Abstract 498
Background
Multidrug resistance is the main obstacle for hepatocellular carcinoma (HCC) treatment. Through bioinformatics prediction, literature review, and real-time PCR, we found that elevated miR-32-5p was associated with tumorigenesis in different cancer types, including HCC. miR-32-5p also contributes to castration resistance, radioresistance and chemoresistance in prostate cancer, but its function in multidrug resistance is still unclear. Exosomes are the most abundant type of extracellular vehicles (EVs), containing RNAs (especially miRs), proteins and other bioactive molecules. Recently, exosomes generated from chemoresistant cells have been proven to deliver miRs and transfer malignant phenotype to sensitive cells. Here we aim to find out the function of miR-32-5p in inducing multidrug resistance and the possible underlying mechanisms.
Methods
We detected the expression of miR-32-5p and PTEN in the cells and exosomes from both the multidrug-resistant and the sensitive cell lines, HCC and para-carcinoma liver tissues through real-time PCR. Dual-luciferase reporter assay verified PTEN is the target of miR-32-5p. Exosomes were obtained and confirmed through ultracentrifuge and Nano Analyzer. Gain- and loss-of-function experiments, rescue experiments, 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 in multidrug-resistant HCC cell line, Bel/5-FU as well as the exosomes derived from 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. Both in vitro and in vivo expriments reveal that exosomal miR-32-5p leads to multidrug resistance by targeting PTEN and activating the PI3K/Akt pathway through promoting EMT and angiogenesis.
Conclusions
Our study demonstrated that the multidrug-resistant cell, Bel/5-FU delivers miR-32-5p to sensitive cell, Bel7402 by exosome and activates the PI3K/Akt pathway to further induce multidrug resistance by modulating angiogenesis and EMT.
Clinical trial identification
Legal entity responsible for the study
The First Affiliated Hospital of Xi'an Jiaotong University.
Funding
National Natural Science Foundation of China (No. 81301909 and 81672810). International cooperation project in science and technology of Shaanxi province (No. 2016KW-017). Natural Science Foundation of Shaanxi Province (No.2017JM8019).
Editorial Acknowledgement
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
1159 - Molecular characterization and search for founding effects in Canarian families with Hereditary Breast and Ovarian Cancer Syndrome
Presenter: Elisenda Llabres Valenti
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
3725 - Effect of the polymorphism rs2066844 of the NOD2 gene on colon cancer incidence in a high cardiovascular risk population. Modulation by gender
Presenter: Judith Begona Ramirez Sabio
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
3708 - Effect of the polymorphisms rs1476413, rs1801131, rs4846052 and rs6541003 of the MTHFR gene on prostate cancer in a high cardiovascular risk population
Presenter: Judith Begona Ramirez Sabio
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
5057 - Association of a genetic variant in cyclin-dependent kinase Inhibitor 2A gene with the increased risk of breast cancer
Presenter: Soodabeh Shahid Sales
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
5970 - Investigating the role of HAT protein TIP60 in regulating functional dynamics of nuclear receptor PXR
Presenter: KARISHMA BAKSHI
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
1360 - The role of downregulated SIRT3 expression in patients with hepatocellular carcinoma
Presenter: Hanhee Jo
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
1634 - Prediction and Intervention of Colorectal Cancer Risk with Artificial Intelligent System
Presenter: Yang Ge
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
4921 - Measuring the Efficiency of Cancer Care in Europe
Presenter: Rikard Althin
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
1235 - Circulating cell-free DNA isolated from plasma of mesenteric veins predicts prognosis in stage II colorectal cancer patients
Presenter: Chih-Yung Yang
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
5169 - _lonality of uterine carcinosarcoma as a factor of clinical prognosis.
Presenter: Natalia Levitskaya
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract