CD44 variant 9 is a potential biomarker of tumor initiating cells predicting survival outcome in hepatitis C virus‐positive patients with resected hepatocellular carcinoma

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.