Hypoxia-Induced PLOD2 is a Key Regulator in Epithelial-Mesenchymal Transition and Chemoresistance in Biliary Tract Cancer
Hypoxia-Induced PLOD2 is a Key Regulator in Epithelial-Mesenchymal Transition and Chemoresistance in Biliary Tract Cancer
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DOI：
10.1245/s10434-018-6670-8
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发表时间：
2018-11-01
影响因子：
3.7
通讯作者：
Mori, Masaki
中科院分区：
文献类型：
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作者：
Okumura, Yuichiro;Noda, Takehiro;Mori, Masaki
背景胆道癌（biliary tract cancer，BTC）由于化疗耐药，预后不良.缺氧引发上皮向间质转化（EMT），这与耐药性密切相关。本研究旨在探讨缺氧诱导基因PLOD 2在BTC中的功能作用及其临床意义。方法采用BTC细胞系，检测PLOD 2在缺氧条件下的表达。用针对PLOD 2的小干扰RNA（siRNA）转染吉西他滨抗性（GR）BTC细胞系，并评价EMT标志物和化学抗性。PLOD 2的表达也采用免疫组织化学法在BTC临床标本切除后。结果体外缺氧可诱导PLOD 2的表达，且在上皮标志物低表达、间充质标志物高表达的BTC-GR细胞系中PLOD 2的表达上调。通过siRNA下调PLOD 2导致化学抗性的改善、上皮标志物的恢复和间充质标志物的减少。在切除的BTC样品中，PLOD 2表达与淋巴结转移（p=0.037）和分期（p=0.001）显著相关。无复发生存期（p=0.011）和总生存期（p
BackgroundThe prognosis of biliary tract cancer (BTC) is unfavorable due to its chemoresistance. Hypoxia triggers epithelial-to-mesenchymal transition (EMT), which is closely related to drug resistance. In this study, we focused on the functional roles of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), a hypoxia-induced gene, in BTC, and assessed the clinical significance of PLOD2.MethodsThe expression of PLOD2 under hypoxia was assessed in BTC cell lines. Gemcitabine-resistant (GR) BTC cell lines were transfected with small interfering RNA (siRNA) against PLOD2, and EMT markers and chemoresistance were evaluated. PLOD2 expression was also characterized using immunohistochemistry in BTC clinical specimens following resection. Patient survival was analyzed and the role of PLOD2 expression was examined.ResultsThe expression of PLOD2 was induced by hypoxia in vitro and was upregulated in BTC-GR cell lines, which had low expression of epithelial markers and high expression of mesenchymal markers. Downregulation of PLOD2 by siRNA resulted in improved chemoresistance, recovery of epithelial markers, and reduction of mesenchymal markers. In the resected BTC samples, PLOD2 expression was significantly correlated with lymph node metastasis (p=0.037) and stage (p=0.001). Recurrence-free survival (p=0.011) and overall survival (p