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Combination of AAV-TRAIL with miR-221-Zip Therapeutic Strategy Overcomes the Resistance to TRAIL Induced Apoptosis in Liver Cancer.

ABSTRACT: TNF-related apoptosis-inducing ligand (TRAIL) possesses the capacity to induce apoptosis in a wide variety of tumor cells without affecting most normal cells. However, it has now emerged that many primary cancer cells are resistant to TRAIL monotherapy. Overcoming the intrinsic or acquired TRAIL resistance is desirable for TRAIL-mediated cancer therapy. In this study, we found that the miR-221/222 cluster was up-regulated in TRAIL-resistant liver cancer cells. Specific inhibitors of miR-221 and/or miR-222, called sponge, TuD and miR-Zip were constructed, and their ability to overcome TRAIL resistance was compared. Among them, AAV-mediated gene therapy using co-expression of TRAIL with miR-221-Zip showed the most synergistic activity in the induction of apoptosis in vitro. In vivo treatment of nude mice bearing human TRAIL-resistant liver cancer xenografts with AAV-TRAIL-miR-221-Zip also led to growth inhibition. This sensitizing effect of miR-221-Zip was associated with increased expression of PTEN, the miR-221 target, as well as with decreasing levels of Survivin. Moreover, miR-221 expression was concomitant with promotion of Survivin expression and suppression of PTEN expression. TRAIL sensitivity of cancer cells isolated from liver cancer tissues or from patients was significantly correlated with miR-221 expression. And miR-221 blood expression levels in liver cancer patients were correlated with TRAIL sensitivity, thus it had the potential to be a predictor of TRAIL sensitivity in liver cancer. These data suggested the potential of combining AAV-TRAIL with miR-221-Zip as a therapeutic intervention for liver cancer.

SUBMITTER: Ma S

PROVIDER: S-EPMC5595128 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Combination of AAV-TRAIL with miR-221-Zip Therapeutic Strategy Overcomes the Resistance to TRAIL Induced Apoptosis in Liver Cancer.

Ma Sisi S Sun Jiazeng J Guo Yabin Y Zhang Peng P Liu Yanxin Y Zheng Dexian D Shi Juan J

Theranostics 20170722 13

TNF-related apoptosis-inducing ligand (TRAIL) possesses the capacity to induce apoptosis in a wide variety of tumor cells without affecting most normal cells. However, it has now emerged that many primary cancer cells are resistant to TRAIL monotherapy. Overcoming the intrinsic or acquired TRAIL resistance is desirable for TRAIL-mediated cancer therapy. In this study, we found that the miR-221/222 cluster was up-regulated in TRAIL-resistant liver cancer cells. Specific inhibitors of miR-221 and/ ...[more]

PMID: 28900506

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Project description:BackgroundEffective targeting therapies for common chronic liver disease nonalcoholic steatohepatitis (NASH) are in urgent need. MicroRNA-targeted therapeutics would be potentially an effective treatment strategy of hepatic diseases. Here we investigated the functional role of miR-221/222 and the therapeutic effects of antimiRs-221/222 in NASH mouse models.MethodsWe generated the miR-221/222flox/flox mice on a C57BL/6?J background and the hepatic miR-221/222 knockout (miR-221/222-LKO) mice. The mice were challenged with the methionine and choline deficient diet (MCDD) or chronic carbon tetrachloride (CCl4) treatment to generate experimental steatohepatitis models. Adenovirus-mediated re-expression of miR-221/222 was performed on the MCDD-fed miR-221/222-LKO mice. The MCDD and control diet-fed mice were treated with locked nucleic acid (LNA)-based antimiRs of miR-221/222 to evaluate the therapeutic effects. Histological analysis, RNA-seq, quantitative PCR and Western blot of liver tissues were carried out to study the hepatic lipid accumulation, inflammation and collagen deposition in mouse models.FindingsHepatic deletion of miR-221/222 resulted in significant reduction of liver fibrosis, lipid deposition and inflammatory infiltration in the MCDD-fed and CCl4-treated mouse models. The hepatic steatosis and fibrosis were dramatically aggravated by miR-221/222 re-expression in MCDD-fed miR-221/222-LKO mice. AntimiRs of miR-221/222 could effectively reduce the MCDD-mediated hepatic steatosis and fibrosis. Systematically mechanistic study revealed that hepatic miR-221/222 controlled the expression of target gene Timp3 and promoted the progression of NASH.InterpretationOur findings demonstrate that miR-221/222 are crucial for the regulation of lipid metabolism, inflammation and fibrosis in the liver. LNA-antimiRs targeted miR-221/222 could reduce steatohepatitis with prominent antifibrotic effect in NASH mice. FUND: This work is supported by the Natural Science Foundation of China (81530020, 81390352 to Dr. Ning and 81522032 to Dr. Cao and 81670793 to Dr. Jiang); National Key Research and Development Program (No. 2016YFC0905001 and 2017YFC0909703 to Dr. Cao); the Shanghai Rising-Star Program (15QA1402900 to Dr. Cao); Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20171905 to Dr. Jiang).

Dataset Information

Combination of AAV-TRAIL with miR-221-Zip Therapeutic Strategy Overcomes the Resistance to TRAIL Induced Apoptosis in Liver Cancer.

Publications

Combination of AAV-TRAIL with miR-221-Zip Therapeutic Strategy Overcomes the Resistance to TRAIL Induced Apoptosis in Liver Cancer.

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