Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway

• Published in: Journal of experimental & clinical cancer research Vol. 37; no. 1; pp. 52 - 18
• Main Authors: Fu, Xiao, Liu, Mengjie, Qu, Shengyang, Ma, Jiequn, Zhang, Yamin, Shi, Tingting, Wen, Hongqing, Yang, Yujuan, Wang, Shuhong, Wang, Jing, Nan, Kejun, Yao, Yu, Tian, Tao
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 12.03.2018; BioMed Central; BMC
• Subjects: 3' Untranslated Regions; Adult; Aged; Analysis; Animals; Apoptosis; Biological Transport; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Development and progression; Disease Models, Animal; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug therapy; Epithelial-Mesenchymal Transition - genetics; Exosome; Exosomes - metabolism; Female; Gene Expression Regulation, Neoplastic; Genes, Reporter; Genetic aspects; Hepatocellular carcinoma; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Mice; MicroRNA; microRNA-32-5p; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Multidrug resistance; Neoplasm Staging; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Physiological aspects; Proto-Oncogene Proteins c-akt; PTEN; PTEN Phosphohydrolase - genetics; Risk factors; RNA Interference; Signal Transduction; Xenograft Model Antitumor Assays; China; PTEN; Hepatocellular carcinoma; Exosome; Multidrug resistance; microRNA-32-5p
• ISSN: 0392-9078; 1756-9966; 1756-9966
• DOI: 10.1186/s13046-018-0677-7

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.