Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway.
Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway.
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外泌体 microRNA-32-5p 通过 PI3K/Akt 途径诱导肝细胞癌多药耐药
DOI：
10.1186/s13046-018-0677-7
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发表时间：
2018-03-12
期刊：
影响因子：
--
通讯作者：
Tian T
中科院分区：
文献类型：
--
作者：
Fu X;Liu M;Qu S;Ma J;Zhang Y;Shi T;Wen H;Yang Y;Wang S;Wang J;Nan K;Yao Y;Tian T
多药耐药是肝细胞癌（HCC）治疗的主要障碍。miR-32- 5 p参与了HCC的进展，但其在多药耐药中的功能尚不清楚。本研究旨在探讨miR-32- 5 p在诱导多药耐药中的作用及其诱导敏感细胞向耐药细胞转化的机制。采用实时荧光定量PCR方法检测miR-32- 5 p和PTEN在多药耐药细胞系（Bel/5-FU）、敏感细胞系（Bel 7402）、肝癌及癌旁肝组织中的表达。双荧光素酶报告基因检测证实PTEN是miR-32- 5 p的靶点。从敏感和多药耐药细胞系中获得外泌体，并通过超离心和纳米分析仪进行确认。使用功能获得和丧失实验、拯救实验、PI 3 K/Akt途径抑制剂、外泌体生物发生抑制剂和裸小鼠异种移植模型来确定miR-32- 5 p和PTEN以及外泌体miR-32- 5 p的潜在机制体外和体内诱导多药耐药。在Bel/5-FU中，miR-32- 5 p显著升高，但PTEN降低。miR-32- 5 p和PTEN在HCC细胞系和患者中呈负相关;此外，miR-32- 5 p高表达和PTEN低表达与不良预后呈正相关。miR-32- 5 p的过表达通过抑制PTEN激活PI 3 K/Akt通路，并通过外泌体通过促进血管生成和上皮-间质转化（EMT）诱导多药耐药。我们的研究表明，多药耐药细胞Bel/5-FU通过exosomes将miR-32- 5 p递送到敏感细胞Bel 7402，并激活PI 3 K/Akt通路，通过调节血管生成和EMT进一步诱导多药耐药。本文的在线版本（10.1186/s13046-018-0677-7）包含补充材料，可供授权用户使用。
Multidrug resistance is the main obstacle for hepatocellular carcinoma (HCC) treatment. miR-32-5p is involved in HCC progression but its function in multidrug resistance is still unclear. Here we aim to find out the function of miR-32-5p in inducing multidrug resistance and its underlying mechanisms of transforming sensitive cell to resistant cell. We detected the expression of miR-32-5p and PTEN in the multidrug-resistant cell line (Bel/5-FU) and the sensitive cell line (Bel7402), HCC and para-carcinoma liver tissues through real-time PCR. Dual-luciferase reporter assay verified PTEN is the target of miR-32-5p. Exosomes from sensitive and multidrug resistant cell line were obtained and confirmed through ultracentrifuge and Nano Analyzer. Gain- and loss-of-function experiments, rescue experiments, a PI3K/Akt pathway inhibitor, an exosome biogenesis inhibitor, and nude mice xenograft models were used to determine the underlying mechanisms of miR-32-5p and PTEN, as well as exosomal miR-32-5p in inducing multidrug resistance in vitro and in vivo. miR-32-5p was significantly elevated but PTEN was reduced in Bel/5-FU. An inverse correlation between miR-32-5p and PTEN was confirmed in HCC cell lines and patients; moreover, high expression of miR-32-5p and low expression of PTEN were positively associated with poor prognosis. Over-expression of miR-32-5p activated the PI3K/Akt pathway by suppressing PTEN and induced multidrug resistance via exosomes through promoting angiogenesis and epithelial-mesenchymal transition (EMT). Our study demonstrated that the multidrug-resistant cell, Bel/5-FU delivers miR-32-5p to sensitive cell, Bel7402 by exosomes and activates the PI3K/Akt pathway to further induce multidrug resistance by modulating angiogenesis and EMT. The online version of this article (10.1186/s13046-018-0677-7) contains supplementary material, which is available to authorized users.
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作者：
Hua J;Ding T;Yang L
通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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