Dataset Information

PU.1/microRNA-142-3p targets ATG5/ATG16L1 to inactivate autophagy and sensitize hepatocellular carcinoma cells to sorafenib.

ABSTRACT: Sorafenib is currently the only systemic agent approved for treatment of advanced hepatocellular carcinoma (HCC). However, intrinsic and acquired resistance to sorafenib remains a great challenge with respect to improving the prognoses of patients with HCC. The cyto-protective functions of autophagy have been suggested as a potential mechanism by which chemoresistance or targeted drug resistance occurs in tumour cells. In the present study, miR-142-3p was identified as a novel autophagy-regulating microRNA (miRNA) that plays a vital role in sorafenib resistance in HCC cells. Gain- and loss-of-function assays revealed that ectopic miR-142-3p upregulation sensitized HCC cells to sorafenib by reducing sorafenib-induced autophagy, enhancing sorafenib-induced apoptosis and inhibiting cell growth, whereas miR-142-3p inhibition exerted contrasting effects. Bioinformatics analysis and luciferase reporter and rescue assays showed that autophagy-related 5 (ATG5) and autophagy-related 16-like 1 (ATG16L1) are potential targets through which miR-142-3p regulates autophagy inhibition. Furthermore, we verified that PU.1 regulated the expression of miR-142-3p in conjunction with our cellular experiments and the related results in the literature. Our findings show that targeting the PU.1-miR-142-3p-ATG5/ATG16L1 axis may be a useful therapeutic strategy for preventing cyto-protective autophagy to overcome sorafenib resistance.

SUBMITTER: Zhang K

PROVIDER: S-EPMC5833744 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PU.1/microRNA-142-3p targets ATG5/ATG16L1 to inactivate autophagy and sensitize hepatocellular carcinoma cells to sorafenib.

Zhang Kai K Chen Jing J Zhou Hao H Chen Ying Y Zhi Yingru Y Zhang Bei B Chen Longbang L Chu Xiaoyuan X Wang Rui R Zhang Chunni C

Cell death & disease 20180222 3

Sorafenib is currently the only systemic agent approved for treatment of advanced hepatocellular carcinoma (HCC). However, intrinsic and acquired resistance to sorafenib remains a great challenge with respect to improving the prognoses of patients with HCC. The cyto-protective functions of autophagy have been suggested as a potential mechanism by which chemoresistance or targeted drug resistance occurs in tumour cells. In the present study, miR-142-3p was identified as a novel autophagy-regulati ...[more]

PMID: 29472524

Similar Datasets

Project description:Autophagy and apoptosis are associated with cardiovascular diseases. Emerging evidence shows that microRNAs (miRs) are critical in the development of pathological processes underlying cardiovascular diseases by regulating the induction of apoptosis and autophagy. The present study aimed to investigate the role of miR‑103a‑3p in cardiomyocyte injury through autophagy and apoptosis. H9c2 cells were cultured under hypoxia and reoxygenation (H/R) conditions and were used to mimic cells under ischemia. The transfection of cells with miR‑103a‑3p (mimics and inhibitors) was performed to examine its function in cardiomyocytes. The expression levels of miR‑103a‑3p were evaluated by reverse transcription‑quantitative polymerase chain reaction analysis. Cell viability was determined using an MTT assay, and the lactate dehydrogenase assay (LDH) was used to investigate cell injury. The expression levels of B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein, Beclin‑1, autophagy‑related 5 (Atg5), cleaved caspase‑3 and cleaved caspase‑9 were detected using western blotting. Immunofluorescence assays were performed to detect the expression of LC3 as a marker of autophagy. The target gene of miR‑103a‑3p was identified using dual‑luciferase reporter assays. The results revealed that the expression levels of miR‑103a‑3p were significantly downregulated in cardiomyocytes under H/R conditions. Injury of the cardiomyocytes was evaluated under H/R conditions. Following transfection of the cells with miR‑103a‑3p inhibitors, cell injury was increased, as determined by LDH and MTT assays. The expression levels of apoptotic proteins were consistent with the results obtained in the LDH and cell viability assays. The induction of autophagy was increased in cells under H/R conditions and cells with miR‑103a‑3p inhibitor transfection, whereas the induction of autophagy was decreased in cells transfected with miR‑103a‑3p mimics. In addition, the data indicated that miR‑103a‑3p directly targeted Atg5, which regulated the induction of autophagy and apoptosis. Taken together, these findings indicate that, following the inhibition of miR‑103a‑3p, Atg5 promotes autophagy and apoptosis in cardiomyocytes by directly targeting Atg5. Therefore, miR‑103a‑3p can be considered a potential therapeutic target for myocardial ischemia.

Dataset Information

PU.1/microRNA-142-3p targets ATG5/ATG16L1 to inactivate autophagy and sensitize hepatocellular carcinoma cells to sorafenib.

Publications

PU.1/microRNA-142-3p targets ATG5/ATG16L1 to inactivate autophagy and sensitize hepatocellular carcinoma cells to sorafenib.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets