RAE1 promotes nitrosamine-induced malignant transformation of human esophageal epithelial cells through PPARα-mediated lipid metabolism

Ling He; Xiangjun Zhou; Jia Liu; Yina Yao; Junyuan Lin; Jialong Chen; Shizhen Qiu; Zeyu Liu; Yingzheng He; Yujie Yi; Xueqiong Zhou; Fei Zou

doi:10.1016/j.ecoenv.2023.115513

RAE1 promotes nitrosamine-induced malignant transformation of human esophageal epithelial cells through PPARα-mediated lipid metabolism

Ecotoxicol Environ Saf. 2023 Oct 15:265:115513. doi: 10.1016/j.ecoenv.2023.115513. Epub 2023 Sep 27.

Authors

Ling He¹, Xiangjun Zhou¹, Jia Liu¹, Yina Yao¹, Junyuan Lin¹, Jialong Chen², Shizhen Qiu¹, Zeyu Liu¹, Yingzheng He¹, Yujie Yi¹, Xueqiong Zhou³, Fei Zou⁴

Affiliations

¹ Department of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, 1838 Guangzhou Road North, Guangzhou 510515, China.
² Department of Preventive Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, China.
³ Department of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, 1838 Guangzhou Road North, Guangzhou 510515, China. Electronic address: xue4131@i.smu.edu.cn.
⁴ Department of Occupational Health and Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, 1838 Guangzhou Road North, Guangzhou 510515, China. Electronic address: zfei@smu.edu.cn.

PMID: 37774541
DOI: 10.1016/j.ecoenv.2023.115513

Abstract

Esophageal cancer (EC) is the sixth cause of cancer-related deaths and still is a significant public health problem globally. Nitrosamines exposure represents a major health concern increasing EC risks. Exploring the mechanisms induced by nitrosamines may contribute to the prevention and early detection of EC. However, the mechanism of nitrosamine carcinogenesis remains unclear. Ribonucleic acid export 1 (RAE1), has an important role in mediating diverse cancer types, but, to date, there has been no study for any functional role of RAE1 in esophageal carcinogenesis. Here, we successfully verified the nitrosamine-induced malignant transformation cell (MNNG-M) by xenograft tumor model, based on which it was found that RAE1 was upregulation in the early stage of nitrosamine-induced esophageal carcinogenesis and EC tissues. RAE1 knockdown led to severe blockade in G2/M phase and significant inhibition of proliferation of MNNG-M cells, whereas RAE1 overexpression had the opposite effect. In addition, peroxisome proliferator-activated receptor-alpha (PPARα), was demonstrated as a downstream target gene of RAE1, and its down-regulation reduced lipid accumulation, resulting in causing cells accumulation in the G2/M phase. Mechanistically, we found that RAE1 regulates the lipid metabolism by maintaining the stability of PPARα mRNA. Taken together, our study reveals that RAE1 promotes malignant transformation of human esophageal epithelial cells (Het-1A) by regulating PPARα-mediated lipid metabolism to affect cell cycle progression, and offers a new explanation of the mechanisms underlying esophageal carcinogenesis.

Keywords: Esophageal epithelial cells; Malignant transformation; Nitrosamine; Peroxisome proliferator-activated receptor alpha; Ribonucleic acid export 1.