An IKK/NF-κB Activation/p53 Deletion Sequence Drives Liver Carcinogenesis and Tumor Differentiation
Background: Most liver tumors arise on the basis of chronic liver diseases that trigger inflammatory responses. Besides inflammation, subsequent defects in the p53-signaling pathway frequently occurs in liver cancer. In this study, we analyzed the consequences of inflammation and p53 loss in liver c...
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| Veröffentlicht in: | Cancers 2019-09, Vol.11 (10), p.1410 |
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| creator | Svinarenko, Michael Katz, Sarah-Fee Tharehalli, Umesh Mulaw, Medhanie A. Maier, Harald J. Sunami, Yoshiaki Fischer, Sarah K. Chen, Yuexin Heurich, Sabine Erkert, Lena Tannapfel, Andrea Wirth, Thomas Schirmbeck, Reinhold Seufferlein, Thomas Lechel, André |
| description | Background: Most liver tumors arise on the basis of chronic liver diseases that trigger inflammatory responses. Besides inflammation, subsequent defects in the p53-signaling pathway frequently occurs in liver cancer. In this study, we analyzed the consequences of inflammation and p53 loss in liver carcinogenesis. Methods: We used inducible liver-specific transgenic mouse strains to analyze the consequences of NF-κB/p65 activation mimicking chronic inflammation and subsequent p53 loss. Results: Ikk2ca driven NF-κB/p65 activation in mice results in liver fibrosis, the formation of ectopic lymphoid structures and carcinogenesis independent of p53 expression. Subsequent deletion of Trp53 led to an increased tumor formation, metastasis and a shift in tumor differentiation towards intrahepatic cholangiocarcinoma. In addition, loss of Trp53 in an inflammatory liver resulted in elevated chromosomal instability and indicated a distinct aberration pattern. Conclusions: In conclusion, activation of NF-κB/p65 mimicking chronic inflammation provokes the formation of liver carcinoma. Collateral disruption of Trp53 supports tumor progression and influences tumor differentiation and heterogeneity. |
| doi_str_mv | 10.3390/cancers11101410 |
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Besides inflammation, subsequent defects in the p53-signaling pathway frequently occurs in liver cancer. In this study, we analyzed the consequences of inflammation and p53 loss in liver carcinogenesis. Methods: We used inducible liver-specific transgenic mouse strains to analyze the consequences of NF-κB/p65 activation mimicking chronic inflammation and subsequent p53 loss. Results: Ikk2ca driven NF-κB/p65 activation in mice results in liver fibrosis, the formation of ectopic lymphoid structures and carcinogenesis independent of p53 expression. Subsequent deletion of Trp53 led to an increased tumor formation, metastasis and a shift in tumor differentiation towards intrahepatic cholangiocarcinoma. In addition, loss of Trp53 in an inflammatory liver resulted in elevated chromosomal instability and indicated a distinct aberration pattern. Conclusions: In conclusion, activation of NF-κB/p65 mimicking chronic inflammation provokes the formation of liver carcinoma. Collateral disruption of Trp53 supports tumor progression and influences tumor differentiation and heterogeneity.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers11101410</identifier><identifier>PMID: 31546614</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Age ; Carcinogenesis ; Cholangiocarcinoma ; Chromosomes ; Fibrosis ; Gene expression ; Genomic instability ; Inflammation ; Liver cancer ; Liver diseases ; Metastases ; Mimicry ; NF-κB protein ; p53 Protein ; Principal components analysis ; Signal transduction ; Transgenic mice ; Tumors</subject><ispartof>Cancers, 2019-09, Vol.11 (10), p.1410</ispartof><rights>2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 by the authors. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c398t-5a2dd4bbf8af9466f3504cc256961284c5bdae7b2b60c41b3a226fb3ae97fc93</citedby><cites>FETCH-LOGICAL-c398t-5a2dd4bbf8af9466f3504cc256961284c5bdae7b2b60c41b3a226fb3ae97fc93</cites><orcidid>0000-0002-4907-5017 ; 0000-0003-0221-6959 ; 0000-0002-1235-7512</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827060/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827060/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids></links><search><creatorcontrib>Svinarenko, Michael</creatorcontrib><creatorcontrib>Katz, Sarah-Fee</creatorcontrib><creatorcontrib>Tharehalli, Umesh</creatorcontrib><creatorcontrib>Mulaw, Medhanie A.</creatorcontrib><creatorcontrib>Maier, Harald J.</creatorcontrib><creatorcontrib>Sunami, Yoshiaki</creatorcontrib><creatorcontrib>Fischer, Sarah K.</creatorcontrib><creatorcontrib>Chen, Yuexin</creatorcontrib><creatorcontrib>Heurich, Sabine</creatorcontrib><creatorcontrib>Erkert, Lena</creatorcontrib><creatorcontrib>Tannapfel, Andrea</creatorcontrib><creatorcontrib>Wirth, Thomas</creatorcontrib><creatorcontrib>Schirmbeck, Reinhold</creatorcontrib><creatorcontrib>Seufferlein, Thomas</creatorcontrib><creatorcontrib>Lechel, André</creatorcontrib><title>An IKK/NF-κB Activation/p53 Deletion Sequence Drives Liver Carcinogenesis and Tumor Differentiation</title><title>Cancers</title><description>Background: Most liver tumors arise on the basis of chronic liver diseases that trigger inflammatory responses. Besides inflammation, subsequent defects in the p53-signaling pathway frequently occurs in liver cancer. In this study, we analyzed the consequences of inflammation and p53 loss in liver carcinogenesis. Methods: We used inducible liver-specific transgenic mouse strains to analyze the consequences of NF-κB/p65 activation mimicking chronic inflammation and subsequent p53 loss. Results: Ikk2ca driven NF-κB/p65 activation in mice results in liver fibrosis, the formation of ectopic lymphoid structures and carcinogenesis independent of p53 expression. Subsequent deletion of Trp53 led to an increased tumor formation, metastasis and a shift in tumor differentiation towards intrahepatic cholangiocarcinoma. In addition, loss of Trp53 in an inflammatory liver resulted in elevated chromosomal instability and indicated a distinct aberration pattern. Conclusions: In conclusion, activation of NF-κB/p65 mimicking chronic inflammation provokes the formation of liver carcinoma. Collateral disruption of Trp53 supports tumor progression and influences tumor differentiation and heterogeneity.</description><subject>Age</subject><subject>Carcinogenesis</subject><subject>Cholangiocarcinoma</subject><subject>Chromosomes</subject><subject>Fibrosis</subject><subject>Gene expression</subject><subject>Genomic instability</subject><subject>Inflammation</subject><subject>Liver cancer</subject><subject>Liver diseases</subject><subject>Metastases</subject><subject>Mimicry</subject><subject>NF-κB protein</subject><subject>p53 Protein</subject><subject>Principal components analysis</subject><subject>Signal transduction</subject><subject>Transgenic mice</subject><subject>Tumors</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdUU1PGzEQtSoqQJQzV0u9cNnG37t7qRQSaBFROZC75fWOqdHGDvZuJP4aP6K_qU5BFTCH-dA8vfdGg9AZJd84b8nMmmAhZUopoYKST-iYkZpVSrXi4E1_hE5zfiAlOKe1qg_REadSKEXFMernAV_f3Mx-XVV_ni_w3I5-Z0Yfw2wrOV7CAPsB38HjBEUNL5PfQcarkhNemGR9iPcQIPuMTejxetrEhJfeOUgQRv-P6wv67MyQ4fS1nqD11eV68bNa3f64XsxXleVtM1bSsL4XXeca49riz3FJhLVMqlZR1ggru95A3bFOEStoxw1jypUCbe1sy0_Q9xfa7dRtoLdFP5lBb5PfmPSko_H6_Sb43_o-7rRqWE0UKQTnrwQplnvzqDc-WxgGEyBOWTPWKqUEkXutrx-gD3FKoVynmRS1FIyQpqBmLyibYs4J3H8zlOj9D_WHH_K_nuuQHQ</recordid><startdate>20190921</startdate><enddate>20190921</enddate><creator>Svinarenko, Michael</creator><creator>Katz, Sarah-Fee</creator><creator>Tharehalli, Umesh</creator><creator>Mulaw, Medhanie A.</creator><creator>Maier, Harald J.</creator><creator>Sunami, Yoshiaki</creator><creator>Fischer, Sarah K.</creator><creator>Chen, Yuexin</creator><creator>Heurich, Sabine</creator><creator>Erkert, Lena</creator><creator>Tannapfel, Andrea</creator><creator>Wirth, Thomas</creator><creator>Schirmbeck, Reinhold</creator><creator>Seufferlein, Thomas</creator><creator>Lechel, André</creator><general>MDPI AG</general><general>MDPI</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4907-5017</orcidid><orcidid>https://orcid.org/0000-0003-0221-6959</orcidid><orcidid>https://orcid.org/0000-0002-1235-7512</orcidid></search><sort><creationdate>20190921</creationdate><title>An IKK/NF-κB Activation/p53 Deletion Sequence Drives Liver Carcinogenesis and Tumor Differentiation</title><author>Svinarenko, Michael ; 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Besides inflammation, subsequent defects in the p53-signaling pathway frequently occurs in liver cancer. In this study, we analyzed the consequences of inflammation and p53 loss in liver carcinogenesis. Methods: We used inducible liver-specific transgenic mouse strains to analyze the consequences of NF-κB/p65 activation mimicking chronic inflammation and subsequent p53 loss. Results: Ikk2ca driven NF-κB/p65 activation in mice results in liver fibrosis, the formation of ectopic lymphoid structures and carcinogenesis independent of p53 expression. Subsequent deletion of Trp53 led to an increased tumor formation, metastasis and a shift in tumor differentiation towards intrahepatic cholangiocarcinoma. In addition, loss of Trp53 in an inflammatory liver resulted in elevated chromosomal instability and indicated a distinct aberration pattern. Conclusions: In conclusion, activation of NF-κB/p65 mimicking chronic inflammation provokes the formation of liver carcinoma. 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| subjects | Age Carcinogenesis Cholangiocarcinoma Chromosomes Fibrosis Gene expression Genomic instability Inflammation Liver cancer Liver diseases Metastases Mimicry NF-κB protein p53 Protein Principal components analysis Signal transduction Transgenic mice Tumors |
| title | An IKK/NF-κB Activation/p53 Deletion Sequence Drives Liver Carcinogenesis and Tumor Differentiation |
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