title: MiR-199a-3p regulates mTOR and c-Met to influence the doxorubicin sensitivity of human hepatocarcinoma cells.
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.
authors.affiliation: Centro di Ricerca Biomedica Applicata e Dipartimento di Medicina Interna, Policlinico S.Orsola-Malpighi e Università di Bologna, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fornari
authors.forename: Maddalena
authors.initials: M
authors.lastname: Milazzo
authors.forename: Pasquale
authors.initials: P
authors.lastname: Chieco
authors.forename: Massimo
authors.initials: M
authors.lastname: Negrini
authors.forename: George Adrian
authors.initials: GA
authors.lastname: Calin
authors.forename: Gian Luca
authors.initials: GL
authors.lastname: Grazi
authors.forename: Daniela
authors.initials: D
authors.lastname: Pollutri
authors.forename: Carlo Maria
authors.initials: CM
authors.lastname: Croce
authors.forename: Luigi
authors.initials: L
authors.lastname: Bolondi
authors.forename: Laura
authors.initials: L
authors.lastname: Gramantieri
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases
chemical_list: D000903:Antibiotics, Antineoplastic; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; C531408:mirn199 microRNA, human; D004317:Doxorubicin; D008156:Luciferases; C546842:MTOR protein, human; D019859:Proto-Oncogene Proteins c-met; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases