepatocellular carcinoma
Author(s) -
Kakehashi Anna,
Ishii Naomi,
Sugihara Eiji,
Gi Min,
Saya Hideyuki,
Wanibuchi Hideki
Publication year - 2016
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12908
Subject(s) - hepatocellular carcinoma , hepatitis c virus , biomarker , cancer research , immunohistochemistry , oxidative stress , population , medicine , alkaline phosphatase , cancer stem cell , pathology , cancer , biology , immunology , virus , enzyme , biochemistry , environmental health
This study investigated whether the expression of CD 44 variant 9 ( CD 44v9) might be a functional marker of tumor‐initiating stem‐like cells in primary hepatocellular carcinomas ( HCC s) 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 CD 44v9 was validated immunohistochemically in all HCC s, followed by comparative proteome, survival, and clinicopathological analyses. CD 44 variant 8–‐10 was further evaluated in diethylnitrosamine‐induced HCC s of C57Bl/6J mice. Focally localized CD 44v + cells with a membranous staining pattern were detected in human HCV + and mouse HCC s. CD 44v9 + cells of HCC s were predominantly negative for Ki67 and P‐p38, indicating decrease of cell proliferation in the CD 44v9 + 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. CD 44v9 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 HCC s, and high alkaline phosphatase levels compared with patients with negative expression. CD 44v9 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.