Novel function of PERP-428 variants impacts lung cancer risk through the differential regulation of PTEN/MDM2/p53-mediated antioxidant activity

doi:10.1016/j.freeradbiomed.2021.02.017

中山醫學大學機構典藏 CSMUIR > 中山醫學大學研究成果 > 期刊論文 > Item 310902500/24064

Please use this identifier to cite or link to this item: https://ir.csmu.edu.tw:8080/ir/handle/310902500/24064

Title:	Novel function of PERP-428 variants impacts lung cancer risk through the differential regulation of PTEN/MDM2/p53-mediated antioxidant activity
Authors:	Liao, CY;Yang, SF;Wu, TJ;Chang, H;Huang, CYF;Liu, YF;Wang, CH;Liou, JC;Hsu, SL;Lee, H;Sheu, GT;Chang, JT
Keywords:	PERP;SNP;p53;MDM2;PTEN;Catalase;Glutathione reductase
Date:	2021
Issue Date:	2022-08-05T09:47:15Z (UTC)
Publisher:	ELSEVIER SCIENCE INC
ISSN:	0891-5849
Abstract:	Lung cancer is the leading cause of cancer-related deaths worldwide. Identifying genetic risk factors and understanding their mechanisms will help reduce lung cancer incidence. The p53 apoptosis effect is related to PMP22 (PERP), a tetraspan membrane protein, and an apoptotic effector protein downstream of p53. Although historically considered a tumor suppressor, PERP is highly expressed in lung cancers. Stable knockdown of PERP expression induces CL1-5 and A549 lung cancer cell death, but transient knockdown has no effect. Interestingly, relative to the PERP-428GG genotype, PERP-428CC was associated with the highest lung cancer risk (OR = 5.38; 95% CI = 2.12?13.65, p < 0.001), followed by the PERP-428CG genotype (OR = 2.34; 95% CI = 1.55?3.55, p < 0.001). Ectopic expression of PERP-428G, but not PERP-428C, protects lung cancer cells against ROS-induced DNA damage. Mechanistically, PERP-428 SNPs differentially regulate p53 protein stability. p53 negatively regulates the expression of the antioxidant enzymes catalase (CAT) and glutathione reductase (GR), thereby modulating redox status. p53 protein stability is higher in PERP-428C-expressing cells than in PERP-428Gexpressing cells because MDM2 expression is decreased and p53 Ser20 phosphorylation is enhanced in PERP428C-expressing cells. The MDM2 mRNA level is decreased in PERP-428C-expressing cells via PTEN-mediated downregulation of the MDM2 constitutive p1 promoter. This study reveals that in individuals with PERP428CC, CAT/GR expression is decreased via the PTEN/MDM2/p53 pathway. These individuals have an increased lung cancer risk. Preventive antioxidants and avoidance of ROS stressors are recommended to prevent lung cancer or other ROS-related chronic diseases.
URI:	http://dx.doi.org/10.1016/j.freeradbiomed.2021.02.017 https://www.webofscience.com/wos/woscc/full-record/WOS:000646397100001 https://ir.csmu.edu.tw:8080/handle/310902500/24064
Relation:	FREE RADICAL BIOLOGY AND MEDICINE ,2021,v167 , P307-320
Appears in Collections:	[中山醫學大學研究成果] 期刊論文

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