title: Cytoplasmic localization of Nrf2 promotes colorectal cancer with more aggressive tumors via upregulation of PSMD4.
abstract: Differences in subcellular localization of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) have been associated with poor outcomes in human cancers. However, the prognostic value of subcellular localization of Nrf2 in colorectal cancer and the underlying mechanism in tumor invasion remain unknown. We enrolled tumors from colorectal patients to evaluate Nrf2, NQO1, and HO-1 expression by immunohistochemistry. NQO1 and HO-1 positive tumors showed nearly complete expression of Nrf2 in the nucleus and/or showed partial expression in the nucleus/cytoplasm (nNrf2); however, tumors negative for NQO1 and HO-1 showed almost complete expression of Nrf2 in the cytoplasm and/or partial expression in the nucleus/cytoplasm (cNrf2). Kaplan-Meier and Cox regression analysis indicated poorer overall survival in patients with cNrf2 tumors than with nNrf2 tumors. Cell models provided evidence that cNrf2, rather than nNrf2, was responsible for cell invasion and soft agar growth triggered by activation of the NF-κB/AKT/β-catenin cascade. Mechanistically, cNrf2 persistently increased PSMD4 expression by the HIF1α/β-catenin axis, whereas PSMD4 reciprocally enhanced Nrf2 nuclear export by increasing CRM1 expression through p53 degradation. The mechanistic action of the cell model was further confirmed with a nude mouse animal model in which xenograft tumors induced by cNrf2 were nearly completely suppressed by the proteasomal inhibitor carfilzomib or the β-catenin inhibitor XAV939. We therefore suggest that PSMD4 or β-catenin might be potential targets for suppressing tumor aggressiveness, and consequently, improving outcomes in patients whose tumors express cNrf2.
authors.affiliation: Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC.
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Lin
authors.affiliation: Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC.
authors.forename: Jinghua Tsai
authors.initials: JT
authors.lastname: Chang
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: De-Wei
authors.initials: DW
authors.lastname: Wu
authors.affiliation: Department of Surgery, School of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC.
authors.forename: Chi-Chou
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan, ROC. Electronic address: hl@tmu.edu.tw.
authors.forename: Huei
authors.initials: H
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D003593:Cytoplasm / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D016601:RNA-Binding Proteins
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C498506:PSMD4 protein, human; D016601:RNA-Binding Proteins; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D046988:Proteasome Endopeptidase Complex
keywords: Colorectal cancer; Cytoplasmic Nrf2; PSMD4