Inhibition of Wnt/β-catenin signaling downregulates P-glycoprotein and reverses multi-drug resistance of cholangiocarcinoma
Inhibition of Wnt/β-catenin signaling downregulates P-glycoprotein and reverses multi-drug resistance of cholangiocarcinoma
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DOI：
10.1111/cas.12223
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发表时间：
2013-10-01
期刊：
影响因子：
5.7
通讯作者：
Liu, Chang-Qin
中科院分区：
文献类型：
--
作者：
Shen, Dong-Yan;Zhang, Wei;Liu, Chang-Qin
多药耐药（MDR）的发展是成功治疗癌症的主要障碍。然而，导致胆管癌（CCA）多药耐药的因素和机制仍不清楚，化疗耐药的胆管癌预后差。本研究建立了人多药耐药CCA细胞系QBC 939/5-FU。与QBC 939细胞相比，QBC 939/5-FU细胞具有形态圆整、核质比高、细胞周期短、生长快、耐化疗等特点。P-gp和β-catenin在QBC 939/5-FU细胞中表达上调。此外，Wnt 3a处理后，QBC 939/5-FU细胞对常用化疗药物的敏感性显著降低，而Wnt/β-catenin siRNA抑制Wnt/β-catenin通路可逆转QBC 939/5-FU细胞对化疗药物的多药耐药。分子生物学研究表明，Wnt/β-catenin通路的激活导致P-gp表达上调，并参与了QBC 939/5-FU细胞的多药耐药。提取的暹罗鳄鱼3号（ESC-3）胆汁可增强QBC 939/5-FU细胞对5-FU、顺铂的药物敏感性，并下调β-catenin和P-gp的表达。CCA组织的临床数据进一步证实了Wnt/β-catenin途径与P-gp的相关性。本研究首次揭示了Wnt/β-catenin激活在CCA多药耐药中的作用，为临床治疗CCA提供了有益的靶点。
The development of multi-drug resistance (MDR) represents a major obstacle in the successful treatment of cancers. However, the factors and mechanisms that lead to MDR in cholangiocarcinoma (CCA), a chemoresistant bile duct carcinoma with a poor prognosis, remain unclear. In this study, we established a human MDR CCA cell line QBC939/5-FU. Compared with QBC939 cells, a rounder shape, a higher nuclear-cytoplasmic ratio, a shorter cell cycle, faster growth and resistance to chemotherapeutics are major characteristics of QBC939/5-FU cells. P-glycoprotein (P-gp) and -catenin were upregulated in QBC939/5-FU cells. Furthermore, the drug susceptibility of QBC939 cells to common chemotherapeutics was significantly decreased after Wnt3a treatment, whereas inhibition of Wnt/-catenin pathway by -catenin siRNA reversed the MDR of QBC939/5-FU cells to chemotherapeutics. Molecular study revealed that activation of Wnt/-catenin pathway resulted in upregulation of P-gp and contributed to MDR of QBC939/5-FU cells. Extraction of Siamese Crocodile 3 (ESC-3) bile enhanced the drug sensitivity of QBC939/5-FU cells to 5-FU, paralleled with downregulation of -catenin and P-gp. The association of Wnt/-catenin pathway and P-gp was further confirmed by the clinical data for CCA tissues. Our study represents the first implication of Wnt/-catenin activation in the MDR of CCA, which may be a beneficial target for the clinical treatment of CCA.