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首页> 外文期刊>Cancer science. >CD44 variant-dependent redox status regulation in liver fluke-associated cholangiocarcinoma: A target for cholangiocarcinoma treatment
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CD44 variant-dependent redox status regulation in liver fluke-associated cholangiocarcinoma: A target for cholangiocarcinoma treatment

机译：肝吸虫相关胆管癌中CD44变体依赖性氧化还原状态调节：胆管癌治疗的目标。

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摘要

Expression of CD44, especially the variant isoforms (CD44v) 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 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-induced hamster CCA tissues (at 60, 90, 120, and 180 days) reveals a decreased phospho-p38(MAPK) signal, whereas the CD44v signal was increased during bile duct transformation. Patients with CCA showed CD44v overexpression and negative-phospho-p38(MAPK) patients a significantly shorter survival rate than the low CD44v signal and positive-phos-pho-p38(MAPK) patients (P = 0.030). Knockdown of CD44 showed that xCT and glutathione levels were decreased, leading to a high level of ROS. We examined xCT-targeted CD44v 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 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 xCTtargeting 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.
机译：CD44的表达，尤其是这种主要癌症干细胞标志物的变异同工型（CD44v）的表达，通过稳定xCT（胱氨酸-谷氨酸转运蛋白）和促进谷胱甘肽合成，促进了活性氧（ROS）防御。这增强了癌症的发展并增加了化学疗法的抵抗力。我们调查CD44v在胆管癌（CCA）ROS防御系统的调节中的作用。免疫组织化学染色在Viistrichis viverrini诱导的仓鼠CCA组织（60、90、120和180天）中CD44v和p38（MAPK）表达（主要的ROS靶标）显示磷酸-p38（MAPK）信号降低，而CD44v胆管转化过程中信号增加。 CCA患者显示CD44v过表达，负磷酸p38（MAPK）患者的存活率明显低于低CD44v信号和正磷酸p38（MAPK）患者（P = 0.030）。击倒CD44表明xCT和谷胱甘肽水平降低，导致ROS升高。我们检查了使用柳氮磺胺吡啶的xCT靶向CD44v癌症干细胞疗法。处理后谷胱甘肽减少而ROS增加，导致抑制细胞增殖和诱导细胞死亡。因此，CD44v的积累导致转化胆管细胞中p38（MAPK）的抑制。 CCA细胞的氧化还原状态调节取决于CD44v的表达以贡献xCT功能，并且与患者预后不良有关。因此，xCT抑制剂可以抑制细胞生长并激活细胞死亡。这表明靶向xCT的药物可能会通过阻断细胞的ROS防御系统的机制而使对现有药物（例如吉西他滨）敏感而改善CCA治疗。

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