Nuclear factor-erythroid 2-related factor 3 (NRF3) is low expressed in colorectal cancer and its down-regulation promotes colorectal cancer malignance through activating EGFR and p38/MAPK

American Journal of Cancer Research

Chan Chen¹  Yuejin Li²  Shan Zhou³  Jinping Lu⁴ 

[1] Department of Clinical Laboratory, Changsha Central Hospital, Changsha 410013, China;Department of Clinical Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China;Department of Clinical Laboratory, Zhuhai Hospital, Jinan University, Zhuhai 519000, Guangdong, China;Hormel Institute, University of Minnesota, 801 16 Avenue NE, Austin, MN 55912, USA

关键词: NRF3;    colorectal cancer;    EGFR;    p38;    tumorigenesis;   

DOI  :  

学科分类：肿瘤学

来源: e-Century Publishing Corporation

【 摘 要 】

Nuclear factor-erythroid 2-related factor 3 (NRF3), a nuclear transcription factor, has been implicated in various cellular processes including carcinogenesis. However, mechanisms underlying its regulation in carcinogenesis are unclear. Herein, we found that NRF3 is lowly expressed in colorectal cancer (CRC) tissues and cells, and NRF3 low-expressions in CRC tissue samples are associated with CRC carcinogenesis and poor patient outcomes. Nrf3-knockdown increased CRC cell growth, colony formation, and cell motility and invasion, and Nrf3-knockin dramatically decreased CRC cell growth and colony formation. Mechanistically, NRF3 increased CRC cell apoptosis and arrested cell G2/M stage. NRF3 was found to be reversely with epidermal growth factor receptor (EGFR) and p38. Strikingly, Nrf3-knockin dramatically decreased phosphorylated-EGFR at Tyrosine845 (pEGFR Tyr845) and phosphorylated-p38 at Threonine180/Tyrosine182 (p-p38 Thr180/Tyr182) expressions, and Nrf3-knockdown increased pEGFR Tyr845 and p-p38 Thr180/Tyr182. Moreover, NRF3 regulated EGFR and p38 down-stream molecules, protein kinase B (AKT), activating transcription factor (ATF) 2, and C/EBP homologous protein (CHOP) expressions. NRF3 loss-increased CRC growth through EGFR and p38 was confirmed in nude mice. Collectively, NRF3-loss in CRC cell increases EGFR and p38 phosphorylation activation, enhances cell proliferation and decreases cell apoptosis, and finally promotes CRC malignance.

【 授权许可】

CC BY-NC