title: Nrf2 is commonly activated in papillary thyroid carcinoma, and it controls antioxidant transcriptional responses and viability of cancer cells.
abstract: BACKGROUND
  The antioxidant transcription factor NFE2-related factor 2 (Nrf2), encoded by NFE2L2, has been implicated as mediator of thyroid cancer cell line resistance to proteasome inhibitors. However, the activity status of the Nrf2 pathway in human thyroid cancer remains unknown.
  
  
  OBJECTIVE
  The aims of this study were assessment of the activity status of the Nrf2 pathway in papillary thyroid carcinoma (PTC) and investigation of its role(s) in antioxidant transcriptional responses and viability of cancer cells.
  
  
  METHODS
  We conducted retrospective immunohistochemical analyses of PTC specimens, adjacent normal tissue, and benign lesions; assays of viability and gene expression in the PTC cell lines K1 and TPC-1 after genetic/pharmacological manipulation of Nrf2; and DNA sequencing at an academic medical center.
  
  
  METHODS
  The study included 42 PTC and 42 benign lesions (24 adenomas and 18 nodular hyperplasias).
  
  
  METHODS
  We assessed the abundance of Nrf2, Nqo1, Keap1, and 4HNE; cell line viability and mRNA expression of Nrf2, Nqo1, and Trdx1; and the sequence of NFE2L2, KEAP1, and BRAF.
  
  
  RESULTS
  Nrf2 and its target Nqo1 were undetectable in normal tissue; their levels were significantly higher in PTC than in benign lesions (P < .0001 and P = .024, respectively). The Nrf2 inhibitor Keap1 was variably abundant in PTC, and its levels did not correlate with Nrf2 (P = .37), arguing against decreased levels as the mechanism for Nrf2 activation. The oxidized lipid 4HNE was more abundant in PTC than normal tissue (P < .001), indicating oxidative stress. Nrf2 mediated transcriptional antioxidant responses in both the PTC cell lines K1 and TPC-1 and in the nontransformed cell line TAD2, but it conferred a viability advantage specifically in the PTC cell lines.
  
  
  CONCLUSIONS
  The high activity of Nrf2 in PTC warrants further exploration of this pathway's potential diagnostic, prognostic, and/or therapeutic utility in PTC.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, University of Patras Medical School, 26500 Patras, Greece.
authors.forename: Panos G
authors.initials: PG
authors.lastname: Ziros
authors.forename: Stavroula D
authors.initials: SD
authors.lastname: Manolakou
authors.forename: Ioannis G
authors.initials: IG
authors.lastname: Habeos
authors.forename: Ioannis
authors.initials: I
authors.lastname: Lilis
authors.forename: Dionysios V
authors.initials: DV
authors.lastname: Chartoumpekis
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Koika
authors.forename: Paula
authors.initials: P
authors.lastname: Soares
authors.forename: Venetsana E
authors.initials: VE
authors.lastname: Kyriazopoulou
authors.forename: Chrisoula D
authors.initials: CD
authors.lastname: Scopa
authors.forename: Dionysios J
authors.initials: DJ
authors.lastname: Papachristou
authors.forename: Gerasimos P
authors.initials: GP
authors.lastname: Sykiotis
mesh_terms: D000447:Aldehydes / Q000032:analysis; D000975:Antioxidants / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D000072019:Kelch-Like ECH-Associated Protein 1; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000032:analysis; D051267:NF-E2-Related Factor 2 / Q000032:analysis / Q000502:physiology*; D018384:Oxidative Stress; D012189:Retrospective Studies; D015398:Signal Transduction; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C027576:4-hydroxy-2-nonenal