Department of Internal Medicine, Division of Endocrinology, University of Patras Medical School, 26500 Patras, Greece.
J Clin Endocrinol Metab. 2013 Aug;98(8):E1422-7. doi: 10.1210/jc.2013-1510. Epub 2013 Jun 13.
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.
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.
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.
The study included 42 PTC and 42 benign lesions (24 adenomas and 18 nodular hyperplasias).
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.
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.
The high activity of Nrf2 in PTC warrants further exploration of this pathway's potential diagnostic, prognostic, and/or therapeutic utility in PTC.
抗氧化转录因子 NFE2 相关因子 2（Nrf2）由 NFE2L2 编码，被认为是甲状腺癌细胞系对蛋白酶体抑制剂耐药的中介。然而，人类甲状腺癌中 Nrf2 通路的活性状态尚不清楚。
本研究旨在评估甲状腺乳头状癌（PTC）中 Nrf2 通路的活性状态，并研究其在抗氧化转录反应和癌细胞活力中的作用。
我们对 PTC 标本、相邻正常组织和良性病变进行了回顾性免疫组织化学分析；对 PTC 细胞系 K1 和 TPC-1 进行了 Nrf2 基因/药物操作后的活力和基因表达检测；并在学术医疗中心进行了 DNA 测序。
研究包括 42 例 PTC 和 42 例良性病变（24 例腺瘤和 18 例结节性增生）。
我们评估了 Nrf2、Nqo1、Keap1 和 4HNE 的丰度；细胞系活力和 Nrf2、Nqo1 和 Trdx1 的 mRNA 表达；以及 NFE2L2、KEAP1 和 BRAF 的序列。
Nrf2 和其靶基因 Nqo1 在正常组织中无法检测到；它们在 PTC 中的水平明显高于良性病变（P<0.0001 和 P=0.024）。Nrf2 抑制剂 Keap1 在 PTC 中丰度不同，其水平与 Nrf2 无相关性（P=0.37），表明 Nrf2 的激活机制不是水平降低。PTC 中的氧化脂质 4HNE 比正常组织更丰富（P<0.001），表明存在氧化应激。Nrf2 在 PTC 细胞系 K1 和 TPC-1 以及非转化细胞系 TAD2 中介导了转录抗氧化反应，但仅在 PTC 细胞系中赋予了活力优势。
PTC 中 Nrf2 的高活性提示该通路在 PTC 中的潜在诊断、预后和/或治疗价值值得进一步研究。
