miR-218-5p restores sensitivity to gemcitabine through PRKCE/MDR1 axis in gallbladder cancer.
miR-218-5p restores sensitivity to gemcitabine through PRKCE/MDR1 axis in gallbladder cancer.
复制标题
miR-218-5p通过PRKCE/MDR1轴恢复胆囊癌对吉西他滨的敏感性
DOI：
10.1038/cddis.2017.178
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发表时间：
2017-05-11
影响因子：
9
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Wang H;Zhan M;Xu SW;Chen W;Long MM;Shi YH;Liu Q;Mohan M;Wang J
胆囊癌（GBC）是胆道最常见的恶性肿瘤之一，其特点是具有高度的化疗耐药性。尽管近几十年来抗癌药物治疗多种癌症取得了巨大进展，但仍缺乏有效的抗GBC治疗方法。因此，非常需要研究确定 GBC 耐药性的机制。在这项研究中，我们表明 miR-218-5p 在 GBC 吉西他滨耐药中发挥着关键作用。 GBC 中的 miR-218-5p 水平显着低于邻近的非癌组织，并且也与患者预后相关。虽然 miR-218-5p 过表达消除了 GBC 细胞对吉西他滨的耐药性，但其沉默却表现出相反的效果。通过六个microRNA靶点预测算法，我们发现PRKCE是miR-218-5p的潜在靶点。此外，miR-218-5p过表达抑制了含有PRKCE 3'-UTR的报告构建体的荧光素酶活性，并降低了PRKCE的表达。进一步的研究表明，miR-218-5p 通过消除 PRKCE 诱导的 MDR1/P-gp 上调来提高吉西他滨的敏感性。综上所述，我们的结果表明 miR-218-5p 与 PRKCE/MDR1 轴异常表达之间的密切相关性是吉西他滨耐受性的关键决定因素，并为 GBC 患者提出了基于 miR-218-5p 的新型临床干预目标。
Gallbladder cancer (GBC) is one of the most common malignancy of the biliary tract characterized by its high chemoresistant tendency. Although great progresses have been made in recent decades for treating many cancers with anticancer drugs, effective therapeutics methods for anti-GBC are still lacking. Therefore, investigations into identifying the mechanisms underlying the drug resistance of GBC are greatly needed. In this study, we show that miR-218-5p plays a critical role in gemcitabine resistance of GBC. miR-218-5p levels were significantly lower in GBC than adjacent non-cancer tissues, and which were also associated with patient prognosis. While miR-218-5p overexpression abrogated gemcitabine resistance of GBC cells, silencing of which exhibited the opposite effects. Via six microRNA targets prediction algorithms, we found that PRKCE is a potential target of miR-218-5p. Moreover, miR-218-5p overexpression repressed the luciferase activity of reporter constructs containing 3′-UTR of PRKCE and also reduced PRKCE expression. Further studies revealed that miR-218-5p promotes sensitivity of gemcitabine by abolishing PRKCE-induced upregulation of MDR1/P-gp. Taken together, our results imply that an intimate correlation between miR-218-5p and PRKCE/MDR1 axis abnormal expression is a key determinant of gemcitabine tolerance, and suggest a novel miR-218-5p-based clinical intervention target for GBC patients.
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