PTPN23[Thr] variant reduces susceptibility and tumorigenesis in esophageal squamous cell carcinoma through dephosphorylation of EGFR

Siyuan Niu; Jialing Ma; Yueping Li; Xinying Yue; Ke Shi; Miaoxin Pan; Lina Song; Yuqian Tan; Linglong Gu; Shasha Liu; Jiang Chang

doi:10.1016/j.canlet.2024.216936

PTPN23[Thr] variant reduces susceptibility and tumorigenesis in esophageal squamous cell carcinoma through dephosphorylation of EGFR

Cancer Lett. 2024 May 3:592:216936. doi: 10.1016/j.canlet.2024.216936. Online ahead of print.

Authors

Siyuan Niu¹, Jialing Ma¹, Yueping Li¹, Xinying Yue¹, Ke Shi¹, Miaoxin Pan¹, Lina Song¹, Yuqian Tan¹, Linglong Gu¹, Shasha Liu¹, Jiang Chang²

Affiliations

¹ Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
² Department of Health Toxicology, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. Electronic address: changjiang815@hust.edu.cn.

PMID: 38704135
DOI: 10.1016/j.canlet.2024.216936

Abstract

Post-translational modifications (PTMs) have emerged as pivotal regulators of the development of cancers, including esophageal squamous cell carcinoma (ESCC). Here, we conducted a comprehensive analysis of PTM-related genetic variants associated with ESCC risk using large-scale genome-wide and exome-wide association datasets. We observed significant enrichment of PTM-related variants in the ESCC risk loci and identified five variants that were significantly associated with ESCC risk. Among them, rs6780013 in PTPN23 exhibited the highest level of significance in ESCC susceptibility in 9,728 ESCC cases and 10,977 controls (odds ratio [OR] = 0.85, 95 % confidence interval [CI] = 0.81- 0.89, P = 9.77 × 10^-14). Further functional investigations revealed that PTPN23[Thr] variant binds to EGFR and modulates its phosphorylation at Thr699. PTPN23[Thr] variant substantially inhibited ESCC cell proliferation both in vitro and in vivo. Our findings underscore the critical role of PTPN23[Thr]-EGFR interaction in ESCC development, providing more insights into the pathogenesis of this cancer.

Keywords: EGFR Thr699; Esophageal cancer; Genetic susceptibility; PTPN23 rs6780013; Post-translational protein modification.