PMID- 31793679 OWN - NLM STAT- MEDLINE DCOM- 20200420 LR - 20200420 IS - 1098-2744 (Electronic) IS - 0899-1987 (Linking) VI - 59 IP - 2 DP - 2020 Feb TI - Ornithine decarboxylase inhibition downregulates multiple pathways involved in the formation of precancerous lesions of esophageal squamous cell cancer. PG - 215-226 LID - 10.1002/mc.23144 [doi] AB - The high incidence and mortality of esophageal squamous cell cancer (ESCC) is a major health problem worldwide. Precancerous lesions of ESCC may either progress to cancer or revert to normal epithelium with appropriate interventions; the bidirectional instability of the precancerous lesions of ESCC provides opportunities for intervention. Reports suggest that the upregulation of ornithine decarboxylase (ODC) is closely related to carcinogenesis. In this study, we investigated whether ODC may act as a target for chemoprevention in ESCC. Immunohistochemistry (IHC) assays indicate that ODC expression is higher in esophageal precancerous lesions compared with normal tissue controls. Its overexpression promotes cell proliferation and transformation of normal esophageal epithelial cells, and its activity is increased after N-nitrosomethylbenzylamine (NMBA) induction in Shantou human embryonic esophageal cell line (SHEE) and human immortalized cells (Het1A) cells. In addition, p38 alpha, extracellular regulated kinase (ERK1/2) in the mitogen-activated protein kinase pathway and protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (p70S6K) pathways are activated in response to NMBA treatment. Difluoromethylornithine (DFMO) is an ODC inhibitor, which inhibits NMBA-induced activation of p38 alpha, ERK1/2 and AKT/mTOR/p70S6K pathways; this has been verified by Western blotting. DFMO was also found to suppress the development of esophageal precancerous lesions in an NMBA-induced rat model; IHC demonstrated p38 alpha, ERK1/2, and AKT/mTOR/p70S6K pathways to be downregulated in these rats. These findings indicate the mechanisms by which ODC inhibition suppresses the development of esophageal precancerous lesions by downregulating p38 alpha, ERK1/2, and AKT/mTOR/p70S6k signaling pathways, ODC may be a potential target for chemoprevention in ESCC. CI - (c) 2019 Wiley Periodicals, Inc. FAU - Xie, Yifei AU - Xie Y AD - Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. FAU - Dong, Christopher D AU - Dong CD AD - Wartburg College, Waverly, IA. FAU - Wu, Qiong AU - Wu Q AD - Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. AD - China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China. FAU - Jiang, Yanan AU - Jiang Y AD - Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. AD - Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, China. FAU - Yao, Ke AU - Yao K AD - The Hormel Institute, University of Minnesota, Austin, Minnesota. FAU - Zhang, Jing AU - Zhang J AD - Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. FAU - Zhao, Simin AU - Zhao S AD - Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. FAU - Ren, Ying AU - Ren Y AD - Pathology Department, Henan Provincial People's Hospital, Zhengzhou, Henan, China. FAU - Yuan, Qiang AU - Yuan Q AD - Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. FAU - Chen, Xinhuan AU - Chen X AD - Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. AD - Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, China. FAU - Liu, Zhongyi AU - Liu Z AD - College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, China. FAU - Zhao, Jimin AU - Zhao J AD - Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. AD - Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, China. FAU - Liu, Kangdong AU - Liu K AUID- ORCID: 0000-0003-4762-6185 AD - Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. AD - China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China. AD - Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, China. AD - Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, Henan, China. AD - Henan Provincial Key Laboratory of Esophageal Cancer, Zhengzhou, Henan, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191203 PL - United States TA - Mol Carcinog JT - Molecular carcinogenesis JID - 8811105 RN - 0 (Carcinogens) RN - 0 (Ornithine Decarboxylase Inhibitors) RN - 937-40-6 (nitrosobenzylmethylamine) RN - EC 4.1.1.17 (Ornithine Decarboxylase) RN - M43H21IO8R (Dimethylnitrosamine) SB - IM MH - Carcinogens/pharmacology MH - Carcinoma, Squamous Cell/genetics/*metabolism/pathology MH - Cell Line MH - Cell Line, Tumor MH - Cell Proliferation/drug effects/genetics MH - Cell Transformation, Neoplastic/drug effects/genetics MH - Dimethylnitrosamine/analogs & derivatives/pharmacology MH - Down-Regulation/drug effects MH - Esophageal Neoplasms/genetics/*metabolism/pathology MH - Humans MH - Ornithine Decarboxylase/genetics/*metabolism MH - Ornithine Decarboxylase Inhibitors/*pharmacology MH - Precancerous Conditions/genetics/*metabolism/pathology MH - Signal Transduction/*drug effects/genetics OTO - NOTNLM OT - N-nitrosomethylbenzylamine OT - chemoprevention OT - esophageal neoplasms OT - ornithine decarboxylase inhibitor OT - preneoplastic EDAT- 2019/12/04 06:00 MHDA- 2020/04/21 06:00 CRDT- 2019/12/04 06:00 PHST- 2019/09/28 00:00 [received] PHST- 2019/11/22 00:00 [revised] PHST- 2019/11/25 00:00 [accepted] PHST- 2019/12/04 06:00 [pubmed] PHST- 2020/04/21 06:00 [medline] PHST- 2019/12/04 06:00 [entrez] AID - 10.1002/mc.23144 [doi] PST - ppublish SO - Mol Carcinog. 2020 Feb;59(2):215-226. doi: 10.1002/mc.23144. Epub 2019 Dec 3.