| miR-375 Inhibits Autophagy and Reduces Viability of Hepatocellular Carcinoma Cells Under Hypoxic Conditions. | |
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MedLine Citation:
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PMID: 22504094 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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BACKGROUND & AIMS: Tumor cells survive hypoxic conditions by inducing autophagy. We investigated the roles of microRNAs (miRNAs) in regulating autophagy of hepatocellular carcinoma (HCC) cells under hypoxic conditions. METHODS: We used gain- and loss-of-function methods to evaluate the effect of miRNAs on autophagy in human HCC cell lines (Huh7 and Hep3B) under hypoxic conditions. Autophagy was quantified by immunoblot, immunofluoresence, and transmission electron microscopy analyses, and following incubation of cells with bafilomycin A1. We used a luciferase reporter assay to confirm associations between miRNAs and their targets. We analyzed growth of HCC xenograft tumors in nude mice. RESULTS: MiR-375 was downregulated in HCC cells and tissues; it inhibited autophagy under hypoxic conditions by suppressing the conversion of LC3I to LC3II and thereby autophagic flux. The ability of miR-375 to inhibit autophagy was independent of its ability to regulate PDK1-AKT-mTOR signaling, but instead involved suppression of ATG7, an autophagy-associated gene. miR-375 bound directly to a predicted site in the 3' untranslated region of ATG7. Upregulating miR-375 or downregulating ATG7 inhibited mitochondrial autophagy of HCC cells, reduced the elimination of damaged mitochondria under hypoxia, increased release of mitochondrial apoptotic proteins, and reduced viability of HCC cells. In mice, xenograft tumors that expressed miR-375 had fewer autophagic cells, larger areas of necrosis, and grew more slowly than tumors from HCC cells that expressed lower levels of miR-375. CONCLUSION: MiR-375 inhibits autophagy by reducing expression of ATG7 and impairs viability of HCC cells under hypoxic conditions in culture and in mice. miRNAs that inhibit autophagy of cancer cells might be developed as therapeutics. |
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Authors:
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Ying Chang; Wei Yan; Xingxing He; Lemeng Zhang; Chuanjiang Li; Hai Huang; Gary Nace; David A Geller; Jusheng Lin; Allan Tsung |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-4-12 |
Journal Detail:
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Title: Gastroenterology Volume: - ISSN: 1528-0012 ISO Abbreviation: - Publication Date: 2012 Apr |
Date Detail:
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Created Date: 2012-4-16 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0374630 Medline TA: Gastroenterology Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA; Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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