Antithrombin Insufficiency Promotes Susceptibility to Liver Tumorigenesis
Antithrombin (AT) is not only a major regulator of hemostasis, but it shows anti-inflammatory properties as well. We aimed to investigate whether AT-insufficient mice increase susceptibility to liver tumorigenesis. We induced the development of liver tumor in AT-insufficient (AT+/−) mice and wild-ty...
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| Veröffentlicht in: | The Journal of surgical research 2019-04, Vol.236, p.198-208 |
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| creator | Iwako, Hiroshi Tashiro, Hirotaka Okimoto, Sho Yamaguchi, Megumi Abe, Tomoyuki Kuroda, Shintaro Kobayashi, Tsuyoshi Ohdan, Hideki |
| description | Antithrombin (AT) is not only a major regulator of hemostasis, but it shows anti-inflammatory properties as well. We aimed to investigate whether AT-insufficient mice increase susceptibility to liver tumorigenesis.
We induced the development of liver tumor in AT-insufficient (AT+/−) mice and wild-type (AT+/+) mice by treating them with diethylnitrosamine (DEN) and CCl4. The development of liver tumors and liver inflammation were compared between these mouse groups. Following this, AT was administered to the AT-insufficient mice treated with DEN and CCl4.
Tumor size and the number of DEN and CCl4-induced liver tumors significantly increased in AT-insufficient mice compared with the wild-type mice. Serum transaminase levels, cell death, and the expression of cleaved caspase-3 in liver were increased in AT+/−. Furthermore, hepatic neutrophil infiltrations and serum interleukin 6 and tumor necrosis factor-α levels were significantly elevated in AT-insufficient mice. The levels of 8-OHdG, oxidative DNA damage marker, in liver were significantly increased in AT-insufficient mice. Administration of AT led to a significant decrease in DEN- and CCl4-induced liver injury and inflammation in AT-insufficient mice, compared with the wild-type group.
AT insufficiency led to increased susceptibility to liver tumorigenesis by increasing hepatic inflammation. |
| doi_str_mv | 10.1016/j.jss.2018.11.026 |
| format | Article |
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We induced the development of liver tumor in AT-insufficient (AT+/−) mice and wild-type (AT+/+) mice by treating them with diethylnitrosamine (DEN) and CCl4. The development of liver tumors and liver inflammation were compared between these mouse groups. Following this, AT was administered to the AT-insufficient mice treated with DEN and CCl4.
Tumor size and the number of DEN and CCl4-induced liver tumors significantly increased in AT-insufficient mice compared with the wild-type mice. Serum transaminase levels, cell death, and the expression of cleaved caspase-3 in liver were increased in AT+/−. Furthermore, hepatic neutrophil infiltrations and serum interleukin 6 and tumor necrosis factor-α levels were significantly elevated in AT-insufficient mice. The levels of 8-OHdG, oxidative DNA damage marker, in liver were significantly increased in AT-insufficient mice. Administration of AT led to a significant decrease in DEN- and CCl4-induced liver injury and inflammation in AT-insufficient mice, compared with the wild-type group.
AT insufficiency led to increased susceptibility to liver tumorigenesis by increasing hepatic inflammation.</description><identifier>ISSN: 0022-4804</identifier><identifier>EISSN: 1095-8673</identifier><identifier>DOI: 10.1016/j.jss.2018.11.026</identifier><identifier>PMID: 30694755</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Antithrombin ; Antithrombin III - administration & dosage ; Antithrombin III - genetics ; Antithrombin III - metabolism ; Carbon Tetrachloride - toxicity ; Carcinoma, Hepatocellular - blood ; Carcinoma, Hepatocellular - chemically induced ; Carcinoma, Hepatocellular - pathology ; Diethylnitrosamine - toxicity ; Female ; Hepatocellular carcinoma ; Humans ; Inflammation ; Inflammation Mediators - blood ; Inflammation Mediators - metabolism ; Liver - pathology ; Liver Neoplasms, Experimental - blood ; Liver Neoplasms, Experimental - chemically induced ; Liver Neoplasms, Experimental - pathology ; Male ; Mice ; Mice, Transgenic ; Reactive oxygen species</subject><ispartof>The Journal of surgical research, 2019-04, Vol.236, p.198-208</ispartof><rights>2018 Elsevier Inc.</rights><rights>Copyright © 2018 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c462t-26661816c3138bb464cbc7eeb712caf4d7c210ddf065a60ab053beae7bd59b13</citedby><cites>FETCH-LOGICAL-c462t-26661816c3138bb464cbc7eeb712caf4d7c210ddf065a60ab053beae7bd59b13</cites><orcidid>0000-0003-2615-8183 ; 0000-0001-9881-0420</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jss.2018.11.026$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,778,782,3539,27907,27908,45978</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30694755$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Iwako, Hiroshi</creatorcontrib><creatorcontrib>Tashiro, Hirotaka</creatorcontrib><creatorcontrib>Okimoto, Sho</creatorcontrib><creatorcontrib>Yamaguchi, Megumi</creatorcontrib><creatorcontrib>Abe, Tomoyuki</creatorcontrib><creatorcontrib>Kuroda, Shintaro</creatorcontrib><creatorcontrib>Kobayashi, Tsuyoshi</creatorcontrib><creatorcontrib>Ohdan, Hideki</creatorcontrib><title>Antithrombin Insufficiency Promotes Susceptibility to Liver Tumorigenesis</title><title>The Journal of surgical research</title><addtitle>J Surg Res</addtitle><description>Antithrombin (AT) is not only a major regulator of hemostasis, but it shows anti-inflammatory properties as well. We aimed to investigate whether AT-insufficient mice increase susceptibility to liver tumorigenesis.
We induced the development of liver tumor in AT-insufficient (AT+/−) mice and wild-type (AT+/+) mice by treating them with diethylnitrosamine (DEN) and CCl4. The development of liver tumors and liver inflammation were compared between these mouse groups. Following this, AT was administered to the AT-insufficient mice treated with DEN and CCl4.
Tumor size and the number of DEN and CCl4-induced liver tumors significantly increased in AT-insufficient mice compared with the wild-type mice. Serum transaminase levels, cell death, and the expression of cleaved caspase-3 in liver were increased in AT+/−. Furthermore, hepatic neutrophil infiltrations and serum interleukin 6 and tumor necrosis factor-α levels were significantly elevated in AT-insufficient mice. The levels of 8-OHdG, oxidative DNA damage marker, in liver were significantly increased in AT-insufficient mice. Administration of AT led to a significant decrease in DEN- and CCl4-induced liver injury and inflammation in AT-insufficient mice, compared with the wild-type group.
AT insufficiency led to increased susceptibility to liver tumorigenesis by increasing hepatic inflammation.</description><subject>Animals</subject><subject>Antithrombin</subject><subject>Antithrombin III - administration & dosage</subject><subject>Antithrombin III - genetics</subject><subject>Antithrombin III - metabolism</subject><subject>Carbon Tetrachloride - toxicity</subject><subject>Carcinoma, Hepatocellular - blood</subject><subject>Carcinoma, Hepatocellular - chemically induced</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Diethylnitrosamine - toxicity</subject><subject>Female</subject><subject>Hepatocellular carcinoma</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Inflammation Mediators - blood</subject><subject>Inflammation Mediators - metabolism</subject><subject>Liver - pathology</subject><subject>Liver Neoplasms, Experimental - blood</subject><subject>Liver Neoplasms, Experimental - chemically induced</subject><subject>Liver Neoplasms, Experimental - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Reactive oxygen species</subject><issn>0022-4804</issn><issn>1095-8673</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM1OwzAQhC0EoqXwAFxQjlwSvE5iJ-JUIX4qVQKJ3q3Y2YCjJim2U6lvj0sLR06rXc2Mdj5CroEmQIHftUnrXMIoFAlAQhk_IVOgZR4XXKSnZEopY3FW0GxCLpxradhLkZ6TSUp5mYk8n5LFvPfGf9qhU6aPFr0bm8Zog73eRW_hOnh00fvoNG68UWZt_C7yQ7Q0W7TRauwGaz6wR2fcJTlrqrXDq-OckdXT4-rhJV6-Pi8e5stYZ5z5mHHOoQCuU0gLpTKeaaUFohLAdNVktdAMaF03lOcVp5WieaqwQqHqvFSQzsjtIXZjh68RnZedCd-t11WPw-gkAxGqMV4UQQoHqbaDcxYbubGmq-xOApV7gLKVAaDcA5QAMgAMnptj_Kg6rP8cv8SC4P4gwNBxa9BK94MLa2NRe1kP5p_4bxCKgnc</recordid><startdate>201904</startdate><enddate>201904</enddate><creator>Iwako, Hiroshi</creator><creator>Tashiro, Hirotaka</creator><creator>Okimoto, Sho</creator><creator>Yamaguchi, Megumi</creator><creator>Abe, Tomoyuki</creator><creator>Kuroda, Shintaro</creator><creator>Kobayashi, Tsuyoshi</creator><creator>Ohdan, Hideki</creator><general>Elsevier Inc</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>7X8</scope><orcidid>https://orcid.org/0000-0003-2615-8183</orcidid><orcidid>https://orcid.org/0000-0001-9881-0420</orcidid></search><sort><creationdate>201904</creationdate><title>Antithrombin Insufficiency Promotes Susceptibility to Liver Tumorigenesis</title><author>Iwako, Hiroshi ; Tashiro, Hirotaka ; Okimoto, Sho ; Yamaguchi, Megumi ; Abe, Tomoyuki ; Kuroda, Shintaro ; Kobayashi, Tsuyoshi ; Ohdan, Hideki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c462t-26661816c3138bb464cbc7eeb712caf4d7c210ddf065a60ab053beae7bd59b13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Antithrombin</topic><topic>Antithrombin III - administration & dosage</topic><topic>Antithrombin III - genetics</topic><topic>Antithrombin III - metabolism</topic><topic>Carbon Tetrachloride - toxicity</topic><topic>Carcinoma, Hepatocellular - blood</topic><topic>Carcinoma, Hepatocellular - chemically induced</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Diethylnitrosamine - toxicity</topic><topic>Female</topic><topic>Hepatocellular carcinoma</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Inflammation Mediators - blood</topic><topic>Inflammation Mediators - metabolism</topic><topic>Liver - pathology</topic><topic>Liver Neoplasms, Experimental - blood</topic><topic>Liver Neoplasms, Experimental - chemically induced</topic><topic>Liver Neoplasms, Experimental - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Reactive oxygen species</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Iwako, Hiroshi</creatorcontrib><creatorcontrib>Tashiro, Hirotaka</creatorcontrib><creatorcontrib>Okimoto, Sho</creatorcontrib><creatorcontrib>Yamaguchi, Megumi</creatorcontrib><creatorcontrib>Abe, Tomoyuki</creatorcontrib><creatorcontrib>Kuroda, Shintaro</creatorcontrib><creatorcontrib>Kobayashi, Tsuyoshi</creatorcontrib><creatorcontrib>Ohdan, Hideki</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of surgical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Iwako, Hiroshi</au><au>Tashiro, Hirotaka</au><au>Okimoto, Sho</au><au>Yamaguchi, Megumi</au><au>Abe, Tomoyuki</au><au>Kuroda, Shintaro</au><au>Kobayashi, Tsuyoshi</au><au>Ohdan, Hideki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antithrombin Insufficiency Promotes Susceptibility to Liver Tumorigenesis</atitle><jtitle>The Journal of surgical research</jtitle><addtitle>J Surg Res</addtitle><date>2019-04</date><risdate>2019</risdate><volume>236</volume><spage>198</spage><epage>208</epage><pages>198-208</pages><issn>0022-4804</issn><eissn>1095-8673</eissn><abstract>Antithrombin (AT) is not only a major regulator of hemostasis, but it shows anti-inflammatory properties as well. We aimed to investigate whether AT-insufficient mice increase susceptibility to liver tumorigenesis.
We induced the development of liver tumor in AT-insufficient (AT+/−) mice and wild-type (AT+/+) mice by treating them with diethylnitrosamine (DEN) and CCl4. The development of liver tumors and liver inflammation were compared between these mouse groups. Following this, AT was administered to the AT-insufficient mice treated with DEN and CCl4.
Tumor size and the number of DEN and CCl4-induced liver tumors significantly increased in AT-insufficient mice compared with the wild-type mice. Serum transaminase levels, cell death, and the expression of cleaved caspase-3 in liver were increased in AT+/−. Furthermore, hepatic neutrophil infiltrations and serum interleukin 6 and tumor necrosis factor-α levels were significantly elevated in AT-insufficient mice. The levels of 8-OHdG, oxidative DNA damage marker, in liver were significantly increased in AT-insufficient mice. Administration of AT led to a significant decrease in DEN- and CCl4-induced liver injury and inflammation in AT-insufficient mice, compared with the wild-type group.
AT insufficiency led to increased susceptibility to liver tumorigenesis by increasing hepatic inflammation.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>30694755</pmid><doi>10.1016/j.jss.2018.11.026</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-2615-8183</orcidid><orcidid>https://orcid.org/0000-0001-9881-0420</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antithrombin Antithrombin III - administration & dosage Antithrombin III - genetics Antithrombin III - metabolism Carbon Tetrachloride - toxicity Carcinoma, Hepatocellular - blood Carcinoma, Hepatocellular - chemically induced Carcinoma, Hepatocellular - pathology Diethylnitrosamine - toxicity Female Hepatocellular carcinoma Humans Inflammation Inflammation Mediators - blood Inflammation Mediators - metabolism Liver - pathology Liver Neoplasms, Experimental - blood Liver Neoplasms, Experimental - chemically induced Liver Neoplasms, Experimental - pathology Male Mice Mice, Transgenic Reactive oxygen species |
| title | Antithrombin Insufficiency Promotes Susceptibility to Liver Tumorigenesis |
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