Abstract
MicroRNAs (miRNA) have rapidly emerged as modulators of gene expression in cancer in which they may have great diagnostic and therapeutic import. MicroRNA-199a-3p (miR-199a-3p) is downregulated in several human malignancies including hepatocellular carcinoma (HCC). Here, we show that miR-199a-3p targets mammalian target of rapamycin (mTOR) and c-Met in HCC cells. Restoring attenuated levels of miR-199a-3p in HCC cells led to G(1)-phase cell cycle arrest, reduced invasive capability, enhanced susceptibility to hypoxia, and increased sensitivity to doxorubicin-induced apoptosis. These in vitro findings were confirmed by an analysis of human HCC tissues, which revealed an inverse correlation linking miR-199a-3p and mTOR as well as a shorter time to recurrence after HCC resection in patients with lower miR-199a-3p expression. These results suggest that tactics to regulate mTOR and c-Met by elevating levels of miR-199a-3p may have therapeutic benefits in highly lethal cancers such as HCC.
MeSH terms
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Aged
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Aged, 80 and over
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Antibiotics, Antineoplastic / pharmacology*
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Apoptosis / drug effects
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Blotting, Western
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / pathology
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Cell Adhesion / drug effects
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Cell Cycle / drug effects
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Doxorubicin / pharmacology*
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Drug Resistance, Neoplasm*
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Intracellular Signaling Peptides and Proteins / genetics*
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Intracellular Signaling Peptides and Proteins / metabolism
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Liver Cirrhosis / drug therapy
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Liver Cirrhosis / genetics
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Liver Cirrhosis / pathology
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Liver Neoplasms / drug therapy
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Liver Neoplasms / genetics
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Liver Neoplasms / pathology
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Luciferases / metabolism
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Male
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MicroRNAs / physiology*
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Middle Aged
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-met / genetics*
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Proto-Oncogene Proteins c-met / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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TOR Serine-Threonine Kinases
Substances
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Antibiotics, Antineoplastic
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Intracellular Signaling Peptides and Proteins
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MicroRNAs
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RNA, Messenger
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mirn199 microRNA, human
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Doxorubicin
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Luciferases
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MTOR protein, human
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Proto-Oncogene Proteins c-met
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases