Metformin requires 4E-BPs to induce apoptosis and repress translation of Mcl-1 in hepatocellular carcinoma cells.
Identifieur interne : 000799 ( Main/Exploration ); précédent : 000798; suivant : 000800Metformin requires 4E-BPs to induce apoptosis and repress translation of Mcl-1 in hepatocellular carcinoma cells.
Auteurs : Mamatha Bhat [Canada, États-Unis] ; Akiko Yanagiya [Canada] ; Tyson Graber [Canada] ; Nataliya Razumilava [États-Unis] ; Steve Bronk [États-Unis] ; Domenick Zammit [Canada] ; Yunhao Zhao [Canada] ; Chadi Zakaria [Canada] ; Peter Metrakos [Canada] ; Michael Pollak [Canada] ; Nahum Sonenberg [Canada] ; Gregory Gores [États-Unis] ; Maritza Jaramillo [Canada] ; Masahiro Morita [Canada] ; Tommy Alain [Canada]Source :
- Oncotarget [ 1949-2553 ] ; 2017.
Abstract
Metformin inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, which is frequently upregulated in hepatocellular carcinoma (HCC). Metformin has also been shown to induce apoptosis in this cancer. Here, we investigate whether metformin-induced apoptosis in HCC is mediated by the downstream mTORC1 effectors eukaryotic initiation factor 4E and (eIF4E)-binding proteins (4E-BPs). Further, we ask whether changes in 4E-BPs activity during metformin treatment negatively regulate translation of the anti-apoptotic myeloid cell leukemia 1 (Mcl-1) mRNA. A genetic HCC mouse model was employed to assess the ability of metformin to reduce tumor formation, induce apoptosis, and control 4E-BP1 activation and Mcl-1 protein expression. In parallel, the HCC cell line Huh7 was transduced with scrambled shRNA (control) or shRNAs targeting 4E-BP1 and 4E-BP2 (4E-BP knock-down (KD)) to measure differences in mRNA translation, apoptosis, and Mcl-1 protein expression after metformin treatment. In addition, immunohistochemical staining of eIF4E and 4E-BP1 protein levels was addressed in a HCC patient tissue microarray. We found that metformin decreased HCC tumor burden, and tumor tissues showed elevated apoptosis with reduced Mcl-1 and phosphorylated 4E-BP1 protein levels. In control but not 4E-BP KD Huh7 cells, metformin induced apoptosis and repressed Mcl-1 mRNA translation and protein levels. Immunostaining of HCC patient tumor tissues revealed a varying ratio of eIF4E/4E-BP1 expression. Our results propose that metformin induces apoptosis in mouse and cellular models of HCC through activation of 4E-BPs, thus tumors with elevated expression of 4E-BPs may display improved clinical chemopreventive benefit of metformin.
DOI: 10.18632/oncotarget.10671
PubMed: 28881582
PubMed Central: PMC5584165
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last="Zhao">Yunhao Zhao</name><affiliation wicri:level="3"><nlm:affiliation>Departments of Medicine and Oncology, Lady Davis Institute for Medical Research and Segal Cancer Center, Montreal, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Departments of Medicine and Oncology, Lady Davis Institute for Medical Research and Segal Cancer Center, Montreal</wicri:regionArea><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Zakaria, Chadi" sort="Zakaria, Chadi" uniqKey="Zakaria C" first="Chadi" last="Zakaria">Chadi Zakaria</name><affiliation wicri:level="4"><nlm:affiliation>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal</wicri:regionArea><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author><author><name sortKey="Metrakos, Peter" sort="Metrakos, Peter" uniqKey="Metrakos P" first="Peter" last="Metrakos">Peter Metrakos</name><affiliation wicri:level="3"><nlm:affiliation>Department of Surgery, McGill University Health Centre, Montreal, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Surgery, McGill University Health Centre, Montreal</wicri:regionArea><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Pollak, Michael" sort="Pollak, Michael" uniqKey="Pollak M" first="Michael" last="Pollak">Michael Pollak</name><affiliation wicri:level="3"><nlm:affiliation>Departments of Medicine and Oncology, Lady Davis Institute for Medical Research and Segal Cancer Center, Montreal, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Departments of Medicine and Oncology, Lady Davis Institute for Medical Research and Segal Cancer Center, Montreal</wicri:regionArea><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Sonenberg, Nahum" sort="Sonenberg, Nahum" uniqKey="Sonenberg N" first="Nahum" last="Sonenberg">Nahum Sonenberg</name><affiliation wicri:level="4"><nlm:affiliation>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal</wicri:regionArea><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author><author><name sortKey="Gores, Gregory" sort="Gores, Gregory" uniqKey="Gores G" first="Gregory" last="Gores">Gregory Gores</name><affiliation wicri:level="2"><nlm:affiliation>Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Minnesota</region></placeName><wicri:cityArea>Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester</wicri:cityArea></affiliation></author><author><name sortKey="Jaramillo, Maritza" sort="Jaramillo, Maritza" uniqKey="Jaramillo M" first="Maritza" last="Jaramillo">Maritza Jaramillo</name><affiliation wicri:level="1"><nlm:affiliation>INRS Institut Armand-Frappier Research Centre, Laval, Quebec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>INRS Institut Armand-Frappier Research Centre, Laval, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Morita, Masahiro" sort="Morita, Masahiro" uniqKey="Morita M" first="Masahiro" last="Morita">Masahiro Morita</name><affiliation wicri:level="4"><nlm:affiliation>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal</wicri:regionArea><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author><author><name sortKey="Alain, Tommy" sort="Alain, Tommy" uniqKey="Alain T" first="Tommy" last="Alain">Tommy Alain</name><affiliation wicri:level="1"><nlm:affiliation>Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Children's 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cells.</title><author><name sortKey="Bhat, Mamatha" sort="Bhat, Mamatha" uniqKey="Bhat M" first="Mamatha" last="Bhat">Mamatha Bhat</name><affiliation wicri:level="4"><nlm:affiliation>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal</wicri:regionArea><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation><affiliation wicri:level="1"><nlm:affiliation>Division of Gastroenterology, University Health Network and University of Toronto, Toronto, Canada, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Gastroenterology, University Health Network and University of Toronto, Toronto, Canada</wicri:regionArea><wicri:noRegion>Canada</wicri:noRegion></affiliation><affiliation wicri:level="2"><nlm:affiliation>Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Minnesota</region></placeName><wicri:cityArea>Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester</wicri:cityArea></affiliation></author><author><name sortKey="Yanagiya, Akiko" sort="Yanagiya, Akiko" uniqKey="Yanagiya A" first="Akiko" last="Yanagiya">Akiko Yanagiya</name><affiliation wicri:level="4"><nlm:affiliation>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal</wicri:regionArea><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author><author><name sortKey="Graber, Tyson" sort="Graber, Tyson" uniqKey="Graber T" first="Tyson" last="Graber">Tyson Graber</name><affiliation wicri:level="1"><nlm:affiliation>Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Razumilava, Nataliya" sort="Razumilava, Nataliya" uniqKey="Razumilava N" first="Nataliya" last="Razumilava">Nataliya Razumilava</name><affiliation wicri:level="2"><nlm:affiliation>Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Minnesota</region></placeName><wicri:cityArea>Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:affiliation>Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan</wicri:regionArea><placeName><region type="state">Michigan</region></placeName></affiliation></author><author><name sortKey="Bronk, Steve" sort="Bronk, Steve" uniqKey="Bronk S" first="Steve" last="Bronk">Steve Bronk</name><affiliation wicri:level="2"><nlm:affiliation>Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Minnesota</region></placeName><wicri:cityArea>Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester</wicri:cityArea></affiliation></author><author><name sortKey="Zammit, Domenick" sort="Zammit, Domenick" uniqKey="Zammit D" first="Domenick" last="Zammit">Domenick Zammit</name><affiliation wicri:level="4"><nlm:affiliation>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal</wicri:regionArea><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author><author><name sortKey="Zhao, Yunhao" sort="Zhao, Yunhao" uniqKey="Zhao Y" first="Yunhao" last="Zhao">Yunhao Zhao</name><affiliation wicri:level="3"><nlm:affiliation>Departments of Medicine and Oncology, Lady Davis Institute for Medical Research and Segal Cancer Center, Montreal, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Departments of Medicine and Oncology, Lady Davis Institute for Medical Research and Segal Cancer Center, Montreal</wicri:regionArea><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Zakaria, Chadi" sort="Zakaria, Chadi" uniqKey="Zakaria C" first="Chadi" last="Zakaria">Chadi Zakaria</name><affiliation wicri:level="4"><nlm:affiliation>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal</wicri:regionArea><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author><author><name sortKey="Metrakos, Peter" sort="Metrakos, Peter" uniqKey="Metrakos P" first="Peter" last="Metrakos">Peter Metrakos</name><affiliation wicri:level="3"><nlm:affiliation>Department of Surgery, McGill University Health Centre, Montreal, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Surgery, McGill University Health Centre, Montreal</wicri:regionArea><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Pollak, Michael" sort="Pollak, Michael" uniqKey="Pollak M" first="Michael" last="Pollak">Michael Pollak</name><affiliation wicri:level="3"><nlm:affiliation>Departments of Medicine and Oncology, Lady Davis Institute for Medical Research and Segal Cancer Center, Montreal, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Departments of Medicine and Oncology, Lady Davis Institute for Medical Research and Segal Cancer Center, Montreal</wicri:regionArea><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Sonenberg, Nahum" sort="Sonenberg, Nahum" uniqKey="Sonenberg N" first="Nahum" last="Sonenberg">Nahum Sonenberg</name><affiliation wicri:level="4"><nlm:affiliation>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal</wicri:regionArea><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author><author><name sortKey="Gores, Gregory" sort="Gores, Gregory" uniqKey="Gores G" first="Gregory" last="Gores">Gregory Gores</name><affiliation wicri:level="2"><nlm:affiliation>Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Minnesota</region></placeName><wicri:cityArea>Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester</wicri:cityArea></affiliation></author><author><name sortKey="Jaramillo, Maritza" sort="Jaramillo, Maritza" uniqKey="Jaramillo M" first="Maritza" last="Jaramillo">Maritza Jaramillo</name><affiliation wicri:level="1"><nlm:affiliation>INRS Institut Armand-Frappier Research Centre, Laval, Quebec, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>INRS Institut Armand-Frappier Research Centre, Laval, Quebec</wicri:regionArea><wicri:noRegion>Quebec</wicri:noRegion></affiliation></author><author><name sortKey="Morita, Masahiro" sort="Morita, Masahiro" uniqKey="Morita M" first="Masahiro" last="Morita">Masahiro Morita</name><affiliation wicri:level="4"><nlm:affiliation>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal</wicri:regionArea><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName><orgName type="university">Université McGill</orgName></affiliation></author><author><name sortKey="Alain, Tommy" sort="Alain, Tommy" uniqKey="Alain T" first="Tommy" last="Alain">Tommy Alain</name><affiliation wicri:level="1"><nlm:affiliation>Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author></analytic><series><title level="j">Oncotarget</title><idno type="eISSN">1949-2553</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Metformin inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, which is frequently upregulated in hepatocellular carcinoma (HCC). Metformin has also been shown to induce apoptosis in this cancer. Here, we investigate whether metformin-induced apoptosis in HCC is mediated by the downstream mTORC1 effectors eukaryotic initiation factor 4E and (eIF4E)-binding proteins (4E-BPs). Further, we ask whether changes in 4E-BPs activity during metformin treatment negatively regulate translation of the anti-apoptotic <i>myeloid cell leukemia 1</i> (<i>Mcl-1</i>) mRNA. A genetic HCC mouse model was employed to assess the ability of metformin to reduce tumor formation, induce apoptosis, and control 4E-BP1 activation and Mcl-1 protein expression. In parallel, the HCC cell line Huh7 was transduced with scrambled shRNA (control) or shRNAs targeting 4E-BP1 and 4E-BP2 (4E-BP knock-down (KD)) to measure differences in mRNA translation, apoptosis, and Mcl-1 protein expression after metformin treatment. In addition, immunohistochemical staining of eIF4E and 4E-BP1 protein levels was addressed in a HCC patient tissue microarray. We found that metformin decreased HCC tumor burden, and tumor tissues showed elevated apoptosis with reduced Mcl-1 and phosphorylated 4E-BP1 protein levels. In control but not 4E-BP KD Huh7 cells, metformin induced apoptosis and repressed <i>Mcl-1</i> mRNA translation and protein levels. Immunostaining of HCC patient tumor tissues revealed a varying ratio of eIF4E/4E-BP1 expression. Our results propose that metformin induces apoptosis in mouse and cellular models of HCC through activation of 4E-BPs, thus tumors with elevated expression of 4E-BPs may display improved clinical chemopreventive benefit of metformin.</div></front></TEI><pubmed><MedlineCitation Status="PubMed-not-MEDLINE" Owner="NLM"><PMID Version="1">28881582</PMID><DateCompleted><Year>2017</Year><Month>09</Month><Day>25</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Electronic">1949-2553</ISSN><JournalIssue CitedMedium="Internet"><Volume>8</Volume><Issue>31</Issue><PubDate><Year>2017</Year><Month>Aug</Month><Day>01</Day></PubDate></JournalIssue><Title>Oncotarget</Title><ISOAbbreviation>Oncotarget</ISOAbbreviation></Journal><ArticleTitle>Metformin requires 4E-BPs to induce apoptosis and repress translation of Mcl-1 in hepatocellular carcinoma cells.</ArticleTitle><Pagination><MedlinePgn>50542-50556</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.18632/oncotarget.10671</ELocationID><Abstract><AbstractText>Metformin inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, which is frequently upregulated in hepatocellular carcinoma (HCC). Metformin has also been shown to induce apoptosis in this cancer. Here, we investigate whether metformin-induced apoptosis in HCC is mediated by the downstream mTORC1 effectors eukaryotic initiation factor 4E and (eIF4E)-binding proteins (4E-BPs). Further, we ask whether changes in 4E-BPs activity during metformin treatment negatively regulate translation of the anti-apoptotic <i>myeloid cell leukemia 1</i> (<i>Mcl-1</i>) mRNA. A genetic HCC mouse model was employed to assess the ability of metformin to reduce tumor formation, induce apoptosis, and control 4E-BP1 activation and Mcl-1 protein expression. In parallel, the HCC cell line Huh7 was transduced with scrambled shRNA (control) or shRNAs targeting 4E-BP1 and 4E-BP2 (4E-BP knock-down (KD)) to measure differences in mRNA translation, apoptosis, and Mcl-1 protein expression after metformin treatment. In addition, immunohistochemical staining of eIF4E and 4E-BP1 protein levels was addressed in a HCC patient tissue microarray. We found that metformin decreased HCC tumor burden, and tumor tissues showed elevated apoptosis with reduced Mcl-1 and phosphorylated 4E-BP1 protein levels. In control but not 4E-BP KD Huh7 cells, metformin induced apoptosis and repressed <i>Mcl-1</i> mRNA translation and protein levels. Immunostaining of HCC patient tumor tissues revealed a varying ratio of eIF4E/4E-BP1 expression. Our results propose that metformin induces apoptosis in mouse and cellular models of HCC through activation of 4E-BPs, thus tumors with elevated expression of 4E-BPs may display improved clinical chemopreventive benefit of metformin.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Bhat</LastName><ForeName>Mamatha</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Division of Gastroenterology, University Health Network and University of Toronto, Toronto, Canada, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yanagiya</LastName><ForeName>Akiko</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Graber</LastName><ForeName>Tyson</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Razumilava</LastName><ForeName>Nataliya</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bronk</LastName><ForeName>Steve</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zammit</LastName><ForeName>Domenick</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhao</LastName><ForeName>Yunhao</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Departments of Medicine and Oncology, Lady Davis Institute for Medical Research and Segal Cancer Center, Montreal, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zakaria</LastName><ForeName>Chadi</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Metrakos</LastName><ForeName>Peter</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Surgery, McGill University Health Centre, Montreal, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pollak</LastName><ForeName>Michael</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Departments of Medicine and Oncology, Lady Davis Institute for Medical Research and Segal Cancer Center, Montreal, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sonenberg</LastName><ForeName>Nahum</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gores</LastName><ForeName>Gregory</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jaramillo</LastName><ForeName>Maritza</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>INRS Institut Armand-Frappier Research Centre, Laval, Quebec, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y" EqualContrib="Y"><LastName>Morita</LastName><ForeName>Masahiro</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Goodman Cancer Centre, Department of Biochemistry, McGill University, Montreal, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y" EqualContrib="Y"><LastName>Alain</LastName><ForeName>Tommy</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Children's Hospital of Eastern Ontario Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 DK059427</GrantID><Acronym>DK</Acronym><Agency>NIDDK NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R56 DK059427</GrantID><Acronym>DK</Acronym><Agency>NIDDK NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>07</Month><Day>18</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Oncotarget</MedlineTA><NlmUniqueID>101532965</NlmUniqueID><ISSNLinking>1949-2553</ISSNLinking></MedlineJournalInfo><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">4E-BPs</Keyword><Keyword MajorTopicYN="N">hepatocellular carcinoma</Keyword><Keyword MajorTopicYN="N">mRNA translation</Keyword><Keyword MajorTopicYN="N">mTORC1</Keyword><Keyword MajorTopicYN="N">metformin</Keyword></KeywordList><CoiStatement>CONFLICTS OF INTEREST The authors have no potential conflict of interest to report.</CoiStatement></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year><Month>10</Month><Day>04</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2016</Year><Month>07</Month><Day>06</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>9</Month><Day>9</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2016</Year><Month>7</Month><Day>18</Day><Hour>0</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2016</Year><Month>7</Month><Day>18</Day><Hour>0</Hour><Minute>1</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">28881582</ArticleId><ArticleId IdType="doi">10.18632/oncotarget.10671</ArticleId><ArticleId IdType="pii">10671</ArticleId><ArticleId IdType="pmc">PMC5584165</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Cancer Res. 2006 Nov 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sort="Zammit, Domenick" uniqKey="Zammit D" first="Domenick" last="Zammit">Domenick Zammit</name><name sortKey="Zhao, Yunhao" sort="Zhao, Yunhao" uniqKey="Zhao Y" first="Yunhao" last="Zhao">Yunhao Zhao</name></country><country name="États-Unis"><noRegion><name sortKey="Bhat, Mamatha" sort="Bhat, Mamatha" uniqKey="Bhat M" first="Mamatha" last="Bhat">Mamatha Bhat</name></noRegion><name sortKey="Bhat, Mamatha" sort="Bhat, Mamatha" uniqKey="Bhat M" first="Mamatha" last="Bhat">Mamatha Bhat</name><name sortKey="Bronk, Steve" sort="Bronk, Steve" uniqKey="Bronk S" first="Steve" last="Bronk">Steve Bronk</name><name sortKey="Gores, Gregory" sort="Gores, Gregory" uniqKey="Gores G" first="Gregory" last="Gores">Gregory Gores</name><name sortKey="Razumilava, Nataliya" sort="Razumilava, Nataliya" uniqKey="Razumilava N" first="Nataliya" last="Razumilava">Nataliya Razumilava</name><name sortKey="Razumilava, Nataliya" sort="Razumilava, Nataliya" uniqKey="Razumilava N" first="Nataliya" last="Razumilava">Nataliya Razumilava</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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