CD44 variant-dependent redox status regulation in liver fluke-associated cholangiocarcinoma: a target for CCA treatment

Summary

CD44 expression, especially the variant isoforms (CD44v) of this major cancer stem cell (CSC) marker, contributes to reactive oxygen species (ROS) defense via stabilizing xCT (a cystine-glutamate transporter) and promoting glutathione (GSH) synthesis. This enhances cancer development and increases chemotherapy resistance. We investigate the role of CD44v in the regulation of the ROS defense system in cholangiocarcinoma (CCA). Immunohistochemical staining of CD44v and p38^MAPK (a major ROS target) expression in Opisthorchis viverrini (Ov)-induced hamster CCA tissues (at 60, 90, 120, 180 days) reveals a decreased phospho-p38^MAPK signal, whereas the CD44v signal was increased during bile duct transformation. CCA patients showed CD44v overexpression and negative-phospho-p38^MAPK patients a significantly shorter survival rate than the low CD44v signal and positive-phospho-p38^MAPK patients (p=0. 030). Knockdown of CD44 showed that xCT and GSH levels were decreased, leading to a high level of ROS. We examined xCT-targeted CD44v-CSCs therapy using sulfasalazine (SSZ). Glutathione decreased and ROS increased after the treatment, leading to inhibition of cell proliferation and induction of cell death. Thus, the accumulation of CD44v leads to the suppression of p38^MAPK in transforming bile duct cells. The redox status regulation of CCA cells depends on the expression of CD44v to contribute the xCT function and is a link to the poor prognosis of patients. Thus, an xCT inhibitor could inhibit cell growth and activate cell death. This suggests that an xCT-targeting drug may improve CCA therapy by sensitization to the available drug, e.g. gemcitabine, by blocking the mechanism of the cell's ROS defensive system.

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