Hepatocellular carcinoma-related cyclin D1 is selectively regulated by autophagy degradation system.
Identifieur interne : 000586 ( Main/Exploration ); précédent : 000585; suivant : 000587Hepatocellular carcinoma-related cyclin D1 is selectively regulated by autophagy degradation system.
Auteurs : Shan-Ying Wu [Taïwan] ; Sheng-Hui Lan [Taïwan] ; Shang-Rung Wu [Taïwan] ; Yen-Chi Chiu [Taïwan] ; Xi-Zhang Lin [Taïwan] ; Ih-Jen Su [Taïwan] ; Ting-Fen Tsai [Taïwan] ; Chia-Jui Yen [Taïwan] ; Tsung-Hsueh Lu [Taïwan] ; Fu-Wen Liang [Taïwan] ; Chung-Yi Li [Taïwan] ; Huey-Jen Su [Taïwan] ; Chun-Li Su [Taïwan] ; Hsiao-Sheng Liu [Taïwan]Source :
- Hepatology (Baltimore, Md.) [ 1527-3350 ] ; 2018.
Descripteurs français
- KwdFr :
- Adulte (MeSH), Adulte d'âge moyen (MeSH), Animaux (MeSH), Autophagie (MeSH), Autophagosomes (métabolisme), Carcinome hépatocellulaire (mortalité), Carcinome hépatocellulaire (métabolisme), Carcinome hépatocellulaire (étiologie), Cycline D1 (métabolisme), Femelle (MeSH), Humains (MeSH), Lignée cellulaire tumorale (MeSH), Mâle (MeSH), Points de contrôle du cycle cellulaire (MeSH), Prolifération cellulaire (MeSH), Protéines associées aux microtubules (métabolisme), Rat Sprague-Dawley (MeSH), Souris SCID (MeSH), Souris transgéniques (MeSH), Sujet âgé (MeSH), Sujet âgé de 80 ans ou plus (MeSH), Séquestosome-1 (métabolisme), Taïwan (épidémiologie), Tumeurs du foie (mortalité), Tumeurs du foie (métabolisme), Tumeurs du foie (étiologie), Ubiquitination (MeSH).
- MESH :
- mortalité : Carcinome hépatocellulaire, Tumeurs du foie.
- métabolisme : Autophagosomes, Carcinome hépatocellulaire, Cycline D1, Protéines associées aux microtubules, Séquestosome-1, Tumeurs du foie.
- épidémiologie : Taïwan.
- étiologie : Carcinome hépatocellulaire, Tumeurs du foie.
- Adulte, Adulte d'âge moyen, Animaux, Autophagie, Femelle, Humains, Lignée cellulaire tumorale, Mâle, Points de contrôle du cycle cellulaire, Prolifération cellulaire, Rat Sprague-Dawley, Souris SCID, Souris transgéniques, Sujet âgé, Sujet âgé de 80 ans ou plus, Ubiquitination.
- Wicri :
- geographic : Taïwan.
English descriptors
- KwdEn :
- Adult (MeSH), Aged (MeSH), Aged, 80 and over (MeSH), Animals (MeSH), Autophagosomes (metabolism), Autophagy (MeSH), Carcinoma, Hepatocellular (etiology), Carcinoma, Hepatocellular (metabolism), Carcinoma, Hepatocellular (mortality), Cell Cycle Checkpoints (MeSH), Cell Line, Tumor (MeSH), Cell Proliferation (MeSH), Cyclin D1 (metabolism), Female (MeSH), Humans (MeSH), Liver Neoplasms (etiology), Liver Neoplasms (metabolism), Liver Neoplasms (mortality), Male (MeSH), Mice, SCID (MeSH), Mice, Transgenic (MeSH), Microtubule-Associated Proteins (metabolism), Middle Aged (MeSH), Rats, Sprague-Dawley (MeSH), Sequestosome-1 Protein (metabolism), Taiwan (epidemiology), Ubiquitination (MeSH).
- MESH :
- chemical , metabolism : Cyclin D1, Microtubule-Associated Proteins, Sequestosome-1 Protein.
- geographic , epidemiology : Taiwan.
- etiology : Carcinoma, Hepatocellular, Liver Neoplasms.
- metabolism : Autophagosomes, Carcinoma, Hepatocellular, Liver Neoplasms.
- mortality : Carcinoma, Hepatocellular, Liver Neoplasms.
- Adult, Aged, Aged, 80 and over, Animals, Autophagy, Cell Cycle Checkpoints, Cell Line, Tumor, Cell Proliferation, Female, Humans, Male, Mice, SCID, Mice, Transgenic, Middle Aged, Rats, Sprague-Dawley, Ubiquitination.
Abstract
Dysfunction of degradation machineries causes cancers, including hepatocellular carcinoma (HCC). Overexpression of cyclin D1 in HCC has been reported. We previously reported that autophagy preferentially recruits and degrades the oncogenic microRNA (miR)-224 to prevent HCC. Therefore, in the present study, we attempted to clarify whether cyclin D1 is another oncogenic factor selectively regulated by autophagy in HCC tumorigenesis. Initially, we found an inverse correlation between low autophagic activity and high cyclin D1 expression in tumors of 147 HCC patients and three murine models, and these results taken together revealed a correlation with poor overall survival of HCC patients, indicating the importance of these two events in HCC development. We found that increased autophagic activity leads to cyclin D1 ubiquitination and selective recruitment to the autophagosome (AP) mediated by a specific receptor, sequestosome 1 (SQSTM1), followed by fusion with lysosome and degradation. Autophagy-selective degradation of ubiquitinated cyclin D1 through SQSTM1 was confirmed using cyclin D1/ubiquitin binding site (K33-238 R) and phosphorylation site (T286A) mutants, lentivirus-mediated silencing autophagy-related 5 (ATG5), autophagy-related 7 (ATG7), and Sqstm1 knockout cells. Functional studies revealed that autophagy-selective degradation of cyclin D1 plays suppressive roles in cell proliferation, colony, and liver tumor formation. Notably, an increase of autophagic activity by pharmacological inducers (amiodarone and rapamycin) significantly suppressed tumor growth in both the orthotopic liver tumor and subcutaneous tumor xenograft models. Our findings provide evidence of the underlying mechanism involved in the regulation of cyclin D1 by selective autophagy to prevent tumor formation.
CONCLUSION
Taken together, our data demonstrate that autophagic degradation machinery and the cell-cycle regulator, cyclin D1, are linked to HCC tumorigenesis. We believe these findings may be of value in the development of alternative therapeutics for HCC patients. (Hepatology 2018;68:141-154).
DOI: 10.1002/hep.29781
PubMed: 29328502
PubMed Central: PMC6055810
Affiliations:
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Cheng Kung University, Tainan, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2018">2018</date><idno type="RBID">pubmed:29328502</idno><idno type="pmid">29328502</idno><idno type="doi">10.1002/hep.29781</idno><idno type="pmc">PMC6055810</idno><idno type="wicri:Area/Main/Corpus">000638</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000638</idno><idno type="wicri:Area/Main/Curation">000638</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000638</idno><idno type="wicri:Area/Main/Exploration">000638</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Hepatocellular carcinoma-related cyclin D1 is selectively regulated by autophagy degradation system.</title><author><name sortKey="Wu, Shan Ying" sort="Wu, Shan Ying" uniqKey="Wu S" first="Shan-Ying" last="Wu">Shan-Ying Wu</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation></author><author><name sortKey="Lan, Sheng Hui" sort="Lan, Sheng Hui" uniqKey="Lan S" first="Sheng-Hui" last="Lan">Sheng-Hui Lan</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation></author><author><name sortKey="Wu, Shang Rung" sort="Wu, Shang Rung" uniqKey="Wu S" first="Shang-Rung" last="Wu">Shang-Rung Wu</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Oral Medicine, National Cheng Kung University, Tainan, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Oral Medicine, National Cheng Kung University, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation></author><author><name sortKey="Chiu, Yen Chi" sort="Chiu, Yen Chi" uniqKey="Chiu Y" first="Yen-Chi" last="Chiu">Yen-Chi Chiu</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation></author><author><name sortKey="Lin, Xi Zhang" sort="Lin, Xi Zhang" uniqKey="Lin X" first="Xi-Zhang" last="Lin">Xi-Zhang Lin</name><affiliation wicri:level="1"><nlm:affiliation>Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Internal Medicine, National Cheng Kung University Hospital, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation></author><author><name sortKey="Su, Ih Jen" sort="Su, Ih Jen" uniqKey="Su I" first="Ih-Jen" last="Su">Ih-Jen Su</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Pathology, National Cheng Kung University Hospital, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation></author><author><name sortKey="Tsai, Ting Fen" sort="Tsai, Ting Fen" uniqKey="Tsai T" first="Ting-Fen" last="Tsai">Ting-Fen Tsai</name><affiliation wicri:level="1"><nlm:affiliation>Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei</wicri:regionArea><wicri:noRegion>Taipei</wicri:noRegion></affiliation></author><author><name sortKey="Yen, Chia Jui" sort="Yen, Chia Jui" uniqKey="Yen C" first="Chia-Jui" last="Yen">Chia-Jui Yen</name><affiliation wicri:level="1"><nlm:affiliation>Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University hospital, College of Medicine, Tainan, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University hospital, College of Medicine, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation></author><author><name sortKey="Lu, Tsung Hsueh" sort="Lu, Tsung Hsueh" uniqKey="Lu T" first="Tsung-Hsueh" last="Lu">Tsung-Hsueh Lu</name><affiliation wicri:level="1"><nlm:affiliation>NCKU Research Center for Health Data and Department of Public Health, College of Medicine, Tainan, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>NCKU Research Center for Health Data and Department of Public Health, College of Medicine, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation></author><author><name sortKey="Liang, Fu Wen" sort="Liang, Fu Wen" uniqKey="Liang F" first="Fu-Wen" last="Liang">Fu-Wen Liang</name><affiliation wicri:level="1"><nlm:affiliation>NCKU Research Center for Health Data and Department of Public Health, College of Medicine, Tainan, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>NCKU Research Center for Health Data and Department of Public Health, College of Medicine, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation></author><author><name sortKey="Li, Chung Yi" sort="Li, Chung Yi" uniqKey="Li C" first="Chung-Yi" last="Li">Chung-Yi Li</name><affiliation wicri:level="1"><nlm:affiliation>NCKU Research Center for Health Data and Department of Public Health, College of Medicine, Tainan, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>NCKU Research Center for Health Data and Department of Public Health, College of Medicine, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation></author><author><name sortKey="Su, Huey Jen" sort="Su, Huey Jen" uniqKey="Su H" first="Huey-Jen" last="Su">Huey-Jen Su</name><affiliation wicri:level="1"><nlm:affiliation>Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation></author><author><name sortKey="Su, Chun Li" sort="Su, Chun Li" uniqKey="Su C" first="Chun-Li" last="Su">Chun-Li Su</name><affiliation wicri:level="1"><nlm:affiliation>Department of Human Development and Family Studies, National Taiwan Normal University, Taipei, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Human Development and Family Studies, National Taiwan Normal University, Taipei</wicri:regionArea><wicri:noRegion>Taipei</wicri:noRegion></affiliation></author><author><name sortKey="Liu, Hsiao Sheng" sort="Liu, Hsiao Sheng" uniqKey="Liu H" first="Hsiao-Sheng" last="Liu">Hsiao-Sheng Liu</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan</wicri:regionArea><wicri:noRegion>Tainan</wicri:noRegion></affiliation></author></analytic><series><title level="j">Hepatology (Baltimore, Md.)</title><idno type="eISSN">1527-3350</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult (MeSH)</term><term>Aged (MeSH)</term><term>Aged, 80 and over (MeSH)</term><term>Animals (MeSH)</term><term>Autophagosomes (metabolism)</term><term>Autophagy (MeSH)</term><term>Carcinoma, Hepatocellular (etiology)</term><term>Carcinoma, Hepatocellular (metabolism)</term><term>Carcinoma, Hepatocellular (mortality)</term><term>Cell Cycle Checkpoints (MeSH)</term><term>Cell Line, Tumor (MeSH)</term><term>Cell Proliferation (MeSH)</term><term>Cyclin D1 (metabolism)</term><term>Female (MeSH)</term><term>Humans (MeSH)</term><term>Liver Neoplasms (etiology)</term><term>Liver Neoplasms (metabolism)</term><term>Liver Neoplasms (mortality)</term><term>Male (MeSH)</term><term>Mice, SCID (MeSH)</term><term>Mice, Transgenic (MeSH)</term><term>Microtubule-Associated Proteins (metabolism)</term><term>Middle Aged (MeSH)</term><term>Rats, Sprague-Dawley (MeSH)</term><term>Sequestosome-1 Protein (metabolism)</term><term>Taiwan (epidemiology)</term><term>Ubiquitination (MeSH)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adulte (MeSH)</term><term>Adulte d'âge moyen (MeSH)</term><term>Animaux (MeSH)</term><term>Autophagie (MeSH)</term><term>Autophagosomes (métabolisme)</term><term>Carcinome hépatocellulaire (mortalité)</term><term>Carcinome hépatocellulaire (métabolisme)</term><term>Carcinome hépatocellulaire (étiologie)</term><term>Cycline D1 (métabolisme)</term><term>Femelle (MeSH)</term><term>Humains (MeSH)</term><term>Lignée cellulaire tumorale (MeSH)</term><term>Mâle (MeSH)</term><term>Points de contrôle du cycle cellulaire (MeSH)</term><term>Prolifération cellulaire (MeSH)</term><term>Protéines associées aux microtubules (métabolisme)</term><term>Rat Sprague-Dawley (MeSH)</term><term>Souris SCID (MeSH)</term><term>Souris transgéniques (MeSH)</term><term>Sujet âgé (MeSH)</term><term>Sujet âgé de 80 ans ou plus (MeSH)</term><term>Séquestosome-1 (métabolisme)</term><term>Taïwan (épidémiologie)</term><term>Tumeurs du foie (mortalité)</term><term>Tumeurs du foie (métabolisme)</term><term>Tumeurs du foie (étiologie)</term><term>Ubiquitination (MeSH)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cyclin D1</term><term>Microtubule-Associated Proteins</term><term>Sequestosome-1 Protein</term></keywords><keywords scheme="MESH" type="geographic" qualifier="epidemiology" xml:lang="en"><term>Taiwan</term></keywords><keywords scheme="MESH" qualifier="etiology" xml:lang="en"><term>Carcinoma, Hepatocellular</term><term>Liver Neoplasms</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Autophagosomes</term><term>Carcinoma, Hepatocellular</term><term>Liver Neoplasms</term></keywords><keywords scheme="MESH" qualifier="mortality" xml:lang="en"><term>Carcinoma, Hepatocellular</term><term>Liver Neoplasms</term></keywords><keywords scheme="MESH" qualifier="mortalité" xml:lang="fr"><term>Carcinome hépatocellulaire</term><term>Tumeurs du foie</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Autophagosomes</term><term>Carcinome hépatocellulaire</term><term>Cycline D1</term><term>Protéines associées aux microtubules</term><term>Séquestosome-1</term><term>Tumeurs du foie</term></keywords><keywords scheme="MESH" qualifier="épidémiologie" xml:lang="fr"><term>Taïwan</term></keywords><keywords scheme="MESH" qualifier="étiologie" xml:lang="fr"><term>Carcinome hépatocellulaire</term><term>Tumeurs du foie</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Aged</term><term>Aged, 80 and over</term><term>Animals</term><term>Autophagy</term><term>Cell Cycle Checkpoints</term><term>Cell Line, Tumor</term><term>Cell Proliferation</term><term>Female</term><term>Humans</term><term>Male</term><term>Mice, SCID</term><term>Mice, Transgenic</term><term>Middle Aged</term><term>Rats, Sprague-Dawley</term><term>Ubiquitination</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adulte</term><term>Adulte d'âge moyen</term><term>Animaux</term><term>Autophagie</term><term>Femelle</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Mâle</term><term>Points de contrôle du cycle cellulaire</term><term>Prolifération cellulaire</term><term>Rat Sprague-Dawley</term><term>Souris SCID</term><term>Souris transgéniques</term><term>Sujet âgé</term><term>Sujet âgé de 80 ans ou plus</term><term>Ubiquitination</term></keywords><keywords scheme="Wicri" type="geographic" xml:lang="fr"><term>Taïwan</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Dysfunction of degradation machineries causes cancers, including hepatocellular carcinoma (HCC). Overexpression of cyclin D1 in HCC has been reported. We previously reported that autophagy preferentially recruits and degrades the oncogenic microRNA (miR)-224 to prevent HCC. Therefore, in the present study, we attempted to clarify whether cyclin D1 is another oncogenic factor selectively regulated by autophagy in HCC tumorigenesis. Initially, we found an inverse correlation between low autophagic activity and high cyclin D1 expression in tumors of 147 HCC patients and three murine models, and these results taken together revealed a correlation with poor overall survival of HCC patients, indicating the importance of these two events in HCC development. We found that increased autophagic activity leads to cyclin D1 ubiquitination and selective recruitment to the autophagosome (AP) mediated by a specific receptor, sequestosome 1 (SQSTM1), followed by fusion with lysosome and degradation. Autophagy-selective degradation of ubiquitinated cyclin D1 through SQSTM1 was confirmed using cyclin D1/ubiquitin binding site (K<sub>33-238</sub> R) and phosphorylation site (T286A) mutants, lentivirus-mediated silencing autophagy-related 5 (ATG5), autophagy-related 7 (ATG7), and Sqstm1 knockout cells. Functional studies revealed that autophagy-selective degradation of cyclin D1 plays suppressive roles in cell proliferation, colony, and liver tumor formation. Notably, an increase of autophagic activity by pharmacological inducers (amiodarone and rapamycin) significantly suppressed tumor growth in both the orthotopic liver tumor and subcutaneous tumor xenograft models. Our findings provide evidence of the underlying mechanism involved in the regulation of cyclin D1 by selective autophagy to prevent tumor formation.</div><div type="abstract" xml:lang="en"><p><b>CONCLUSION</b></p><p>Taken together, our data demonstrate that autophagic degradation machinery and the cell-cycle regulator, cyclin D1, are linked to HCC tumorigenesis. We believe these findings may be of value in the development of alternative therapeutics for HCC patients. (Hepatology 2018;68:141-154).</p></div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">29328502</PMID><DateCompleted><Year>2018</Year><Month>12</Month><Day>28</Day></DateCompleted><DateRevised><Year>2018</Year><Month>12</Month><Day>28</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1527-3350</ISSN><JournalIssue CitedMedium="Internet"><Volume>68</Volume><Issue>1</Issue><PubDate><Year>2018</Year><Month>07</Month></PubDate></JournalIssue><Title>Hepatology (Baltimore, Md.)</Title><ISOAbbreviation>Hepatology</ISOAbbreviation></Journal><ArticleTitle>Hepatocellular carcinoma-related cyclin D1 is selectively regulated by autophagy degradation system.</ArticleTitle><Pagination><MedlinePgn>141-154</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1002/hep.29781</ELocationID><Abstract><AbstractText>Dysfunction of degradation machineries causes cancers, including hepatocellular carcinoma (HCC). Overexpression of cyclin D1 in HCC has been reported. We previously reported that autophagy preferentially recruits and degrades the oncogenic microRNA (miR)-224 to prevent HCC. Therefore, in the present study, we attempted to clarify whether cyclin D1 is another oncogenic factor selectively regulated by autophagy in HCC tumorigenesis. Initially, we found an inverse correlation between low autophagic activity and high cyclin D1 expression in tumors of 147 HCC patients and three murine models, and these results taken together revealed a correlation with poor overall survival of HCC patients, indicating the importance of these two events in HCC development. We found that increased autophagic activity leads to cyclin D1 ubiquitination and selective recruitment to the autophagosome (AP) mediated by a specific receptor, sequestosome 1 (SQSTM1), followed by fusion with lysosome and degradation. Autophagy-selective degradation of ubiquitinated cyclin D1 through SQSTM1 was confirmed using cyclin D1/ubiquitin binding site (K<sub>33-238</sub> R) and phosphorylation site (T286A) mutants, lentivirus-mediated silencing autophagy-related 5 (ATG5), autophagy-related 7 (ATG7), and Sqstm1 knockout cells. Functional studies revealed that autophagy-selective degradation of cyclin D1 plays suppressive roles in cell proliferation, colony, and liver tumor formation. Notably, an increase of autophagic activity by pharmacological inducers (amiodarone and rapamycin) significantly suppressed tumor growth in both the orthotopic liver tumor and subcutaneous tumor xenograft models. Our findings provide evidence of the underlying mechanism involved in the regulation of cyclin D1 by selective autophagy to prevent tumor formation.</AbstractText><AbstractText Label="CONCLUSION">Taken together, our data demonstrate that autophagic degradation machinery and the cell-cycle regulator, cyclin D1, are linked to HCC tumorigenesis. We believe these findings may be of value in the development of alternative therapeutics for HCC patients. (Hepatology 2018;68:141-154).</AbstractText><CopyrightInformation>© 2018 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Wu</LastName><ForeName>Shan-Ying</ForeName><Initials>SY</Initials><AffiliationInfo><Affiliation>Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lan</LastName><ForeName>Sheng-Hui</ForeName><Initials>SH</Initials><AffiliationInfo><Affiliation>Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wu</LastName><ForeName>Shang-Rung</ForeName><Initials>SR</Initials><AffiliationInfo><Affiliation>Institute of Oral Medicine, National Cheng Kung University, Tainan, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chiu</LastName><ForeName>Yen-Chi</ForeName><Initials>YC</Initials><AffiliationInfo><Affiliation>Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lin</LastName><ForeName>Xi-Zhang</ForeName><Initials>XZ</Initials><AffiliationInfo><Affiliation>Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Su</LastName><ForeName>Ih-Jen</ForeName><Initials>IJ</Initials><AffiliationInfo><Affiliation>Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tsai</LastName><ForeName>Ting-Fen</ForeName><Initials>TF</Initials><AffiliationInfo><Affiliation>Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yen</LastName><ForeName>Chia-Jui</ForeName><Initials>CJ</Initials><AffiliationInfo><Affiliation>Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University hospital, College of Medicine, Tainan, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lu</LastName><ForeName>Tsung-Hsueh</ForeName><Initials>TH</Initials><Identifier Source="ORCID">0000-0003-4715-3787</Identifier><AffiliationInfo><Affiliation>NCKU Research Center for Health Data and Department of Public Health, College of Medicine, Tainan, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liang</LastName><ForeName>Fu-Wen</ForeName><Initials>FW</Initials><AffiliationInfo><Affiliation>NCKU Research Center for Health Data and Department of Public Health, College of Medicine, Tainan, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Chung-Yi</ForeName><Initials>CY</Initials><AffiliationInfo><Affiliation>NCKU Research Center for Health Data and Department of Public Health, College of Medicine, Tainan, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Su</LastName><ForeName>Huey-Jen</ForeName><Initials>HJ</Initials><AffiliationInfo><Affiliation>Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Su</LastName><ForeName>Chun-Li</ForeName><Initials>CL</Initials><Identifier Source="ORCID">0000-0001-7617-2077</Identifier><AffiliationInfo><Affiliation>Department of Human Development and Family Studies, National Taiwan Normal University, Taipei, Taiwan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Hsiao-Sheng</ForeName><Initials>HS</Initials><AffiliationInfo><Affiliation>Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2018</Year><Month>03</Month><Day>23</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Hepatology</MedlineTA><NlmUniqueID>8302946</NlmUniqueID><ISSNLinking>0270-9139</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D008869">Microtubule-Associated Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C099718">SQSTM1 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000071456">Sequestosome-1 Protein</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C466626">light chain 3, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>136601-57-5</RegistryNumber><NameOfSubstance UI="D019938">Cyclin D1</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="CommentIn"><RefSource>Autophagy. 2019 Apr;15(4):729-730</RefSource><PMID Version="1">30646811</PMID></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName UI="D000328" MajorTopicYN="N">Adult</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000368" MajorTopicYN="N">Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000369" MajorTopicYN="N">Aged, 80 and over</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000071182" MajorTopicYN="N">Autophagosomes</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001343" MajorTopicYN="Y">Autophagy</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006528" MajorTopicYN="N">Carcinoma, Hepatocellular</DescriptorName><QualifierName UI="Q000209" MajorTopicYN="N">etiology</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName><QualifierName UI="Q000401" MajorTopicYN="N">mortality</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D059447" MajorTopicYN="N">Cell Cycle Checkpoints</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D049109" MajorTopicYN="N">Cell Proliferation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019938" MajorTopicYN="N">Cyclin D1</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008113" MajorTopicYN="N">Liver Neoplasms</DescriptorName><QualifierName UI="Q000209" MajorTopicYN="N">etiology</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName><QualifierName UI="Q000401" MajorTopicYN="N">mortality</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016513" MajorTopicYN="N">Mice, SCID</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008822" MajorTopicYN="N">Mice, Transgenic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008869" MajorTopicYN="N">Microtubule-Associated Proteins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008875" MajorTopicYN="N">Middle Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017207" MajorTopicYN="N">Rats, Sprague-Dawley</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000071456" MajorTopicYN="N">Sequestosome-1 Protein</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013624" MajorTopicYN="N" Type="Geographic">Taiwan</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D054875" MajorTopicYN="N">Ubiquitination</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2017</Year><Month>04</Month><Day>09</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2017</Year><Month>12</Month><Day>18</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2018</Year><Month>01</Month><Day>02</Day></PubMedPubDate><PubMedPubDate 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Yen Chi" uniqKey="Chiu Y" first="Yen-Chi" last="Chiu">Yen-Chi Chiu</name><name sortKey="Lan, Sheng Hui" sort="Lan, Sheng Hui" uniqKey="Lan S" first="Sheng-Hui" last="Lan">Sheng-Hui Lan</name><name sortKey="Lan, Sheng Hui" sort="Lan, Sheng Hui" uniqKey="Lan S" first="Sheng-Hui" last="Lan">Sheng-Hui Lan</name><name sortKey="Li, Chung Yi" sort="Li, Chung Yi" uniqKey="Li C" first="Chung-Yi" last="Li">Chung-Yi Li</name><name sortKey="Liang, Fu Wen" sort="Liang, Fu Wen" uniqKey="Liang F" first="Fu-Wen" last="Liang">Fu-Wen Liang</name><name sortKey="Lin, Xi Zhang" sort="Lin, Xi Zhang" uniqKey="Lin X" first="Xi-Zhang" last="Lin">Xi-Zhang Lin</name><name sortKey="Liu, Hsiao Sheng" sort="Liu, Hsiao Sheng" uniqKey="Liu H" first="Hsiao-Sheng" last="Liu">Hsiao-Sheng Liu</name><name sortKey="Liu, Hsiao Sheng" sort="Liu, Hsiao Sheng" uniqKey="Liu H" first="Hsiao-Sheng" last="Liu">Hsiao-Sheng Liu</name><name sortKey="Liu, Hsiao Sheng" sort="Liu, Hsiao Sheng" uniqKey="Liu H" first="Hsiao-Sheng" last="Liu">Hsiao-Sheng Liu</name><name sortKey="Lu, Tsung Hsueh" sort="Lu, Tsung Hsueh" uniqKey="Lu T" first="Tsung-Hsueh" last="Lu">Tsung-Hsueh Lu</name><name sortKey="Su, Chun Li" sort="Su, Chun Li" uniqKey="Su C" first="Chun-Li" last="Su">Chun-Li Su</name><name sortKey="Su, Huey Jen" sort="Su, Huey Jen" uniqKey="Su H" first="Huey-Jen" last="Su">Huey-Jen Su</name><name sortKey="Su, Ih Jen" sort="Su, Ih Jen" uniqKey="Su I" first="Ih-Jen" last="Su">Ih-Jen Su</name><name sortKey="Tsai, Ting Fen" sort="Tsai, Ting Fen" uniqKey="Tsai T" first="Ting-Fen" last="Tsai">Ting-Fen Tsai</name><name sortKey="Wu, Shan Ying" sort="Wu, Shan Ying" uniqKey="Wu S" first="Shan-Ying" last="Wu">Shan-Ying Wu</name><name sortKey="Wu, Shang Rung" sort="Wu, Shang Rung" uniqKey="Wu S" first="Shang-Rung" last="Wu">Shang-Rung Wu</name><name sortKey="Yen, Chia Jui" sort="Yen, Chia Jui" uniqKey="Yen C" first="Chia-Jui" last="Yen">Chia-Jui Yen</name></country></tree></affiliations></record>Pour manipuler ce document 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