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Expression of  CD 44, especially the variant isoforms ( CD 44v) of this major cancer stem cell marker, contributes to reactive oxygen species ( ROS ) defense through stabilizing  xCT  (a cystine–glutamate transporter) and promoting glutathione synthesis. This enhances cancer development and increases chemotherapy resistance. We investigate the role of  CD 44v in the regulation of the  ROS  defense system in cholangiocarcinoma ( CCA ). Immunohistochemical staining of  CD 44v and p38  MAPK   (a major  ROS  target) expression in  Opisthorchis viverrini ‐induced hamster  CCA  tissues (at 60, 90, 120, and 180 days) reveals a decreased phospho‐p38  MAPK   signal, whereas the  CD 44v signal was increased during bile duct transformation. Patients with  CCA  showed  CD 44v overexpression and negative‐phospho‐p38  MAPK   patients a significantly shorter survival rate than the low  CD 44v signal and positive‐phospho‐p38  MAPK   patients ( P =  0.030). Knockdown of  CD 44 showed that  xCT  and glutathione levels were decreased, leading to a high level of  ROS . We examined  xCT ‐targeted  CD 44v cancer stem cell therapy using sulfasalazine. Glutathione decreased and  ROS  increased after the treatment, leading to inhibition of cell proliferation and induction of cell death. Thus, the accumulation of  CD 44v leads to the suppression of p38  MAPK   in transforming bile duct cells. The redox status regulation of  CCA  cells depends on the expression of  CD 44v 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.

CD44 variant‐dependent redox status regulation in liver fluke‐associated cholangiocarcinoma: A target for cholangiocarcinoma treatment