{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T17:42:24Z","timestamp":1793295744804,"version":"4.5.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"8-9","license":[{"start":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T00:00:00Z","timestamp":1686268800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Foundation of China","doi-asserted-by":"crossref","award":["82130080"],"award-info":[{"award-number":["82130080"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Foundation of China","doi-asserted-by":"crossref","award":["U1801282"],"award-info":[{"award-number":["U1801282"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Foundation of China","doi-asserted-by":"crossref","award":["81802382"],"award-info":[{"award-number":["81802382"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Foundation of China","doi-asserted-by":"crossref","award":["81702322"],"award-info":[{"award-number":["81702322"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Foundation of China","doi-asserted-by":"crossref","award":["82273145"],"award-info":[{"award-number":["82273145"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Key-Area Research and Development Program of Guangdong Province","award":["2019B020229002"],"award-info":[{"award-number":["2019B020229002"]}]},{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2021A1515010224"],"award-info":[{"award-number":["2021A1515010224"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2022A1515010418"],"award-info":[{"award-number":["2022A1515010418"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["23qnpy139"],"award-info":[{"award-number":["23qnpy139"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007844","name":"National Sun Yat-sen University","doi-asserted-by":"publisher","award":["23qnpy139"],"award-info":[{"award-number":["23qnpy139"]}],"id":[{"id":"10.13039\/100007844","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>EphB6 belongs to the receptor tyrosine kinase, whose low expression is associated with shorter survival of colorectal cancer (CRC) patients. But the role and mechanism of EphB6 in the progression of CRC need further study. In addition, EphB6 was mainly expressed in intestinal neurons. But how EphB6 is involved in functions of intestinal neurons has not been known. In our study, we constructed a mouse xenograft model of CRC by injecting CMT93 cells into the rectum of EphB6-deficient mice. We found that the deletion of EphB6 in mice promoted tumor growth of CMT93 cells in a xenograft model of CRC, which was independent of changes in the gut microbiota. Interestingly, inhibition of intestinal neurons by injecting botulinum toxin A into rectum of EphB6-deficient mice could eliminate the promotive effect of EphB6 deficiency on tumor growth in the xenograft model of CRC. Mechanically, the deletion of EphB6 in mice promoted the tumor growth in CRC by increasing GABA in the tumor microenvironment. Furthermore, EphB6 deficiency in mice increased the expression of synaptosomal-associated protein 25 in the intestinal myenteric plexus, which mediated the release of GABA. Our study concluded that EphB6 knockout in mice promotes tumor growth of CMT93 cells in a xenograft model of CRC by modulating GABA release. Our study found a new regulating mechanism of EphB6 on the tumor progression in CRC that is dependent on intestinal neurons.<\/jats:p>","DOI":"10.1093\/carcin\/bgad041","type":"journal-article","created":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T23:40:43Z","timestamp":1686267643000},"page":"682-694","source":"Crossref","is-referenced-by-count":10,"title":["EphB6 deficiency in intestinal neurons promotes tumor growth in colorectal cancer by neurotransmitter GABA signaling"],"prefix":"10.1093","volume":"44","author":[{"given":"Hao","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou 510120 , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Kang","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou 510120 , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Wen","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou 510120 , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Ming","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University , Guangzhou 510515 , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"En-De","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou 510120 , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Ming","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University , Guangzhou 510515 , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun-Hua","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Guangdong Provincial People\u2019s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University , Guangzhou 510080 , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai-Jun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou 510120 , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Ji","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University , Guangzhou 510515 , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-Ming","family":"Gao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University , Guangzhou 510515 , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou 510120 , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2862-9922","authenticated-orcid":false,"given":"Jian-Ming","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou 510120 , People\u2019s Republic of China"},{"name":"Department of Pathology, Soochow University Medical School , Suzhou 215123 , People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,6,9]]},"reference":[{"key":"2023120208084532500_CIT0001","doi-asserted-by":"crossref","first-page":"2974","DOI":"10.1002\/ijc.25529","article-title":"Somatic mutations and germline sequence variants in patients with familial colorectal cancer","volume":"127","author":"Gylfe","year":"2010","journal-title":"Int. J. Cancer"},{"key":"2023120208084532500_CIT0002","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1139\/O10-145","article-title":"Dancing with the dead: Eph receptors and their kinase-null partners","volume":"89","author":"Truitt","year":"2011","journal-title":"Biochem. Cell Biol."},{"key":"2023120208084532500_CIT0003","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1126\/science.1145720","article-title":"The genomic landscapes of human breast and colorectal cancers","volume":"318","author":"Wood","year":"2007","journal-title":"Science"},{"key":"2023120208084532500_CIT0004","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1007\/s10735-014-9577-0","article-title":"Loss of EphB6 protein expression in human colorectal cancer correlates with poor prognosis","volume":"45","author":"Peng","year":"2014","journal-title":"J. Mol. Histol."},{"key":"2023120208084532500_CIT0005","doi-asserted-by":"crossref","first-page":"a026781","DOI":"10.1101\/cshperspect.a026781","article-title":"Tumor microenvironment and differential responses to therapy","volume":"7","author":"Hirata","year":"2017","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"2023120208084532500_CIT0006","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1002\/1878-0261.12779","article-title":"TGF-\u03b2-induced IGFBP-3 is a key paracrine factor from activated pericytes that promotes colorectal cancer cell migration and invasion","volume":"14","author":"Navarro","year":"2020","journal-title":"Mol. Oncol."},{"key":"2023120208084532500_CIT0007","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.ccell.2017.02.005","article-title":"Nerve dependence: from regeneration to cancer","volume":"31","author":"Boilly","year":"2017","journal-title":"Cancer Cell"},{"key":"2023120208084532500_CIT0008","doi-asserted-by":"crossref","first-page":"1236361","DOI":"10.1126\/science.1236361","article-title":"Autonomic nerve development contributes to prostate cancer progression","volume":"341","author":"Magnon","year":"2013","journal-title":"Science"},{"key":"2023120208084532500_CIT0009","doi-asserted-by":"crossref","first-page":"250ra115","DOI":"10.1126\/scitranslmed.3009569","article-title":"Denervation suppresses gastric tumorigenesis","volume":"6","author":"Zhao","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"2023120208084532500_CIT0010","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/s41593-019-0430-3","article-title":"Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression","volume":"22","author":"Kamiya","year":"2019","journal-title":"Nat. Neurosci."},{"key":"2023120208084532500_CIT0011","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/35058515","article-title":"Multiple roles of EPH receptors and ephrins in neural development","volume":"2","author":"Wilkinson","year":"2001","journal-title":"Nat. Rev. Neurosci."},{"key":"2023120208084532500_CIT0012","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/S1357-2725(99)00096-5","article-title":"Eph receptors and ephrins","volume":"32","author":"Nakamoto","year":"2000","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"2023120208084532500_CIT0013","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.tcb.2007.03.004","article-title":"Bidirectional Eph-ephrin signaling during axon guidance","volume":"17","author":"Egea","year":"2007","journal-title":"Trends Cell Biol."},{"key":"2023120208084532500_CIT0014","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s40478-018-0618-x","article-title":"EphrinB\/EphB forward signaling in M\u00fcller cells causes apoptosis of retinal ganglion cells by increasing tumor necrosis factor alpha production in rat experimental glaucomatous model","volume":"6","author":"Liu","year":"2018","journal-title":"Acta Neuropathol. Commun."},{"key":"2023120208084532500_CIT0015","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1016\/j.cell.2020.08.003","article-title":"The human and mouse enteric nervous system at single-cell resolution","volume":"182","author":"Drokhlyansky","year":"2020","journal-title":"Cell"},{"key":"2023120208084532500_CIT0016","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1186\/s40168-020-00884-z","article-title":"The gut microbiota regulates autism-like behavior by mediating vitamin B(6) homeostasis in EphB6-deficient mice","volume":"8","author":"Li","year":"2020","journal-title":"Microbiome"},{"key":"2023120208084532500_CIT0017","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/s13104-016-1915-8","article-title":"A simple, step-by-step dissection protocol for the rapid isolation of mouse dorsal root ganglia","volume":"9","author":"Sleigh","year":"2016","journal-title":"BMC Res. Notes"},{"key":"2023120208084532500_CIT0018","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/978-1-4939-7649-2_2","article-title":"Preparation of neonatal rat Schwann cells and embryonic dorsal root ganglia neurons for in vitro myelination studies","volume":"1739","author":"Maurel","year":"2018","journal-title":"Methods Mol. Biol."},{"key":"2023120208084532500_CIT0019","doi-asserted-by":"crossref","first-page":"43702","DOI":"10.1038\/srep43702","article-title":"Loss of the EPH receptor B6 contributes to colorectal cancer metastasis","volume":"7","author":"Mateo-Lozano","year":"2017","journal-title":"Sci. Rep."},{"key":"2023120208084532500_CIT0020","doi-asserted-by":"crossref","first-page":"188579","DOI":"10.1016\/j.bbcan.2021.188579","article-title":"Consequence of distinctive expression of MUC2 in colorectal cancers: how much is actually bad","volume":"1876","author":"Gundamaraju","year":"2021","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"2023120208084532500_CIT0021","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/nrgastro.2017.151","article-title":"Optogenetic and chemogenetic techniques for neurogastroenterology","volume":"15","author":"Boesmans","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"2023120208084532500_CIT0022","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.ccell.2016.11.005","article-title":"Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling","volume":"31","author":"Hayakawa","year":"2017","journal-title":"Cancer Cell"},{"key":"2023120208084532500_CIT0023","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.cell.2018.02.052","article-title":"An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics","volume":"173","author":"Liu","year":"2018","journal-title":"Cell"},{"key":"2023120208084532500_CIT0024","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S0165-1838(00)00127-2","article-title":"Types of neurons in the enteric nervous system","volume":"81","author":"Furness","year":"2000","journal-title":"J. Auton. Nerv. Syst."},{"key":"2023120208084532500_CIT0025","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/s41586-020-1996-3","article-title":"Loss of p53 drives neuron reprogramming in head and neck cancer","volume":"578","author":"Amit","year":"2020","journal-title":"Nature"},{"key":"2023120208084532500_CIT0026","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13046-015-0159-0","article-title":"Extrinsic intestinal denervation modulates tumor development in the small intestine of Apc(Min\/+) mice","volume":"34","author":"Liu","year":"2015","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"2023120208084532500_CIT0027","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/s41586-019-1563-y","article-title":"Electrical and synaptic integration of glioma into neural circuits","volume":"573","author":"Venkatesh","year":"2019","journal-title":"Nature"},{"key":"2023120208084532500_CIT0028","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/s41586-019-1576-6","article-title":"Synaptic proximity enables NMDAR signalling to promote brain metastasis","volume":"573","author":"Zeng","year":"2019","journal-title":"Nature"},{"key":"2023120208084532500_CIT0029","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.stem.2015.02.006","article-title":"Basal cell carcinoma preferentially arises from stem cells within hair follicle and mechanosensory niches","volume":"16","author":"Peterson","year":"2015","journal-title":"Cell Stem Cell"},{"key":"2023120208084532500_CIT0030","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.neuron.2015.01.026","article-title":"Neural regulation of hematopoiesis, inflammation, and cancer","volume":"86","author":"Hanoun","year":"2015","journal-title":"Neuron"},{"key":"2023120208084532500_CIT0031","first-page":"303","article-title":"GABA content and GAD activity in colon tumors taken from patients with colon cancer or from xenografted human colon cancer cells growing as sc tumors in athymic nu-nu mice","volume":"49","author":"Kleinrok","year":"1998","journal-title":"J. Physiol. Pharmacol."},{"key":"2023120208084532500_CIT0032","doi-asserted-by":"crossref","first-page":"34","DOI":"10.7150\/thno.29407","article-title":"Loss of ABAT-mediated GABAergic system promotes basal-like breast cancer progression by activating Ca2+-NFAT1 axis","volume":"9","author":"Chen","year":"2019","journal-title":"Theranostics"},{"key":"2023120208084532500_CIT0033","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.neuroscience.2018.09.020","article-title":"The SNAP-25 protein family","volume":"420","author":"K\u00e1dkov\u00e1","year":"2019","journal-title":"Neuroscience"}],"container-title":["Carcinogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/carcin\/advance-article-pdf\/doi\/10.1093\/carcin\/bgad041\/50836369\/bgad041.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/carcin\/article-pdf\/44\/8-9\/682\/53974181\/bgad041.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/carcin\/article-pdf\/44\/8-9\/682\/53974181\/bgad041.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,2]],"date-time":"2023-12-02T08:29:34Z","timestamp":1701505774000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/carcin\/article\/44\/8-9\/682\/7192812"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,9]]},"references-count":33,"journal-issue":{"issue":"8-9","published-online":{"date-parts":[[2023,6,9]]},"published-print":{"date-parts":[[2023,12,2]]}},"URL":"https:\/\/doi.org\/10.1093\/carcin\/bgad041","relation":{},"ISSN":["0143-3334","1460-2180"],"issn-type":[{"value":"0143-3334","type":"print"},{"value":"1460-2180","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,8,1]]},"published":{"date-parts":[[2023,6,9]]}}}