High expression of CD44v9 and xCT in chemoresistant hepatocellular carcinoma: Potential targets by sulfasalazine

摘要

CD44v9 is expressed in cancer stem cells (CSC) and stabilizes the glutamate‐cystine transporter xCT on the cytoplasmic membrane, thereby decreasing intracellular levels of reactive oxygen species (ROS). This mechanism confers ROS resistance to CSC and CD44v9‐expressing cancer cells. The aims of the present study were to assess: (i) expression status of CD44v9 and xCT in hepatocellular carcinoma (HCC) tissues, including those derived from patients treated with hepatic arterial infusion chemoembolization (HAIC) therapy with cisplatin (CDDP); and (ii) whether combination of CDDP with sulfasalazine (SASP), an inhibitor of xCT, was more effective on tumor cells than CDDP alone by inducing style="fixed-case">ROS‐mediated apoptosis. Twenty non‐pretreated style="fixed-case">HCC tissues and 7 style="fixed-case">HCC tissues administered style="fixed-case">HAIC therapy with style="fixed-case">CDDP before surgical resection were subjected to immunohistochemistry analysis of style="fixed-case">CD44v9 and style="fixed-case">xCT expression. Human style="fixed-case">HCC cell lines style="fixed-case">HAK‐1A and style="fixed-case">HAK‐1B were used in this study; the latter was also used for xenograft experiments in nude mice to assess in vivo efficacy of combination treatment. style="fixed-case">CD44v9 positivity was significantly higher in style="fixed-case">HAIC‐treated tissues (5/7) than in non‐pretreated tissues (2/30), suggesting the involvement of style="fixed-case">CD44v9 in the resistance to style="fixed-case">HAIC. style="fixed-case">xCT was significantly expressed in poorly differentiated style="fixed-case">HCC tissues. Combination treatment effectively killed the style="fixed-case">CD44v9‐harboring style="fixed-case">HAK‐1B cells through style="fixed-case">ROS‐mediated apoptosis and significantly decreased xenografted tumor growth. In conclusion, the style="fixed-case">xCT inhibitor style="fixed-case">SASP augmented style="fixed-case">ROS‐mediated apoptosis in style="fixed-case">CDDP‐treated style="fixed-case">HCC cells, in which the style="fixed-case">CD44v9‐ style="fixed-case">xCT system functioned. As style="fixed-case">CD44v9 is typically expressed in style="fixed-case">HAIC‐resistant style="fixed-case">HCC cells, combination treatment with style="fixed-case">SASP with style="fixed-case">CDDP may overcome such drug resistance.