PMID- 29956475 OWN - NLM STAT- MEDLINE DCOM- 20191029 LR - 20210109 IS - 1582-4934 (Electronic) IS - 1582-1838 (Print) IS - 1582-1838 (Linking) VI - 22 IP - 9 DP - 2018 Sep TI - Deoxycholic acid activates epidermal growth factor receptor and promotes intestinal carcinogenesis by ADAM17-dependent ligand release. PG - 4263-4273 LID - 10.1111/jcmm.13709 [doi] AB - High fat diet is implicated in the elevated deoxycholic acid (DCA) in the intestine and correlated with increased colon cancer risk. However, the potential mechanisms of intestinal carcinogenesis by DCA remain unclarified. Here, we investigated the carcinogenic effects and mechanisms of DCA using the intestinal tumour cells and Apc(min/+) mice model. We found that DCA could activate epidermal growth factor receptor (EGFR) and promote the release of EGFR ligand amphiregulin (AREG), but not HB-EGF or TGF-alpha in intestinal tumour cells. Moreover, ADAM-17 was required in DCA-induced promotion of shedding of AREG and activation of EGFR/Akt signalling pathway. DCA significantly increased the multiplicity of intestinal tumours and accelerated adenoma-carcinoma sequence in Apc(min/+) mice. ADAM-17/EGFR signalling axis was also activated in intestinal tumours of DCA-treated Apc(min/+) mice, whereas no significant change occurred in tumour adjacent tissues after DCA exposure. Conclusively, DCA activated EGFR and promoted intestinal carcinogenesis by ADAM17-dependent ligand release. CI - (c) 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. FAU - Dong, Wenxiao AU - Dong W AUID- ORCID: 0000-0002-3052-1638 AD - Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China. FAU - Liu, Li AU - Liu L AD - Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China. FAU - Dou, Yan AU - Dou Y AD - Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China. FAU - Xu, Mengque AU - Xu M AD - Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China. FAU - Liu, Tianyu AU - Liu T AD - Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China. FAU - Wang, Sinan AU - Wang S AD - Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China. FAU - Zhang, Yujie AU - Zhang Y AD - Department of Pathology, General Hospital, Tianjin Medical University, Tianjin, China. FAU - Deng, Baoru AU - Deng B AD - Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China. FAU - Wang, Bangmao AU - Wang B AD - Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China. FAU - Cao, Hailong AU - Cao H AUID- ORCID: 0000-0002-0147-7826 AD - Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180629 PL - England TA - J Cell Mol Med JT - Journal of cellular and molecular medicine JID - 101083777 RN - 0 (Adenomatous Polyposis Coli Protein) RN - 0 (Amphiregulin) RN - 0 (Areg protein, mouse) RN - 0 (adenomatous polyposis coli protein, mouse) RN - 005990WHZZ (Deoxycholic Acid) RN - EC 2.7.10.1 (EGFR protein, mouse) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 3.4.24.86 (ADAM17 Protein) RN - EC 3.4.24.86 (Adam17 protein, mouse) SB - IM MH - ADAM17 Protein/*genetics/metabolism MH - Adenoma/chemically induced/*genetics/metabolism/pathology MH - Adenomatous Polyposis Coli Protein/deficiency/genetics MH - Amphiregulin/*genetics/metabolism MH - Animals MH - Carcinogenesis/genetics/metabolism/pathology MH - Cell Line, Tumor MH - Deoxycholic Acid/*administration & dosage MH - Epithelial Cells/metabolism/pathology MH - ErbB Receptors/*genetics/metabolism MH - *Gene Expression Regulation, Neoplastic MH - HCT116 Cells MH - Humans MH - Intestinal Neoplasms/chemically induced/*genetics/metabolism/pathology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Protein Binding MH - Proto-Oncogene Proteins c-akt/genetics/metabolism MH - Signal Transduction PMC - PMC6111862 OTO - NOTNLM OT - a disintegrin and metalloprotease-17 OT - deoxycholic acid OT - epidermal growth factor receptor OT - intestinal carcinogenesis EDAT- 2018/06/30 06:00 MHDA- 2019/10/30 06:00 PMCR- 2018/09/01 CRDT- 2018/06/30 06:00 PHST- 2017/08/30 00:00 [received] PHST- 2018/05/04 00:00 [accepted] PHST- 2018/06/30 06:00 [pubmed] PHST- 2019/10/30 06:00 [medline] PHST- 2018/06/30 06:00 [entrez] PHST- 2018/09/01 00:00 [pmc-release] AID - JCMM13709 [pii] AID - 10.1111/jcmm.13709 [doi] PST - ppublish SO - J Cell Mol Med. 2018 Sep;22(9):4263-4273. doi: 10.1111/jcmm.13709. Epub 2018 Jun 29.