Myc-induced liver tumors in transgenic zebrafish can regress in tp53 null mutation
Hepatocellular carcinoma (HCC) is currently one of the top lethal cancers with an increasing trend. Deregulation of MYC in HCC is frequently detected and always correlated with poor prognosis. As the zebrafish genome contains two differentially expressed zebrafish myc orthologs, myca and mycb, it re...
Gespeichert in:
| Veröffentlicht in: | PloS one 2015-01, Vol.10 (1), p.e0117249-e0117249 |
|---|---|
| Hauptverfasser: | , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | e0117249 |
|---|---|
| container_issue | 1 |
| container_start_page | e0117249 |
| container_title | PloS one |
| container_volume | 10 |
| creator | Sun, Lili Nguyen, Anh Tuan Spitsbergen, Jan M Gong, Zhiyuan |
| description | Hepatocellular carcinoma (HCC) is currently one of the top lethal cancers with an increasing trend. Deregulation of MYC in HCC is frequently detected and always correlated with poor prognosis. As the zebrafish genome contains two differentially expressed zebrafish myc orthologs, myca and mycb, it remains unclear about the oncogenicity of the two zebrafish myc genes. In the present study, we developed two transgenic zebrafish lines to over-express myca and mycb respectively in the liver using a mifepristone-inducible system and found that both myc genes were oncogenic. Moreover, the transgenic expression of myca in hepatocytes caused robust liver tumors with several distinct phenotypes of variable severity. ~5% of myca transgenic fish developing multinodular HCC with cirrhosis after 8 months of induced myca expression. Apoptosis was also observed with myca expression; introduction of homozygous tp53(-/-) mutation into the myca transgenic fish reduced apoptosis and accelerated tumor progression. The malignant status of hepatocytes was dependent on continued expression of myca; withdrawal of the mifepristone inducer resulted in a rapid regression of liver tumors, and the tumor regression occurred even in the tp53(-/-) mutation background. Thus, our data demonstrated the robust oncogenicity of zebrafish myca and the requirement of sustained Myc overexpression for maintenance of the liver tumor phenotype in this transgenic model. Furthermore, tumor regression is independent of the function of Tp53. |
| doi_str_mv | 10.1371/journal.pone.0117249 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_1658445651</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A422548000</galeid><doaj_id>oai_doaj_org_article_c147eb542c67451386b7855373cb9d54</doaj_id><sourcerecordid>A422548000</sourcerecordid><originalsourceid>FETCH-LOGICAL-c692t-3de86cceec0fe927369310c368e6cac338e0fa31e1262c5e522a1500e6aaef093</originalsourceid><addsrcrecordid>eNqNkktr3DAUhU1padK0_6C0hkJpF57qbXtTCKGPgZRA-tgKjXzt0SBLE8kOTX99NRknjEsWRQsJ6TvnSlcny15itMC0xB82fgxO2cXWO1ggjEvC6kfZMa4pKQRB9PHB-ih7FuMGIU4rIZ5mR4QLTCiqj7PLbze6MK4ZNTS5NdcQ8mHsfYi5cfkQlIsdOKPzP7AKqjVxnWvl8gBdgLhntpzmbrQ278dBDca759mTVtkIL6b5JPv5-dOPs6_F-cWX5dnpeaFFTYaCNlAJrQE0aqEmJRU1xUhTUYHQSlNaAWoVxYCJIJoDJ0RhjhAIpaBFNT3JXu99t9ZHObUjSix4xRgXHCdiuScarzZyG0yvwo30ysjbDR86qcJgtAWpMSthxRnRomRJWolVWXFOS6pXdcNZ8vo4VRtXPTQaXOqOnZnOT5xZy85fS0YRZUQkg3eTQfBXI8RB9iZqsFY58OPtvQkjCLMqoW_-QR9-3UR1Kj3AuNanunpnKk8ZIZxVCKFELR6g0migNzplpzVpfyZ4PxMkZoDfQ6fGGOXy--X_sxe_5uzbA3YNyg7r6O24i0ycg2wP6uBjDNDeNxkjuYv-XTfkLvpyin6SvTr8oHvRXdbpX4hU_Mo</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1658445651</pqid></control><display><type>article</type><title>Myc-induced liver tumors in transgenic zebrafish can regress in tp53 null mutation</title><source>PLoS</source><source>MEDLINE</source><source>Full-Text Journals in Chemistry (Open access)</source><source>DOAJ Directory of Open Access Journals</source><source>PubMed Central</source><source>EZB Electronic Journals Library</source><creator>Sun, Lili ; Nguyen, Anh Tuan ; Spitsbergen, Jan M ; Gong, Zhiyuan</creator><creatorcontrib>Sun, Lili ; Nguyen, Anh Tuan ; Spitsbergen, Jan M ; Gong, Zhiyuan</creatorcontrib><description>Hepatocellular carcinoma (HCC) is currently one of the top lethal cancers with an increasing trend. Deregulation of MYC in HCC is frequently detected and always correlated with poor prognosis. As the zebrafish genome contains two differentially expressed zebrafish myc orthologs, myca and mycb, it remains unclear about the oncogenicity of the two zebrafish myc genes. In the present study, we developed two transgenic zebrafish lines to over-express myca and mycb respectively in the liver using a mifepristone-inducible system and found that both myc genes were oncogenic. Moreover, the transgenic expression of myca in hepatocytes caused robust liver tumors with several distinct phenotypes of variable severity. ~5% of myca transgenic fish developing multinodular HCC with cirrhosis after 8 months of induced myca expression. Apoptosis was also observed with myca expression; introduction of homozygous tp53(-/-) mutation into the myca transgenic fish reduced apoptosis and accelerated tumor progression. The malignant status of hepatocytes was dependent on continued expression of myca; withdrawal of the mifepristone inducer resulted in a rapid regression of liver tumors, and the tumor regression occurred even in the tp53(-/-) mutation background. Thus, our data demonstrated the robust oncogenicity of zebrafish myca and the requirement of sustained Myc overexpression for maintenance of the liver tumor phenotype in this transgenic model. Furthermore, tumor regression is independent of the function of Tp53.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0117249</identifier><identifier>PMID: 25612309</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animal genetic engineering ; Animals ; Animals, Genetically Modified ; Apoptosis ; Carcinoma, Hepatocellular - genetics ; Carcinoma, Hepatocellular - metabolism ; Cirrhosis ; Danio rerio ; Deregulation ; Development and progression ; Fish ; Gene expression ; Genes ; Genetic aspects ; Genetic research ; Genetically modified animals ; Genomes ; Hepatocellular carcinoma ; Hepatocytes ; Liver ; Liver cancer ; Liver cirrhosis ; Liver Neoplasms - genetics ; Liver Neoplasms - metabolism ; Mifepristone ; Mutation ; Myc protein ; p53 Protein ; Proto-Oncogene Proteins c-myc - biosynthesis ; Proto-Oncogene Proteins c-myc - genetics ; Regression models ; Rodents ; Transgenic fish ; Tumor proteins ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Tumors ; Zebrafish ; Zebrafish - genetics ; Zebrafish - metabolism ; Zebrafish Proteins - genetics ; Zebrafish Proteins - metabolism</subject><ispartof>PloS one, 2015-01, Vol.10 (1), p.e0117249-e0117249</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Sun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Sun et al 2015 Sun et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-3de86cceec0fe927369310c368e6cac338e0fa31e1262c5e522a1500e6aaef093</citedby><cites>FETCH-LOGICAL-c692t-3de86cceec0fe927369310c368e6cac338e0fa31e1262c5e522a1500e6aaef093</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303426/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303426/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25612309$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, Lili</creatorcontrib><creatorcontrib>Nguyen, Anh Tuan</creatorcontrib><creatorcontrib>Spitsbergen, Jan M</creatorcontrib><creatorcontrib>Gong, Zhiyuan</creatorcontrib><title>Myc-induced liver tumors in transgenic zebrafish can regress in tp53 null mutation</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Hepatocellular carcinoma (HCC) is currently one of the top lethal cancers with an increasing trend. Deregulation of MYC in HCC is frequently detected and always correlated with poor prognosis. As the zebrafish genome contains two differentially expressed zebrafish myc orthologs, myca and mycb, it remains unclear about the oncogenicity of the two zebrafish myc genes. In the present study, we developed two transgenic zebrafish lines to over-express myca and mycb respectively in the liver using a mifepristone-inducible system and found that both myc genes were oncogenic. Moreover, the transgenic expression of myca in hepatocytes caused robust liver tumors with several distinct phenotypes of variable severity. ~5% of myca transgenic fish developing multinodular HCC with cirrhosis after 8 months of induced myca expression. Apoptosis was also observed with myca expression; introduction of homozygous tp53(-/-) mutation into the myca transgenic fish reduced apoptosis and accelerated tumor progression. The malignant status of hepatocytes was dependent on continued expression of myca; withdrawal of the mifepristone inducer resulted in a rapid regression of liver tumors, and the tumor regression occurred even in the tp53(-/-) mutation background. Thus, our data demonstrated the robust oncogenicity of zebrafish myca and the requirement of sustained Myc overexpression for maintenance of the liver tumor phenotype in this transgenic model. Furthermore, tumor regression is independent of the function of Tp53.</description><subject>Animal genetic engineering</subject><subject>Animals</subject><subject>Animals, Genetically Modified</subject><subject>Apoptosis</subject><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Cirrhosis</subject><subject>Danio rerio</subject><subject>Deregulation</subject><subject>Development and progression</subject><subject>Fish</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic research</subject><subject>Genetically modified animals</subject><subject>Genomes</subject><subject>Hepatocellular carcinoma</subject><subject>Hepatocytes</subject><subject>Liver</subject><subject>Liver cancer</subject><subject>Liver cirrhosis</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - metabolism</subject><subject>Mifepristone</subject><subject>Mutation</subject><subject>Myc protein</subject><subject>p53 Protein</subject><subject>Proto-Oncogene Proteins c-myc - biosynthesis</subject><subject>Proto-Oncogene Proteins c-myc - genetics</subject><subject>Regression models</subject><subject>Rodents</subject><subject>Transgenic fish</subject><subject>Tumor proteins</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumors</subject><subject>Zebrafish</subject><subject>Zebrafish - genetics</subject><subject>Zebrafish - metabolism</subject><subject>Zebrafish Proteins - genetics</subject><subject>Zebrafish Proteins - metabolism</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkktr3DAUhU1padK0_6C0hkJpF57qbXtTCKGPgZRA-tgKjXzt0SBLE8kOTX99NRknjEsWRQsJ6TvnSlcny15itMC0xB82fgxO2cXWO1ggjEvC6kfZMa4pKQRB9PHB-ih7FuMGIU4rIZ5mR4QLTCiqj7PLbze6MK4ZNTS5NdcQ8mHsfYi5cfkQlIsdOKPzP7AKqjVxnWvl8gBdgLhntpzmbrQ278dBDca759mTVtkIL6b5JPv5-dOPs6_F-cWX5dnpeaFFTYaCNlAJrQE0aqEmJRU1xUhTUYHQSlNaAWoVxYCJIJoDJ0RhjhAIpaBFNT3JXu99t9ZHObUjSix4xRgXHCdiuScarzZyG0yvwo30ysjbDR86qcJgtAWpMSthxRnRomRJWolVWXFOS6pXdcNZ8vo4VRtXPTQaXOqOnZnOT5xZy85fS0YRZUQkg3eTQfBXI8RB9iZqsFY58OPtvQkjCLMqoW_-QR9-3UR1Kj3AuNanunpnKk8ZIZxVCKFELR6g0migNzplpzVpfyZ4PxMkZoDfQ6fGGOXy--X_sxe_5uzbA3YNyg7r6O24i0ycg2wP6uBjDNDeNxkjuYv-XTfkLvpyin6SvTr8oHvRXdbpX4hU_Mo</recordid><startdate>20150122</startdate><enddate>20150122</enddate><creator>Sun, Lili</creator><creator>Nguyen, Anh Tuan</creator><creator>Spitsbergen, Jan M</creator><creator>Gong, Zhiyuan</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150122</creationdate><title>Myc-induced liver tumors in transgenic zebrafish can regress in tp53 null mutation</title><author>Sun, Lili ; Nguyen, Anh Tuan ; Spitsbergen, Jan M ; Gong, Zhiyuan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-3de86cceec0fe927369310c368e6cac338e0fa31e1262c5e522a1500e6aaef093</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animal genetic engineering</topic><topic>Animals</topic><topic>Animals, Genetically Modified</topic><topic>Apoptosis</topic><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Cirrhosis</topic><topic>Danio rerio</topic><topic>Deregulation</topic><topic>Development and progression</topic><topic>Fish</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genetic research</topic><topic>Genetically modified animals</topic><topic>Genomes</topic><topic>Hepatocellular carcinoma</topic><topic>Hepatocytes</topic><topic>Liver</topic><topic>Liver cancer</topic><topic>Liver cirrhosis</topic><topic>Liver Neoplasms - genetics</topic><topic>Liver Neoplasms - metabolism</topic><topic>Mifepristone</topic><topic>Mutation</topic><topic>Myc protein</topic><topic>p53 Protein</topic><topic>Proto-Oncogene Proteins c-myc - biosynthesis</topic><topic>Proto-Oncogene Proteins c-myc - genetics</topic><topic>Regression models</topic><topic>Rodents</topic><topic>Transgenic fish</topic><topic>Tumor proteins</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumors</topic><topic>Zebrafish</topic><topic>Zebrafish - genetics</topic><topic>Zebrafish - metabolism</topic><topic>Zebrafish Proteins - genetics</topic><topic>Zebrafish Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sun, Lili</creatorcontrib><creatorcontrib>Nguyen, Anh Tuan</creatorcontrib><creatorcontrib>Spitsbergen, Jan M</creatorcontrib><creatorcontrib>Gong, Zhiyuan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Opposing Viewpoints Resource Center</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>ProQuest Nursing and Allied Health Journals</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>ProQuest Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Database (1962 - current)</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>Biological Sciences</collection><collection>Agriculture Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest advanced technologies & aerospace journals</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Applied & Life Sciences</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sun, Lili</au><au>Nguyen, Anh Tuan</au><au>Spitsbergen, Jan M</au><au>Gong, Zhiyuan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Myc-induced liver tumors in transgenic zebrafish can regress in tp53 null mutation</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-01-22</date><risdate>2015</risdate><volume>10</volume><issue>1</issue><spage>e0117249</spage><epage>e0117249</epage><pages>e0117249-e0117249</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Hepatocellular carcinoma (HCC) is currently one of the top lethal cancers with an increasing trend. Deregulation of MYC in HCC is frequently detected and always correlated with poor prognosis. As the zebrafish genome contains two differentially expressed zebrafish myc orthologs, myca and mycb, it remains unclear about the oncogenicity of the two zebrafish myc genes. In the present study, we developed two transgenic zebrafish lines to over-express myca and mycb respectively in the liver using a mifepristone-inducible system and found that both myc genes were oncogenic. Moreover, the transgenic expression of myca in hepatocytes caused robust liver tumors with several distinct phenotypes of variable severity. ~5% of myca transgenic fish developing multinodular HCC with cirrhosis after 8 months of induced myca expression. Apoptosis was also observed with myca expression; introduction of homozygous tp53(-/-) mutation into the myca transgenic fish reduced apoptosis and accelerated tumor progression. The malignant status of hepatocytes was dependent on continued expression of myca; withdrawal of the mifepristone inducer resulted in a rapid regression of liver tumors, and the tumor regression occurred even in the tp53(-/-) mutation background. Thus, our data demonstrated the robust oncogenicity of zebrafish myca and the requirement of sustained Myc overexpression for maintenance of the liver tumor phenotype in this transgenic model. Furthermore, tumor regression is independent of the function of Tp53.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25612309</pmid><doi>10.1371/journal.pone.0117249</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-01, Vol.10 (1), p.e0117249-e0117249 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1658445651 |
| source | PLoS; MEDLINE; Full-Text Journals in Chemistry (Open access); DOAJ Directory of Open Access Journals; PubMed Central; EZB Electronic Journals Library |
| subjects | Animal genetic engineering Animals Animals, Genetically Modified Apoptosis Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - metabolism Cirrhosis Danio rerio Deregulation Development and progression Fish Gene expression Genes Genetic aspects Genetic research Genetically modified animals Genomes Hepatocellular carcinoma Hepatocytes Liver Liver cancer Liver cirrhosis Liver Neoplasms - genetics Liver Neoplasms - metabolism Mifepristone Mutation Myc protein p53 Protein Proto-Oncogene Proteins c-myc - biosynthesis Proto-Oncogene Proteins c-myc - genetics Regression models Rodents Transgenic fish Tumor proteins Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumors Zebrafish Zebrafish - genetics Zebrafish - metabolism Zebrafish Proteins - genetics Zebrafish Proteins - metabolism |
| title | Myc-induced liver tumors in transgenic zebrafish can regress in tp53 null mutation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-14T19%3A01%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Myc-induced%20liver%20tumors%20in%20transgenic%20zebrafish%20can%20regress%20in%20tp53%20null%20mutation&rft.jtitle=PloS%20one&rft.au=Sun,%20Lili&rft.date=2015-01-22&rft.volume=10&rft.issue=1&rft.spage=e0117249&rft.epage=e0117249&rft.pages=e0117249-e0117249&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0117249&rft_dat=%3Cgale_plos_%3EA422548000%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1658445651&rft_id=info:pmid/25612309&rft_galeid=A422548000&rft_doaj_id=oai_doaj_org_article_c147eb542c67451386b7855373cb9d54&rfr_iscdi=true |