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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.

cancer science

CD 44 variant 9 is a potential biomarker of tumor initiating cells predicting survival outcome in hepatitis C virus‐positive patients with resected hepatocellular carcinoma