MiR-199a-3p Regulates mTOR and c-Met to Influence the Doxorubicin Sensitivity of Human Hepatocarcinoma Cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-06, Vol.70 (12), p.5184-5193
• Main Authors: FORNARI, Francesca, MILAZZO, Maddalena, CHIECO, Pasquale, NEGRINI, Massimo, CALIN, George Adrian, LUCA GRAZI, Gian, POLLUTRI, Daniela, CROCE, Carlo Maria, BOLONDI, Luigi, GRAMANTIERI, Laura
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Antibiotics, Antineoplastic - pharmacology; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Adhesion - drug effects; Cell Cycle - drug effects; Cell Movement - drug effects; Cell Proliferation - drug effects; Doxorubicin - pharmacology; Drug Resistance, Neoplasm; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Liver Cirrhosis - drug therapy; Liver Cirrhosis - genetics; Liver Cirrhosis - pathology; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Luciferases - metabolism; Male; Medical sciences; MicroRNAs - physiology; Middle Aged; Pharmacology. Drug treatments; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; TOR Serine-Threonine Kinases; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-0145

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.