Elevated MMP10/13 mediated barrier disruption and NF-κB activation aggravate colitis and colon tumorigenesis in both individual or full miR-148/152 family knockout mice

Dynamic miRNA alteration is known to occur in colitis-associated colon cancer (CAC), while the molecular mechanisms underpinning how miRNAs modulate the development from chronic inflammation to CAC is lacking. For the first time, we constructed knockout (KO) mice for individual miR-148/152 family me...

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Veröffentlicht in:Cancer letters 2022-03, Vol.529, p.53-69
Hauptverfasser: Tang, Kaiwen, Wu, Zhonghua, Sun, Mingwei, Huang, Xuanzhang, Sun, Jingxu, Shi, Jinxin, Wang, Xin, Miao, Zhifeng, Gao, Peng, Song, Yongxi, Wang, Zhenning
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container_issue
container_start_page 53
container_title Cancer letters
container_volume 529
creator Tang, Kaiwen
Wu, Zhonghua
Sun, Mingwei
Huang, Xuanzhang
Sun, Jingxu
Shi, Jinxin
Wang, Xin
Miao, Zhifeng
Gao, Peng
Song, Yongxi
Wang, Zhenning
description Dynamic miRNA alteration is known to occur in colitis-associated colon cancer (CAC), while the molecular mechanisms underpinning how miRNAs modulate the development from chronic inflammation to CAC is lacking. For the first time, we constructed knockout (KO) mice for individual miR-148/152 family members and entire miR-148/152 family. Based on these KO mice, we conduct the first comprehensive analysis of miR-148/152 family, demonstrating that deficiency of any member of miR-148/152 family aggravate colitis and CAC. Loss of individual miR-148/152 family members or full-family enhance MMP10 and MMP13 expression, causing disruption of intestinal barrier and cleaving pro-TNF-α into bioactive TNF-α fragments to activate NF-κB signaling, thereby aggravating colitis. Individual and full-family deletion also increase accumulation of IKKα and IKKβ, resulting in further hyperactivation of NF-κB signaling, exacerbating colitis and CAC. Moreover, blocking NF-κB signaling exerts a restorative effect on colitis and CAC models only in KO mice. Taken together, these findings demonstrate deleting the full miR-148/152 family or individual members exhibit similar effects in colitis and CAC. Mechanically, miR-148/152 family members deficiency in mice elevates MMP10 and MMP13 to accelerate colitis and CAC via disrupting intestinal barrier function and activating NF-κB signaling, suggesting a potential therapeutic strategy for colitis and CAC. •We firstly constructed knockout (KO) mice for individual miR-148/152 family members and the entire miR-148/152 family.•Deleting miR-148/152 family members caused overexpression of targeted genes MMP10, MMP13, IKKα and IKKβ.•MiR-148/152 family deficiency upregulated MMP10/13, resulting in TNF-α maturation and sequential NF-κB pathway activation.•MiR-148/152 family deficiency mediated IKKα/β overexpression could activate NF-κB signaling pathway.•Our findings suggest impeding NF-κB pathway could treat colitis or colon cancer patients with miR-148/152 downregulation.
doi_str_mv 10.1016/j.canlet.2021.12.033
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For the first time, we constructed knockout (KO) mice for individual miR-148/152 family members and entire miR-148/152 family. Based on these KO mice, we conduct the first comprehensive analysis of miR-148/152 family, demonstrating that deficiency of any member of miR-148/152 family aggravate colitis and CAC. Loss of individual miR-148/152 family members or full-family enhance MMP10 and MMP13 expression, causing disruption of intestinal barrier and cleaving pro-TNF-α into bioactive TNF-α fragments to activate NF-κB signaling, thereby aggravating colitis. Individual and full-family deletion also increase accumulation of IKKα and IKKβ, resulting in further hyperactivation of NF-κB signaling, exacerbating colitis and CAC. Moreover, blocking NF-κB signaling exerts a restorative effect on colitis and CAC models only in KO mice. Taken together, these findings demonstrate deleting the full miR-148/152 family or individual members exhibit similar effects in colitis and CAC. Mechanically, miR-148/152 family members deficiency in mice elevates MMP10 and MMP13 to accelerate colitis and CAC via disrupting intestinal barrier function and activating NF-κB signaling, suggesting a potential therapeutic strategy for colitis and CAC. •We firstly constructed knockout (KO) mice for individual miR-148/152 family members and the entire miR-148/152 family.•Deleting miR-148/152 family members caused overexpression of targeted genes MMP10, MMP13, IKKα and IKKβ.•MiR-148/152 family deficiency upregulated MMP10/13, resulting in TNF-α maturation and sequential NF-κB pathway activation.•MiR-148/152 family deficiency mediated IKKα/β overexpression could activate NF-κB signaling pathway.•Our findings suggest impeding NF-κB pathway could treat colitis or colon cancer patients with miR-148/152 downregulation.</description><identifier>ISSN: 0304-3835</identifier><identifier>EISSN: 1872-7980</identifier><identifier>DOI: 10.1016/j.canlet.2021.12.033</identifier><identifier>PMID: 34979166</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>Animal models ; Animals ; Carcinogenesis - genetics ; Carcinogenesis - metabolism ; Cell Line, Tumor ; Colitis ; Colitis - etiology ; Colitis-associated colon cancer ; Collagenase 3 ; Colon cancer ; Colonic Neoplasms - etiology ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - pathology ; Colorectal cancer ; Disease ; Disease Models, Animal ; Disease Progression ; Drinking water ; Fluorescent Antibody Technique ; Gene expression ; Gene Knockdown Techniques ; Homeostasis ; Humans ; Immunohistochemistry ; Inflammatory bowel disease ; Intestinal Mucosa - metabolism ; Intestinal Mucosa - pathology ; Intestine ; Laboratory animals ; Matrix Metalloproteinase 10 - genetics ; Matrix Metalloproteinase 10 - metabolism ; Matrix Metalloproteinase 13 - genetics ; Matrix Metalloproteinase 13 - metabolism ; Mice ; Mice, Knockout ; MicroRNAs - genetics ; MicroRNAs - metabolism ; miRNA ; miRNAs ; Molecular modelling ; NF-kappa B - metabolism ; NF-κB protein ; Pathogens ; Proteins ; Reagents ; Signal Transduction ; Stromelysin 2 ; Tumor necrosis factor-α ; Tumorigenesis</subject><ispartof>Cancer letters, 2022-03, Vol.529, p.53-69</ispartof><rights>2022 The Authors</rights><rights>Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.</rights><rights>2022. The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c436t-6ec24fdfae884db7d054cbf88304dc175bfd9c5993a0189a72f3eb691c1c4b9f3</citedby><cites>FETCH-LOGICAL-c436t-6ec24fdfae884db7d054cbf88304dc175bfd9c5993a0189a72f3eb691c1c4b9f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.canlet.2021.12.033$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34979166$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tang, Kaiwen</creatorcontrib><creatorcontrib>Wu, Zhonghua</creatorcontrib><creatorcontrib>Sun, Mingwei</creatorcontrib><creatorcontrib>Huang, Xuanzhang</creatorcontrib><creatorcontrib>Sun, Jingxu</creatorcontrib><creatorcontrib>Shi, Jinxin</creatorcontrib><creatorcontrib>Wang, Xin</creatorcontrib><creatorcontrib>Miao, Zhifeng</creatorcontrib><creatorcontrib>Gao, Peng</creatorcontrib><creatorcontrib>Song, Yongxi</creatorcontrib><creatorcontrib>Wang, Zhenning</creatorcontrib><title>Elevated MMP10/13 mediated barrier disruption and NF-κB activation aggravate colitis and colon tumorigenesis in both individual or full miR-148/152 family knockout mice</title><title>Cancer letters</title><addtitle>Cancer Lett</addtitle><description>Dynamic miRNA alteration is known to occur in colitis-associated colon cancer (CAC), while the molecular mechanisms underpinning how miRNAs modulate the development from chronic inflammation to CAC is lacking. For the first time, we constructed knockout (KO) mice for individual miR-148/152 family members and entire miR-148/152 family. Based on these KO mice, we conduct the first comprehensive analysis of miR-148/152 family, demonstrating that deficiency of any member of miR-148/152 family aggravate colitis and CAC. Loss of individual miR-148/152 family members or full-family enhance MMP10 and MMP13 expression, causing disruption of intestinal barrier and cleaving pro-TNF-α into bioactive TNF-α fragments to activate NF-κB signaling, thereby aggravating colitis. Individual and full-family deletion also increase accumulation of IKKα and IKKβ, resulting in further hyperactivation of NF-κB signaling, exacerbating colitis and CAC. Moreover, blocking NF-κB signaling exerts a restorative effect on colitis and CAC models only in KO mice. Taken together, these findings demonstrate deleting the full miR-148/152 family or individual members exhibit similar effects in colitis and CAC. Mechanically, miR-148/152 family members deficiency in mice elevates MMP10 and MMP13 to accelerate colitis and CAC via disrupting intestinal barrier function and activating NF-κB signaling, suggesting a potential therapeutic strategy for colitis and CAC. •We firstly constructed knockout (KO) mice for individual miR-148/152 family members and the entire miR-148/152 family.•Deleting miR-148/152 family members caused overexpression of targeted genes MMP10, MMP13, IKKα and IKKβ.•MiR-148/152 family deficiency upregulated MMP10/13, resulting in TNF-α maturation and sequential NF-κB pathway activation.•MiR-148/152 family deficiency mediated IKKα/β overexpression could activate NF-κB signaling pathway.•Our findings suggest impeding NF-κB pathway could treat colitis or colon cancer patients with miR-148/152 downregulation.</description><subject>Animal models</subject><subject>Animals</subject><subject>Carcinogenesis - genetics</subject><subject>Carcinogenesis - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Colitis</subject><subject>Colitis - etiology</subject><subject>Colitis-associated colon cancer</subject><subject>Collagenase 3</subject><subject>Colon cancer</subject><subject>Colonic Neoplasms - etiology</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Colonic Neoplasms - pathology</subject><subject>Colorectal cancer</subject><subject>Disease</subject><subject>Disease Models, Animal</subject><subject>Disease Progression</subject><subject>Drinking water</subject><subject>Fluorescent Antibody Technique</subject><subject>Gene expression</subject><subject>Gene Knockdown Techniques</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Inflammatory bowel disease</subject><subject>Intestinal Mucosa - metabolism</subject><subject>Intestinal Mucosa - pathology</subject><subject>Intestine</subject><subject>Laboratory animals</subject><subject>Matrix Metalloproteinase 10 - genetics</subject><subject>Matrix Metalloproteinase 10 - metabolism</subject><subject>Matrix Metalloproteinase 13 - genetics</subject><subject>Matrix Metalloproteinase 13 - metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>MicroRNAs - genetics</subject><subject>MicroRNAs - metabolism</subject><subject>miRNA</subject><subject>miRNAs</subject><subject>Molecular modelling</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Pathogens</subject><subject>Proteins</subject><subject>Reagents</subject><subject>Signal Transduction</subject><subject>Stromelysin 2</subject><subject>Tumor necrosis factor-α</subject><subject>Tumorigenesis</subject><issn>0304-3835</issn><issn>1872-7980</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtuFDEQhi1ERIaBGyBkiQ2b7vGjnxskiBKIlASEYG25_Rg8cbcntnukHIkrcAjORM1MYMEiq7Kq_r9s_x9CrygpKaHNalMqOXmTS0YYLSkrCedP0IJ2LSvaviNP0YJwUhW84_Upep7ShhBSV239DJ3yqm972jQL9PPcm53MRuPr6y-UrCjHo9Hu0BlkjM5ErF2K8za7MGE5aXxzUfz-9QFLlR04D931Osr9FqyCd9mlgw7OMMvzGKJbm8kk6LsJDyH_gKrdzulZehwitrP3eHRfC1p1K1ozbOXo_D2-nYK6DXOGmTIv0ImVPpmXD3WJvl-cfzv7VFx9_nh59v6qUBVvctEYxSqrrTRdV-mh1fBnNdiugyy0om09WN2ruu-5JLTrZcssN0PTU0VVNfSWL9Hb495tDHezSVmMLinjvZxMmJNgDQRHWAO5LtGb_6SbMMcJXgcqRtqaNqBbouqoUjGkFI0V2-hGGe8FJWKPUmzEEaXYoxSUCUAJttcPy-cBkPwz_WUHgndHgYE0dgBKJOXMpABfNCoLHdzjN_wBsRezHw</recordid><startdate>20220331</startdate><enddate>20220331</enddate><creator>Tang, Kaiwen</creator><creator>Wu, Zhonghua</creator><creator>Sun, Mingwei</creator><creator>Huang, Xuanzhang</creator><creator>Sun, Jingxu</creator><creator>Shi, Jinxin</creator><creator>Wang, Xin</creator><creator>Miao, Zhifeng</creator><creator>Gao, Peng</creator><creator>Song, Yongxi</creator><creator>Wang, Zhenning</creator><general>Elsevier B.V</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</scope><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>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>20220331</creationdate><title>Elevated MMP10/13 mediated barrier disruption and NF-κB activation aggravate colitis and colon tumorigenesis in both individual or full miR-148/152 family knockout mice</title><author>Tang, Kaiwen ; Wu, Zhonghua ; Sun, Mingwei ; Huang, Xuanzhang ; Sun, Jingxu ; Shi, Jinxin ; Wang, Xin ; Miao, Zhifeng ; Gao, Peng ; Song, Yongxi ; Wang, Zhenning</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c436t-6ec24fdfae884db7d054cbf88304dc175bfd9c5993a0189a72f3eb691c1c4b9f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Carcinogenesis - genetics</topic><topic>Carcinogenesis - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Colitis</topic><topic>Colitis - etiology</topic><topic>Colitis-associated colon cancer</topic><topic>Collagenase 3</topic><topic>Colon cancer</topic><topic>Colonic Neoplasms - etiology</topic><topic>Colonic Neoplasms - metabolism</topic><topic>Colonic Neoplasms - pathology</topic><topic>Colorectal cancer</topic><topic>Disease</topic><topic>Disease Models, Animal</topic><topic>Disease Progression</topic><topic>Drinking water</topic><topic>Fluorescent Antibody Technique</topic><topic>Gene expression</topic><topic>Gene Knockdown Techniques</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Inflammatory bowel disease</topic><topic>Intestinal Mucosa - metabolism</topic><topic>Intestinal Mucosa - pathology</topic><topic>Intestine</topic><topic>Laboratory animals</topic><topic>Matrix Metalloproteinase 10 - genetics</topic><topic>Matrix Metalloproteinase 10 - metabolism</topic><topic>Matrix Metalloproteinase 13 - genetics</topic><topic>Matrix Metalloproteinase 13 - metabolism</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>MicroRNAs - genetics</topic><topic>MicroRNAs - metabolism</topic><topic>miRNA</topic><topic>miRNAs</topic><topic>Molecular modelling</topic><topic>NF-kappa B - metabolism</topic><topic>NF-κB protein</topic><topic>Pathogens</topic><topic>Proteins</topic><topic>Reagents</topic><topic>Signal Transduction</topic><topic>Stromelysin 2</topic><topic>Tumor necrosis factor-α</topic><topic>Tumorigenesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tang, Kaiwen</creatorcontrib><creatorcontrib>Wu, Zhonghua</creatorcontrib><creatorcontrib>Sun, Mingwei</creatorcontrib><creatorcontrib>Huang, Xuanzhang</creatorcontrib><creatorcontrib>Sun, Jingxu</creatorcontrib><creatorcontrib>Shi, Jinxin</creatorcontrib><creatorcontrib>Wang, Xin</creatorcontrib><creatorcontrib>Miao, Zhifeng</creatorcontrib><creatorcontrib>Gao, Peng</creatorcontrib><creatorcontrib>Song, Yongxi</creatorcontrib><creatorcontrib>Wang, Zhenning</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health &amp; 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Mechanically, miR-148/152 family members deficiency in mice elevates MMP10 and MMP13 to accelerate colitis and CAC via disrupting intestinal barrier function and activating NF-κB signaling, suggesting a potential therapeutic strategy for colitis and CAC. •We firstly constructed knockout (KO) mice for individual miR-148/152 family members and the entire miR-148/152 family.•Deleting miR-148/152 family members caused overexpression of targeted genes MMP10, MMP13, IKKα and IKKβ.•MiR-148/152 family deficiency upregulated MMP10/13, resulting in TNF-α maturation and sequential NF-κB pathway activation.•MiR-148/152 family deficiency mediated IKKα/β overexpression could activate NF-κB signaling pathway.•Our findings suggest impeding NF-κB pathway could treat colitis or colon cancer patients with miR-148/152 downregulation.</abstract><cop>Ireland</cop><pub>Elsevier B.V</pub><pmid>34979166</pmid><doi>10.1016/j.canlet.2021.12.033</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record>
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source MEDLINE; Access via ScienceDirect (Elsevier)
subjects Animal models
Animals
Carcinogenesis - genetics
Carcinogenesis - metabolism
Cell Line, Tumor
Colitis
Colitis - etiology
Colitis-associated colon cancer
Collagenase 3
Colon cancer
Colonic Neoplasms - etiology
Colonic Neoplasms - metabolism
Colonic Neoplasms - pathology
Colorectal cancer
Disease
Disease Models, Animal
Disease Progression
Drinking water
Fluorescent Antibody Technique
Gene expression
Gene Knockdown Techniques
Homeostasis
Humans
Immunohistochemistry
Inflammatory bowel disease
Intestinal Mucosa - metabolism
Intestinal Mucosa - pathology
Intestine
Laboratory animals
Matrix Metalloproteinase 10 - genetics
Matrix Metalloproteinase 10 - metabolism
Matrix Metalloproteinase 13 - genetics
Matrix Metalloproteinase 13 - metabolism
Mice
Mice, Knockout
MicroRNAs - genetics
MicroRNAs - metabolism
miRNA
miRNAs
Molecular modelling
NF-kappa B - metabolism
NF-κB protein
Pathogens
Proteins
Reagents
Signal Transduction
Stromelysin 2
Tumor necrosis factor-α
Tumorigenesis
title Elevated MMP10/13 mediated barrier disruption and NF-κB activation aggravate colitis and colon tumorigenesis in both individual or full miR-148/152 family knockout mice
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