Abstract
BackgroundMultidrug 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.MethodsWe 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.ResultsmiR-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).ConclusionsOur 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.
Highlights
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
Literature review, and real-time PCR, we found that elevated miR-32-5p was associated with tumorigenesis in different cancer types, including HCC [20,21,22,23,24,25,26]. miR-32-5p contributes to castration resistance, radioresistance and chemoresistance in prostate cancer [27], but its function in promoting multidrug resistance in HCC remains unclear
Results miR-32-5p was elevated but PTEN was reduced in the multidrug-resistant HCC cell line We used a drug-resistant subtype Bel/5-FU to determine the role of PTEN and PTEN-related miRs in drug resistance
Summary
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. MiR-32-5p is involved in HCC progression but its function in multidrug resistance is still unclear. HCC is the sixth most common malignancy and the fourth leading cause of cancer-related death worldwide. Chemotherapeutic drugs, such as 5-fluorouracil (5-FU), oxaliplatin (OXA), and gemcitabine (GEM) are traditional systemic treatments for advanced HCC patients, but the treatment efficacy is disappointing. The subtle decrease in gene dosage or protein activity of PTEN, especially via post-transcriptional regulation, is involved in the progression and treatment resistance of HCC [8, 9]. How the miR-PTEN network promotes multidrug resistance in HCC remains unknown. MiR-32-5p contributes to castration resistance, radioresistance and chemoresistance in prostate cancer [27], but its function in promoting multidrug resistance in HCC remains unclear Literature review, and real-time PCR, we found that elevated miR-32-5p was associated with tumorigenesis in different cancer types, including HCC [20,21,22,23,24,25,26]. miR-32-5p contributes to castration resistance, radioresistance and chemoresistance in prostate cancer [27], but its function in promoting multidrug resistance in HCC remains unclear
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Journal of Experimental & Clinical Cancer Research
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
