Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"Scaffolding Supports the Hippo","authors":"","doi":"10.1016/j.jcmgh.2024.05.011","DOIUrl":"10.1016/j.jcmgh.2024.05.011","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"18 3","pages":"Article 101363"},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001176/pdfft?md5=61597794f1bd71f3236b26e48d5ddba2&pid=1-s2.0-S2352345X24001176-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141288927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Ties That Bind: Enteric Glia Link T Cells to Plexitis in Crohn’s","authors":"Brian D. Gulbransen","doi":"10.1016/j.jcmgh.2024.03.011","DOIUrl":"10.1016/j.jcmgh.2024.03.011","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"18 1","pages":"Pages 161-162"},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000663/pdfft?md5=bc37fdfdc8cfce1639d80afc44f7ab54&pid=1-s2.0-S2352345X24000663-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140855773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WNT2B Deficiency Causes Enhanced Susceptibility to Colitis Due to Increased Inflammatory Cytokine Production","authors":"Amy E. O’Connell ,&nbsp;Sathuwarman Raveenthiraraj ,&nbsp;Luiz Fernando Silva Oliveira ,&nbsp;Comfort Adegboye ,&nbsp;Venkata Siva Dasuri ,&nbsp;Wanshu Qi ,&nbsp;Radhika S. Khetani ,&nbsp;Akaljot Singh ,&nbsp;Nambirajam Sundaram ,&nbsp;Jasmine Lin ,&nbsp;Prathima Nandivada ,&nbsp;Lorena Rincón-Cruz ,&nbsp;Jeffrey D. Goldsmith ,&nbsp;Jay R. Thiagarajah ,&nbsp;Diana L. Carlone ,&nbsp;Jerrold R. Turner ,&nbsp;Pankaj B. Agrawal ,&nbsp;Michael Helmrath ,&nbsp;David T. Breault","doi":"10.1016/j.jcmgh.2024.04.006","DOIUrl":"10.1016/j.jcmgh.2024.04.006","url":null,"abstract":"<div><h3>Background &amp; aims</h3><p>Humans with WNT2B deficiency have severe intestinal disease, including significant inflammatory injury, highlighting a critical role for WNT2B. We sought to understand how WNT2B contributes to intestinal homeostasis.</p></div><div><h3>Methods</h3><p>We investigated the intestinal health of <em>Wnt2b</em> knock out (KO) mice. We assessed the baseline histology and health of the small intestine and colon, and the impact of inflammatory challenge using dextran sodium sulfate (DSS). We also evaluated human intestinal tissue.</p></div><div><h3>Results</h3><p>Mice with WNT2B deficiency had normal baseline histology but enhanced susceptibility to DSS colitis because of an increased early injury response. Although intestinal stem cells markers were decreased, epithelial proliferation was similar to control subjects. <em>Wnt2b</em> KO mice showed an enhanced inflammatory signature after DSS treatment. <em>Wnt2b</em> KO colon and human WNT2B-deficient organoids had increased levels of <em>CXCR4</em> and <em>IL6</em>, and biopsy tissue from humans showed increased neutrophils.</p></div><div><h3>Conclusions</h3><p>WNT2B is important for regulation of inflammation in the intestine. Absence of WNT2B leads to increased expression of inflammatory cytokines and increased susceptibility to gastrointestinal inflammation, particularly in the colon.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"18 2","pages":"Article 101349"},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001000/pdfft?md5=aad7f8851649bbb9688db7c5a88219f4&pid=1-s2.0-S2352345X24001000-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140871550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NF-κB Inducing Kinase Attenuates Colorectal Cancer by Regulating Noncanonical NF-κB Mediated Colonic Epithelial Cell Regeneration","authors":"Holly A. Morrison ,&nbsp;Kristin Eden ,&nbsp;Brie Trusiano ,&nbsp;Daniel E. Rothschild ,&nbsp;Yufeng Qin ,&nbsp;Paul A. Wade ,&nbsp;Audrey J. Rowe ,&nbsp;Christina Mounzer ,&nbsp;Morgan C. Stephens ,&nbsp;Katherine M. Hanson ,&nbsp;Stephan L. Brown ,&nbsp;Eda K. Holl ,&nbsp;Irving C. Allen","doi":"10.1016/j.jcmgh.2024.05.004","DOIUrl":"10.1016/j.jcmgh.2024.05.004","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Dysregulated colonic epithelial cell (CEC) proliferation is a critical feature in the development of colorectal cancer. We show that NF-κB-inducing kinase (NIK) attenuates colorectal cancer through coordinating CEC regeneration/differentiation via noncanonical NF-κB signaling that is unique from canonical NF-kB signaling.</p></div><div><h3>Methods</h3><p>Initial studies evaluated crypt morphology/functionality, organoid generation, transcriptome profiles, and the microbiome. Inflammation and inflammation-induced tumorigenesis were initiated in whole-body NIK knockout mice (<em>Nik</em>^<em>-/-</em>) and conditional-knockout mice following administration of azoxymethane and dextran sulfate sodium.</p></div><div><h3>Results</h3><p>Human transcriptomic data revealed dysregulated noncanonical NF-kB signaling. In vitro studies evaluating <em>Nik</em>^<em>-/-</em> crypts and organoids derived from mature, nondividing CECs, and colonic stem cells exhibited increased accumulation and stunted growth, respectively. Transcriptomic analysis of <em>Nik</em>^<em>-/-</em> cells revealed gene expression signatures associated with altered differentiation-regeneration. When assessed in vivo, <em>Nik</em>^<em>-/</em>- mice exhibited more severe colitis with dextran sulfate sodium administration and an altered microbiome characterized by increased colitogenic microbiota. In the inflammation-induced tumorigenesis model, we observed both increased tumor burdens and inflammation in mice where NIK is knocked out in CECs (<em>Nik</em>^{<em>ΔCEC</em>}). Interestingly, this was not recapitulated when NIK was conditionally knocked out in myeloid cells (<em>Nik</em>^{<em>ΔMYE</em>}<em>)</em>. Surprisingly, conditional knockout of the canonical pathway in myeloid cells (<em>RelA</em>^{<em>ΔMYE</em>}) revealed decreased tumor burden and inflammation and no significant changes when conditionally knocked out in CECs <em>(RelA</em>^ΔCEC).</p></div><div><h3>Conclusions</h3><p>Dysregulated noncanonical NF-κB signaling is associated with the development of colorectal cancer in a tissue-dependent manner and defines a critical role for NIK in regulating gastrointestinal inflammation and regeneration associated with colorectal cancer.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"18 3","pages":"Article 101356"},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001103/pdfft?md5=6ac6e1f3eb040b81a90657641751df32&pid=1-s2.0-S2352345X24001103-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140946680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesencephalic Astrocyte-derived Neurotrophic Factor Supports Hepatitis B Virus-induced Immunotolerance","authors":"Huiyuan Xie ,&nbsp;Haiyan Deng ,&nbsp;Xiaoping Yang ,&nbsp;Xianxian Gao ,&nbsp;Shanru Yang ,&nbsp;Weiyi Chen ,&nbsp;Yixuan Wang ,&nbsp;Naibin Yang ,&nbsp;Liang Yong ,&nbsp;Xin Hou","doi":"10.1016/j.jcmgh.2024.05.008","DOIUrl":"10.1016/j.jcmgh.2024.05.008","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>The immune tolerance induced by hepatitis B virus (HBV) is a major challenge for achieving effective viral clearance, and the mechanisms involved are not well-understood. One potential factor involved in modulating immune responses is mesencephalic astrocyte-derived neurotrophic factor (MANF), which has been reported to be increased in patients with chronic hepatitis B. In this study, our objective is to examine the role of MANF in regulating immune responses to HBV.</p></div><div><h3>Methods</h3><p>We utilized a commonly used HBV-harboring mouse model, where mice were hydrodynamically injected with the pAAV/HBV1.2 plasmid. We assessed the HBV load by measuring the levels of various markers including hepatitis B surface antigen, hepatitis B envelope antigen, hepatitis B core antigen, HBV DNA, and HBV RNA.</p></div><div><h3>Results</h3><p>Our study revealed that following HBV infection, both myeloid cells and hepatocytes exhibited increased expression of MANF. Moreover, we observed that mice with myeloid-specific MANF knockout (Manf^Mye-/-) displayed reduced HBV load and improved HBV-specific T cell responses. The decreased HBV-induced tolerance in Manf^Mye-/- mice was associated with reduced accumulation of myeloid-derived suppressor cells (MDSCs) in the liver. Restoring MDSC levels in Manf^Mye-/- mice through MDSC adoptive transfer reinstated HBV-induced tolerance. Mechanistically, we found that MANF promoted MDSC expansion by activating the IL-6/STAT3 pathway. Importantly, our study demonstrated the effectiveness of a combination therapy involving an hepatitis B surface antigen vaccine and nanoparticle-encapsulated MANF siRNA in effectively clearing HBV in HBV-carrier mice.</p></div><div><h3>Conclusion</h3><p>The current study reveals that MANF plays a previously unrecognized regulatory role in liver tolerance by expanding MDSCs in the liver through IL-6/STAT3 signaling, leading to MDSC-mediated CD8⁺ T cell exhaustion.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"18 3","pages":"Article 101360"},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001140/pdfft?md5=43d4376f89a1060ffb852ae42d8ee968&pid=1-s2.0-S2352345X24001140-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140961077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterozygous Spink1 Deficiency Promotes Trypsin-dependent Chronic Pancreatitis in Mice","authors":"Alexandra Demcsák,&nbsp;Miklós Sahin-Tóth","doi":"10.1016/j.jcmgh.2024.05.009","DOIUrl":"10.1016/j.jcmgh.2024.05.009","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Heterozygous <em>SPINK1</em> mutations are strong risk factors for chronic pancreatitis in humans, yet heterozygous disruption of mouse <em>Spink1</em> yielded no pancreatic phenotype. To resolve this contradiction, we used CRISPR/Cas9-mediated genome editing to generate heterozygous <em>Spink1</em>-deleted mice (<em>Spink1-KO</em>^het) in the C57BL/6N strain and studied the effect of this allele in trypsin-independent and trypsin-dependent pancreatitis models.</p></div><div><h3>Methods</h3><p>We investigated severity of acute pancreatitis and progression to chronic pancreatitis in <em>Spink1-KO</em>^het mice after transient (10 injections) and prolonged (2 × 8 injections) cerulein hyperstimulation. We crossed <em>Spink1-KO</em>^het mice with <em>T7D23A</em> and <em>T7D22N,K24R</em> mice that carry strongly autoactivating trypsinogen mutants and exhibit spontaneous chronic pancreatitis.</p></div><div><h3>Results</h3><p>Prolonged but not transient cerulein stimulation resulted in increased intrapancreatic trypsin activity and more severe acute pancreatitis in <em>Spink1-KO</em>^het mice relative to the C57BL/6N control strain. After the acute episode, <em>Spink1-KO</em>^het mice developed progressive disease with chronic pancreatitis-like features, whereas C57BL/6N mice recovered rapidly. Trypsinogen mutant mice carrying the <em>Spink1-KO</em>^het allele exhibited strikingly more severe chronic pancreatitis than the respective parent strains.</p></div><div><h3>Conclusions</h3><p>Heterozygous <em>Spink1</em> deficiency caused more severe acute pancreatitis after prolonged cerulein stimulation and promoted chronic pancreatitis after the cerulein-induced acute episode, and in two strains of trypsinogen mutant mice with spontaneous disease. In contrast, acute pancreatitis induced with limited cerulein hyperstimulation was unaffected by heterozygous <em>Spink1</em> deletion, in agreement with recent observations that trypsin activity does not mediate pathologic responses in this model. Taken together, the findings strongly support the notion that loss-of-function <em>SPINK1</em> mutations in humans increase chronic pancreatitis risk in a trypsin-dependent manner.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"18 3","pages":"Article 101361"},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001152/pdfft?md5=fcd6a6d57f664b7a4d6aa24940431b9c&pid=1-s2.0-S2352345X24001152-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141072312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut Bacteria-derived Membrane Vesicles Induce Colonic Dysplasia by Inducing DNA Damage in Colon Epithelial Cells","authors":"Yu Miyakawa ,&nbsp;Motoyuki Otsuka ,&nbsp;Chikako Shibata ,&nbsp;Takahiro Seimiya ,&nbsp;Keisuke Yamamoto ,&nbsp;Rei Ishibashi ,&nbsp;Takahiro Kishikawa ,&nbsp;Eri Tanaka ,&nbsp;Takayuki Isagawa ,&nbsp;Norihiko Takeda ,&nbsp;Noriaki Kamio ,&nbsp;Kenichi Imai ,&nbsp;Mitsuhiro Fujishiro","doi":"10.1016/j.jcmgh.2024.01.010","DOIUrl":"10.1016/j.jcmgh.2024.01.010","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Colorectal cancer (CRC) is the third most common cancer in the world. Gut microbiota has recently been implicated in the development of CRC. <em>Actinomyces odontolyticus</em> is one of the most abundant bacteria in the gut of patients with very early stages of CRC. <em>A odontolyticus</em> is an anaerobic bacterium existing principally in the oral cavity, similar to <em>Fusobacterium nucleatum,</em> which is known as a colon carcinogenic bacterium. Here we newly determined the biological functions of <em>A odontolyticus</em> on colonic oncogenesis.</p></div><div><h3>Methods</h3><p>We examined the induction of intracellular signaling by <em>A odontolyticus</em> in human colonic epithelial cells (CECs). DNA damage levels in CECs were confirmed using the human induced pluripotent stem cell-derived gut organoid model and mouse colon tissues in vivo.</p></div><div><h3>Results</h3><p><em>A odontolyticus</em> secretes membrane vesicles (MVs), which induce nuclear factor kappa B signaling and also produce excessive reactive oxygen species (ROS) in colon epithelial cells. We found that <em>A odontolyticus</em> secretes lipoteichoic acid-rich MVs, promoting inflammatory signaling via TLR2. Simultaneously, those MVs are internalized into the colon epithelial cells, co-localize with the mitochondria, and cause mitochondrial dysfunction, resulting in excessive ROS production and DNA damage. Induction of excessive DNA damage in colonic cells by <em>A odontolyticus</em>-derived MVs was confirmed in the gut organoid model and also in mouse colon tissues.</p></div><div><h3>Conclusions</h3><p><em>A odontolyticus</em> secretes MVs, which cause chronic inflammation and ROS production in colonic epithelial cells, leading to the initiation of CRC.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"17 5","pages":"Pages 745-767"},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000109/pdfft?md5=e23ca47bd954111738ee31e9c0a144d5&pid=1-s2.0-S2352345X24000109-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139668490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover - CDKN2A/p16 and KRAS Synergize in Barrett’s Esophagus Dysplasia","authors":"","doi":"10.1016/S2352-345X(24)00065-1","DOIUrl":"https://doi.org/10.1016/S2352-345X(24)00065-1","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"17 5","pages":"Page OFC"},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000651/pdfft?md5=95d2f2e2521dbfb8b9b24d1cf09c2d4d&pid=1-s2.0-S2352345X24000651-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140557717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sphingosine Kinase 1 Aggravates Liver Fibrosis by Mediating Macrophage Recruitment and Polarization","authors":"Xin Ding ,&nbsp;Xiang Zhang ,&nbsp;Jiafan Cao ,&nbsp;Shiyun Chen ,&nbsp;Yinghua Chen ,&nbsp;Kai Yuan ,&nbsp;Bo Chen ,&nbsp;Guizhi Yang ,&nbsp;Shengwen Li ,&nbsp;Jundong Yang ,&nbsp;Guixiang Wang ,&nbsp;Frank Tacke ,&nbsp;Tian Lan","doi":"10.1016/j.jcmgh.2024.101406","DOIUrl":"10.1016/j.jcmgh.2024.101406","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Sphingosine kinase 1 (SphK1) has distinct roles in the activation of Kupffer cells and hepatic stellate cells in liver fibrosis. Here, we aim to investigate the roles of SphK1 on hepatic macrophage recruitment and polarization in liver fibrosis.</div></div><div><h3>Methods</h3><div>Liver fibrosis was induced by carbon tetrachloride in wild-type and SphK1^-/- mice to study the recruitment and polarization of macrophages. The effects of SphK1 originated from macrophages or other liver cell types on liver fibrosis were further strengthened by bone marrow transplantation. The direct effects of SphK1 on macrophage polarization were also investigated <em>in vitro</em>. Expression analysis of SphK1 and macrophage polarization index was conducted with human liver samples.</div></div><div><h3>Results</h3><div>SphK1 deletion attenuated the recruitment of hepatic macrophages along with reduced M1 and M2 polarization in mice induced by carbon tetrachloride. SphK1 deficiency in endogenous liver cells attenuated macrophage recruitment via C-C motif chemokine ligand 2. Macrophage SphK1 activated the ASK1-JNK1/2-p38 signaling pathway to promote M1 polarization. Furthermore, macrophage SphK1 downregulated small ubiquitin-like modifier-specific peptidase1 to decrease de-SUMOylation of Kruppel-like factor 4 to promote M2 polarization. Finally, we confirmed that SphK1 expression was elevated and positively correlated with macrophage M1 and M2 polarization in human fibrosis livers.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrated that SphK1 aggravated liver fibrosis by promoting macrophage recruitment and M1/M2 polarization. SphK1 in macrophages is a potential therapeutic target for the treatment of liver fibrosis.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"18 6","pages":"Article 101406"},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142301827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel CRISPR/Cas9-mediated Mouse Model of Colon Carcinogenesis","authors":"Hajime Kashima ,&nbsp;Anthony Fischer ,&nbsp;Daniel A. Veronese-Paniagua ,&nbsp;Vered A. Gazit ,&nbsp;Changqing Ma ,&nbsp;Yan Yan ,&nbsp;Marc S. Levin ,&nbsp;Blair B. Madison ,&nbsp;Deborah C. Rubin","doi":"10.1016/j.jcmgh.2024.101390","DOIUrl":"10.1016/j.jcmgh.2024.101390","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Human sporadic colorectal cancer (CRC) results from a multistep pathway with sequential acquisition of specific genetic mutations in the colorectal epithelium. Modeling CRC <em>in vivo</em> is critical for understanding the tumor microenvironment. To accurately recapitulate human CRC pathogenesis, mouse models must include these multi-step genetic abnormalities. The aim of this study was to generate a sporadic CRC model that more closely mimics this multi-step process and to use this model to study the role of a novel Let7 target PLAGL2 in CRC pathogenesis.</div></div><div><h3>Methods</h3><div>We generated a CRISPR/Cas9 somatic mutagenesis mouse model that is inducible and multiplexed for simultaneous inactivation of multiple genes involved in CRC pathogenesis. We used both a doxycycline-inducible transcriptional activator and a doxycycline-inactivated transcriptional repressor to achieve tight, non-leaky expression of the Cas9 nickase. This mouse has transgenic expression of multiple guide RNAs to induce sporadic inactivation in the gut epithelium of 4 tumor suppressor genes commonly mutated in CRC, <em>Apc, Pten</em>, <em>Smad4</em>, and <em>Trp53</em>. These were crossed to <em>Vil-LCL-PLAGL2</em> mice, which have Cre-inducible overexpression of PLAGL2 in the gut epithelium.</div></div><div><h3>Results</h3><div>These mice exhibited random somatic mutations in all 4 targeted tumor suppressor genes, resulting in multiple adenomas and adenocarcinomas in the small bowel and colon. Crosses with <em>Vil-LCL-PLAGL2</em> mice demonstrated that gut-specific PLAGL2 overexpression increased colon tumor growth.</div></div><div><h3>Conclusions</h3><div>This conditional model represents a new CRISPR/Cas9-mediated mouse model of colorectal carcinogenesis. These mice can be used to investigate the role of novel, previously uncharacterized genes in CRC, in the context of multiple commonly mutated tumor suppressor genes and thus more closely mimic human CRC pathogenesis.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"18 5","pages":"Article 101390"},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001450/pdfft?md5=daeaeb5124d1ccf33502431754817647&pid=1-s2.0-S2352345X24001450-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}