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

Autor: Yamin Zhang, Hongqing Wen, Xiao Fu, Shengyang Qu, Kejun Nan, Tao Tian, Jing Wang, Shu-Hong Wang, Yu Yao, Tingting Shi, Yujuan Yang, Jiguang Ma, Mengjie Liu
Rok vydání: 2018
Předmět:
Male
0301 basic medicine
PTEN
Cancer Research
Hepatocellular carcinoma
Angiogenesis
Cell
Apoptosis
microRNA-32-5p
Multidrug resistance
Exosomes
Mice
Phosphatidylinositol 3-Kinases
0302 clinical medicine
Genes
Reporter
3' Untranslated Regions
Neovascularization
Pathologic
biology
Chemistry
Liver Neoplasms
Hematology
Middle Aged
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Gene Expression Regulation
Neoplastic
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Female
RNA Interference
Signal Transduction
Adult
Carcinoma
Hepatocellular
Epithelial-Mesenchymal Transition
lcsh:RC254-282
Exosome
03 medical and health sciences
Cell Line
Tumor
microRNA
medicine
Animals
Humans
PI3K/AKT/mTOR pathway
Aged
Neoplasm Staging
business.industry
Research
PTEN Phosphohydrolase
Biological Transport
Xenograft Model Antitumor Assays
Microvesicles
Multiple drug resistance
Disease Models
Animal
MicroRNAs
030104 developmental biology
Drug Resistance
Neoplasm
Cell culture
biology.protein
Cancer research
business
Proto-Oncogene Proteins c-akt
Zdroj: Journal of Experimental & Clinical Cancer Research : CR
Journal of Experimental & Clinical Cancer Research, Vol 37, Iss 1, Pp 1-18 (2018)
ISSN: 1756-9966
DOI: 10.1186/s13046-018-0677-7
Popis: Background 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. Methods 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. Results 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). Conclusions 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. Electronic supplementary material The online version of this article (10.1186/s13046-018-0677-7) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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