Open AccessCD44 variant‐dependent redox status regulation in liver fluke‐associated cholangiocarcinoma: A target for cholangiocarcinoma treatment
Author(s) -
Thanee Malinee,
Loilome Watcharin,
Techasen Anchalee,
Sugihara Eiji,
Okazaki Shogo,
Abe Shinya,
Ueda Shiho,
Masuko Takashi,
Namwat Nisana,
Khuntikeo Narong,
Titapun Attapol,
Pairojkul Chawalit,
Saya Hideyuki,
Yongvanit Puangrat
Publication year - 2016
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12967
Subject(s) - cd44 , glutathione , biology , cancer research , reactive oxygen species , cancer cell , cell growth , cancer stem cell , lgr5 , cancer , cell , stem cell , microbiology and biotechnology , biochemistry , genetics , enzyme
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.