{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:33:17Z","timestamp":1784334797799,"version":"3.55.0"},"reference-count":28,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2017,11,18]],"date-time":"2017-11-18T00:00:00Z","timestamp":1510963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31330075"],"award-info":[{"award-number":["31330075"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Science and Technology Planning Project of Guangzhou","award":["705241209049"],"award-info":[{"award-number":["705241209049"]}]},{"name":"the Natural Science Foundation of Guangdong Province","award":["2015A030310524"],"award-info":[{"award-number":["2015A030310524"]}]},{"name":"the National Key Research and Development Program of China","award":["2016YFD0500501, 2017YFD0500501"],"award-info":[{"award-number":["2016YFD0500501, 2017YFD0500501"]}]},{"name":"the National Basic Research Program of China","award":["2013CB127302"],"award-info":[{"award-number":["2013CB127302"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Caudal type homeobox 2 (CDX2) is expressed in intestinal epithelial cells and plays a role in gut development and homeostasis by regulating cell proliferation. However, whether CDX2 cooperates with the mammalian target of rapamycin complex 1 (mTORC1) and Wnt\/\u03b2-catenin signaling pathways to stimulate cell proliferation remains unknown. The objective of this study was to investigate the effect of CDX2 on the proliferation of porcine jejunum epithelial cells (IPEC-J2) and the correlation between CDX2, the mTORC1 and Wnt\/\u03b2-catenin signaling pathways. CDX2 overexpression and knockdown cell culture models were established to explore the regulation of CDX2 on both pathways. Pathway-specific antagonists were used to verify the effects. The results showed that CDX2 overexpression increased IPEC-J2 cell proliferation and activated both the mTORC1 and Wnt\/\u03b2-catenin pathways, and that CDX2 knockdown decreased cell proliferation and inhibited both pathways. Furthermore, the mTORC1 and Wnt\/\u03b2-catenin pathway-specific antagonist rapamycin and XAV939 (3,5,7,8-tetrahydro-2-[4-(trifluoromethyl)]-4H \u2013thiopyrano[4,3-d]pyrimidin-4-one) both suppressed the proliferation of IPEC-J2 cells overexpressing CDX2, and that the combination of rapamycin and XAV939 had an additive effect. Regardless of whether the cells were treated with rapamycin or XAV939 alone or in combination, both mTORC1 and Wnt\/\u03b2-catenin pathways were down-regulated, accompanied by a decrease in CDX2 expression. Taken together, our data indicate that CDX2 stimulates porcine intestinal epithelial cell proliferation by activating the mTORC1 and Wnt\/\u03b2-catenin signaling pathways.<\/jats:p>","DOI":"10.3390\/ijms18112447","type":"journal-article","created":{"date-parts":[[2017,11,20]],"date-time":"2017-11-20T11:35:45Z","timestamp":1511177745000},"page":"2447","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["CDX2 Stimulates the Proliferation of Porcine Intestinal Epithelial Cells by Activating the mTORC1 and Wnt\/\u03b2-Catenin Signaling Pathways"],"prefix":"10.3390","volume":"18","author":[{"given":"Hong-Bo","family":"Fan","sequence":"first","affiliation":[{"name":"College of Animal Science\/Guangdong Provincial Key Laboratory of Animal Nutrition Regulation\/National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen-Ya","family":"Zhai","sequence":"additional","affiliation":[{"name":"College of Animal Science\/Guangdong Provincial Key Laboratory of Animal Nutrition Regulation\/National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-Guang","family":"Li","sequence":"additional","affiliation":[{"name":"College of Animal Science\/Guangdong Provincial Key Laboratory of Animal Nutrition Regulation\/National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Qi","family":"Gao","sequence":"additional","affiliation":[{"name":"College of Animal Science\/Guangdong Provincial Key Laboratory of Animal Nutrition Regulation\/National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Chao","family":"Yan","sequence":"additional","affiliation":[{"name":"College of Animal Science\/Guangdong Provincial Key Laboratory of Animal Nutrition Regulation\/National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8289-097X","authenticated-orcid":false,"given":"Zhe-Sheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Science, College of Pharmacy and Health Science, St. John\u2019s University, Queens, NY 11439, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2033-9485","authenticated-orcid":false,"given":"Xiu-Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Animal Science\/Guangdong Provincial Key Laboratory of Animal Nutrition Regulation\/National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,11,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1242\/dev.070722","article-title":"CDX2 determines the fate of postnatal intestinal endoderm","volume":"139","author":"Stringer","year":"2012","journal-title":"Development"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5728","DOI":"10.1038\/ncomms6728","article-title":"Transformation of intestinal stem cells into gastric stem cells on loss of transcription factor CDX2","volume":"5","author":"Simmini","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.bbadis.2010.11.008","article-title":"The role of CDX2 in intestinal homeostasis and inflammation","volume":"1812","author":"Coskun","year":"2011","journal-title":"BBA Mol. Basis Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"593","DOI":"10.4161\/cbt.3.7.913","article-title":"The role of CDX proteins in intestinal development and cancer","volume":"7","author":"Guo","year":"2004","journal-title":"Cancer Biol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"44608","DOI":"10.1074\/jbc.M307435200","article-title":"Silencing of CDX2 expression in colon cancer via a dominant repression pathway","volume":"278","author":"Hinoi","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.3892\/ijo.2013.1875","article-title":"PTEN expression and suppression of proliferation are associated with CDX2 overexpression in gastric cancer cells","volume":"42","author":"Bai","year":"2013","journal-title":"Int. J. Oncol."},{"key":"ref_7","first-page":"G840","article-title":"Heparin-binding EGF-like growth factor gene transcription regulated by CDX2 in the intestinal epithelium","volume":"283","author":"Uesaka","year":"2002","journal-title":"Am. J. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"30597","DOI":"10.18632\/oncotarget.8894","article-title":"CDX2 increases SLC7A7 expression and proliferation of pig intestinal epithelial cells","volume":"21","author":"Li","year":"2016","journal-title":"Oncotarget"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1242\/dev.141085","article-title":"CDX2 is essential for cell proliferation and polarity in porcine blastocysts","volume":"144","author":"Bou","year":"2017","journal-title":"Development"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.stemcr.2015.09.006","article-title":"Distinct processes and transcriptional targets underlie CDX2 requirements in intestinal stem cells and differentiated villus cells","volume":"5","author":"Roman","year":"2015","journal-title":"Stem Cell Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1111\/jcmm.13085","article-title":"Activation of Wnt\/\u03b2-catenin signalling is required for TGF-\u03b2\/Smad2\/3 signalling during myofibroblast proliferation","volume":"21","author":"Xu","year":"2017","journal-title":"J. Cell. Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"38681","DOI":"10.18632\/oncotarget.9583","article-title":"EAAT3 promotes amino acid transport and proliferation of porcine intestinal epithelial cells","volume":"7","author":"Ye","year":"2016","journal-title":"Oncotarget"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1093\/carcin\/bgp213","article-title":"The intestine-specific transcription factor CDX2 inhibits \u03b2-catenin\/TCF transcriptional activity by disrupting the \u03b2-catenin-TCF protein complex","volume":"31","author":"Guo","year":"2010","journal-title":"Carcinogenesis"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4099","DOI":"10.1242\/dev.041582","article-title":"CDX2 regulation of posterior development through non-Hox targets","volume":"136","author":"Savory","year":"2009","journal-title":"Development"},{"key":"ref_15","first-page":"321","article-title":"Overexpression of CDX2 in gastric cancer cells promotes the development of multidrug resistance","volume":"5","author":"Yan","year":"2015","journal-title":"Am. J. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1111\/his.12278","article-title":"BAI3, CDX2 and VIL1: A panel of three antibodies to distinguish small cell from large cell neuroendocrine lung carcinomas","volume":"64","author":"Bari","year":"2014","journal-title":"Histopathology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1007\/s13277-015-3900-6","article-title":"CDX2 inhibits pancreatic adenocarcinoma cell proliferation via promoting tumor suppressor miR-615\u20135p","volume":"37","author":"Jiang","year":"2016","journal-title":"Tumor Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3437","DOI":"10.1007\/s13277-013-0919-4","article-title":"Association between vitamin D receptor gene CDX2 polymorphism and breast cancer susceptibility","volume":"34","author":"Zhou","year":"2013","journal-title":"Tumor Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"33862","DOI":"10.1038\/srep33862","article-title":"Porcine milk-derived exosomes promote proliferation of intestinal epithelial cells","volume":"6","author":"Chen","year":"2016","journal-title":"Sci. Rep. UK"},{"key":"ref_20","first-page":"G504","article-title":"Cooperation between HNF-1 \u03b1, CDX2, and GATA-4 in initiating an enterocytic differentiation program in a normal human intestinal epithelial progenitor cell line","volume":"298","author":"Benoit","year":"2010","journal-title":"Am. J. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"25115","DOI":"10.1074\/jbc.M109.089516","article-title":"Genome-wide analysis of CDX2 binding in intestinal epithelial cells (Caco-2)","volume":"285","author":"Boyd","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_22","first-page":"G1054","article-title":"Intestine-specific transcription factor CDX2 induces E-cadherin function by enhancing the trafficking of E-cadherin to the cell membrane","volume":"299","author":"Funakoshi","year":"2010","journal-title":"Am. J. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.cellsig.2016.09.009","article-title":"Wnt signaling promotes hindgut fate commitment through regulating multi-lineage genes during hESC differentiation","volume":"29","author":"Zhang","year":"2017","journal-title":"Cell Signal."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/j.cell.2006.06.055","article-title":"TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth","volume":"126","author":"Inoki","year":"2006","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13544","DOI":"10.1073\/pnas.0800041105","article-title":"Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in Apc (Delta 716) mice","volume":"105","author":"Fujishita","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/nri2546","article-title":"Immunoregulatory functions of mTOR inhibition","volume":"9","author":"Thomson","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.humpath.2010.07.021","article-title":"Mammalian target of rapamycin regulates expression of \u03b2-catenin in hepatocellular carcinoma","volume":"42","author":"Feng","year":"2011","journal-title":"Hum. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.2527\/jas.2015-9432","article-title":"l-Glutamate deficiency can trigger proliferation inhibition via down regulation of the mTOR\/S6K1 pathway in pig intestinal epithelial cells","volume":"94","author":"Li","year":"2016","journal-title":"J. Anim. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/11\/2447\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:50:10Z","timestamp":1760208610000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/11\/2447"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,18]]},"references-count":28,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2017,11]]}},"alternative-id":["ijms18112447"],"URL":"https:\/\/doi.org\/10.3390\/ijms18112447","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11,18]]}}}