Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4
Chronic inflammation is a known risk factor for tumorigenesis, yet the precise mechanism of this association is currently unknown. The inflammasome, a multiprotein complex formed by NOD-like receptor (NLR) family members, has recently been shown to orchestrate multiple innate and adaptive immune res...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2010-12, Vol.107 (50), p.21635-21640 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Hu, Bo Elinav, Eran Huber, Samuel Booth, Carmen J. Strowig, Till Jin, Chengcheng Eisenbarth, Stephanie C. Flavell, Richard A. |
| description | Chronic inflammation is a known risk factor for tumorigenesis, yet the precise mechanism of this association is currently unknown. The inflammasome, a multiprotein complex formed by NOD-like receptor (NLR) family members, has recently been shown to orchestrate multiple innate and adaptive immune responses, yet its potential role in inflammation-induced cancer has been little studied. Using the azoxymethane and dextran sodium sulfate colitis-associated colorectal cancer model, we show that caspase-1—deficient (Casp1 -/- ) mice have enhanced tumor formation. Surprisingly, the role of caspase-1 in tumorigenesis was not through regulation of colonic inflammation, but rather through regulation of colonic epithelial cell proliferation and apoptosis. Consequently, caspase-1—deficient mice demonstrate increased colonic epithelial cell proliferation in early stages of injury-induced tumor formation and reduced apoptosis in advanced tumors. We suggest a model in which the NLRC4 inflammasome is central to colonic inflammation-induced tumor formation through regulation of epithelial cell response to injury. |
| doi_str_mv | 10.1073/pnas.1016814108 |
| format | Article |
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The inflammasome, a multiprotein complex formed by NOD-like receptor (NLR) family members, has recently been shown to orchestrate multiple innate and adaptive immune responses, yet its potential role in inflammation-induced cancer has been little studied. Using the azoxymethane and dextran sodium sulfate colitis-associated colorectal cancer model, we show that caspase-1—deficient (Casp1 -/- ) mice have enhanced tumor formation. Surprisingly, the role of caspase-1 in tumorigenesis was not through regulation of colonic inflammation, but rather through regulation of colonic epithelial cell proliferation and apoptosis. Consequently, caspase-1—deficient mice demonstrate increased colonic epithelial cell proliferation in early stages of injury-induced tumor formation and reduced apoptosis in advanced tumors. We suggest a model in which the NLRC4 inflammasome is central to colonic inflammation-induced tumor formation through regulation of epithelial cell response to injury.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1016814108</identifier><identifier>PMID: 21118981</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Apoptosis ; Apoptosis Regulatory Proteins - genetics ; Apoptosis Regulatory Proteins - metabolism ; Biological Sciences ; Calcium-Binding Proteins - genetics ; Calcium-Binding Proteins - metabolism ; Cancer ; Caspase 1 - genetics ; Caspase 1 - metabolism ; Cellular biology ; Colitis ; Colitis - chemically induced ; Colitis - metabolism ; Colitis - pathology ; Colon - metabolism ; Colon - pathology ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - pathology ; Colorectal cancer ; Colorectal carcinoma ; Dextran Sulfate - adverse effects ; Epithelial cells ; Humans ; Immune system ; Inflammation ; Inflammation - metabolism ; Inflammation - pathology ; Inflammatory diseases ; Messenger RNA ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Proteins ; Risk factors ; Rodents ; Sodium sulfate ; T lymphocytes ; Tumor burden ; Tumors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2010-12, Vol.107 (50), p.21635-21640</ispartof><rights>Copyright National Academy of Sciences Dec 14, 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c532t-fcaa30d1672d9d51b7b5ed9a25f3589fe57937812a3bb84f30b1a0f1af3e4d233</citedby><cites>FETCH-LOGICAL-c532t-fcaa30d1672d9d51b7b5ed9a25f3589fe57937812a3bb84f30b1a0f1af3e4d233</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/107/50.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25756936$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25756936$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21118981$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hu, Bo</creatorcontrib><creatorcontrib>Elinav, Eran</creatorcontrib><creatorcontrib>Huber, Samuel</creatorcontrib><creatorcontrib>Booth, Carmen J.</creatorcontrib><creatorcontrib>Strowig, Till</creatorcontrib><creatorcontrib>Jin, Chengcheng</creatorcontrib><creatorcontrib>Eisenbarth, Stephanie C.</creatorcontrib><creatorcontrib>Flavell, Richard A.</creatorcontrib><title>Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Chronic inflammation is a known risk factor for tumorigenesis, yet the precise mechanism of this association is currently unknown. The inflammasome, a multiprotein complex formed by NOD-like receptor (NLR) family members, has recently been shown to orchestrate multiple innate and adaptive immune responses, yet its potential role in inflammation-induced cancer has been little studied. Using the azoxymethane and dextran sodium sulfate colitis-associated colorectal cancer model, we show that caspase-1—deficient (Casp1 -/- ) mice have enhanced tumor formation. Surprisingly, the role of caspase-1 in tumorigenesis was not through regulation of colonic inflammation, but rather through regulation of colonic epithelial cell proliferation and apoptosis. Consequently, caspase-1—deficient mice demonstrate increased colonic epithelial cell proliferation in early stages of injury-induced tumor formation and reduced apoptosis in advanced tumors. We suggest a model in which the NLRC4 inflammasome is central to colonic inflammation-induced tumor formation through regulation of epithelial cell response to injury.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis Regulatory Proteins - genetics</subject><subject>Apoptosis Regulatory Proteins - metabolism</subject><subject>Biological Sciences</subject><subject>Calcium-Binding Proteins - genetics</subject><subject>Calcium-Binding Proteins - metabolism</subject><subject>Cancer</subject><subject>Caspase 1 - genetics</subject><subject>Caspase 1 - metabolism</subject><subject>Cellular biology</subject><subject>Colitis</subject><subject>Colitis - chemically induced</subject><subject>Colitis - metabolism</subject><subject>Colitis - pathology</subject><subject>Colon - metabolism</subject><subject>Colon - pathology</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Colonic Neoplasms - pathology</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Dextran Sulfate - adverse effects</subject><subject>Epithelial cells</subject><subject>Humans</subject><subject>Immune system</subject><subject>Inflammation</subject><subject>Inflammation - metabolism</subject><subject>Inflammation - pathology</subject><subject>Inflammatory diseases</subject><subject>Messenger RNA</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Proteins</subject><subject>Risk factors</subject><subject>Rodents</subject><subject>Sodium sulfate</subject><subject>T lymphocytes</subject><subject>Tumor burden</subject><subject>Tumors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUFr3DAQRkVoabZpzjm1iN7dzFiWLV0CZWnSwJJC0pyFbEkbL7a0kexC_n207DbbniShN2-G-Qi5QPiG0LDLrdcp37AWWCGIE7JAkFjUlYR3ZAFQNoWoyuqUfExpAwCSC_hATktEFFLggjzcejfocdRTH3zRezN31tBpHkPs19bb1Cfaezo9WdqFIXia39Gu50FPmWtfaKfTVidbINXe0LvV_bL6RN47PSR7fjjPyOP1j9_Ln8Xq183t8vuq6Dgrp8J1WjMwWDelkYZj27TcGqlL7hgX0lneSNYILDVrW1E5Bi1qcKgds5UpGTsjV3vvdm5Hazrrp6gHtY39qOOLCrpX___4_kmtwx_FABiIneDrQRDD82zTpDZhjj7PrAQKnpfIZYYu91AXQ0rRurcGCGoXgtqFoI4h5Iov_871xv_degboAdhVHnWN4pCpmvGMfN4jmzSFeFTwhteS1ewVc6GXpw</recordid><startdate>20101214</startdate><enddate>20101214</enddate><creator>Hu, Bo</creator><creator>Elinav, Eran</creator><creator>Huber, Samuel</creator><creator>Booth, Carmen J.</creator><creator>Strowig, Till</creator><creator>Jin, Chengcheng</creator><creator>Eisenbarth, Stephanie C.</creator><creator>Flavell, Richard A.</creator><general>National Academy of Sciences</general><general>National Acad Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20101214</creationdate><title>Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4</title><author>Hu, Bo ; 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We suggest a model in which the NLRC4 inflammasome is central to colonic inflammation-induced tumor formation through regulation of epithelial cell response to injury.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>21118981</pmid><doi>10.1073/pnas.1016814108</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis Apoptosis Regulatory Proteins - genetics Apoptosis Regulatory Proteins - metabolism Biological Sciences Calcium-Binding Proteins - genetics Calcium-Binding Proteins - metabolism Cancer Caspase 1 - genetics Caspase 1 - metabolism Cellular biology Colitis Colitis - chemically induced Colitis - metabolism Colitis - pathology Colon - metabolism Colon - pathology Colonic Neoplasms - metabolism Colonic Neoplasms - pathology Colorectal cancer Colorectal carcinoma Dextran Sulfate - adverse effects Epithelial cells Humans Immune system Inflammation Inflammation - metabolism Inflammation - pathology Inflammatory diseases Messenger RNA Mice Mice, Inbred C57BL Mice, Knockout Proteins Risk factors Rodents Sodium sulfate T lymphocytes Tumor burden Tumors |
| title | Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4 |
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