https://doi.org/10.4081/ejh.2023.3622
Nrf2 as a novel diagnostic biomarker for papillary thyroid carcinoma
Submitted: 30 November 2022
Accepted: 28 February 2023
Published: 20 March 2023
Accepted: 28 February 2023
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy. However, it is very difficult to distinguish PTC from benign carcinoma. Thus, specific diagnostic biomarkers are actively pursued. Previous studies observed that Nrf2 was highly expressed in PTC. Based on this research, we hypothesized that Nrf2 may serve as a novel specific diagnostic biomarker. A single-center retrospective study, including 60 patients with PTC and 60 patients with nodular goiter, who underwent thyroidectomy at the Central Theater General Hospital from 2018 to July 2020, was conducted. The clinical data of the patients were collected. Nrf2, BRAF V600E, CK-19, and Gal-3 proteins were compared from paraffin samples of the patients. Through this study, we obtained the following results: i) Nrf2 exhibits high abundance expression in PTC, but not in adjacent to PTC and nodular goiter; increased Nrf2 expression could serve as a valuable biomarker for PTC diagnosis; the sensitivity and specificity for the diagnosis of PTC were 96.70% and 89.40%, respectively. ii) Nrf2 also shows higher expression in PTC with lymph node metastasis, but not adjacent to PTC and nodular goiter, thus the increased Nrf2 expression might serve as a valuable predictor for lymph node metastasis in PTC patients; the sensitivity and specificity for the prediction in lymph node metastasis were 96.00% and 88.57%, respectively; excellent diagnostic agreements were found between Nrf2 and other routine parameters including HO-1, NQO1 and BRAF V600E. iii) The downstream molecular expression of Nrf2 including HO-1 and NQO1 consistently increased. In conclusion, Nrf2 displays a high abundance expression in human PTC, which leads to the higher expression of downstream transcriptional proteins: HO-1 and NQO1. Moreover, Nrf2 can be used as an extra biomarker for differential diagnosis of PTC and a predictive biomarker for lymph node metastasis of PTC.
Chen L, Zhu Y, Zheng K, Zhang H, Guo H, Zhang L, et al. The presence of cancerous nodules in lymph nodes is a novel indicator of distant metastasis and poor survival in patients with papillary thyroid carcinoma. J Cancer Res Clin Oncol 2017;143:1035-42.
DOI: https://doi.org/10.1007/s00432-017-2345-2
Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 2014;159:676-90.
DOI: https://doi.org/10.1016/j.cell.2014.09.050
de Matos LL, Del Giglio AB, Matsubayashi CO, de Lima Farah M, Del Giglio A, da Silva Pinhal MA. Expression of CK-19, galectin-3 and HBME-1 in the differentiation of thyroid lesions: systematic review and diagnostic meta-analysis. Diagn Pathol 2012;7:97.
DOI: https://doi.org/10.1186/1746-1596-7-97
Arcolia V, Journe F, Renaud F, Leteurtre E, Gabius H-J, Remmelink M, et al. Combination of galectin-3, CK19 and HBME-1 immunostaining improves the diagnosis of thyroid cancer. Oncol Lett 2017;14:4183-9.
DOI: https://doi.org/10.3892/ol.2017.6719
Li L, Wang J, Li Z, Qiu S, Cao J, Zhao Y, et al. Diagnostic value of serum lncRNA HOTAIR combined with Galectin-3 in benign and papillary thyroid carcinoma. Cancer Manag Res 2021;13:6517-25.
DOI: https://doi.org/10.2147/CMAR.S312784
Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, et al. Oxidative Stress: harms and benefits for human health. Oxid Med Cell Longev 2017;2017:8416763.
DOI: https://doi.org/10.1155/2017/8416763
Cominacini L, Mozzini C, Garbin U, Pasini A, Stranieri C, Solani E, et al. Endoplasmic reticulum stress and Nrf2 signaling in cardiovascular diseases. Free Radic Biol Med 2015;88:233-42.
DOI: https://doi.org/10.1016/j.freeradbiomed.2015.05.027
Krajka-Kuźniak V, Paluszczak J, Baer-Dubowska W. The Nrf2-ARE signaling pathway: An update on its regulation and possible role in cancer prevention and treatment. Pharmacol Rep 2017;69:393-402.
DOI: https://doi.org/10.1016/j.pharep.2016.12.011
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013;6:pl1.
DOI: https://doi.org/10.1126/scisignal.2004088
Luzón-Toro B, Fernández RM, Martos-Martínez JM, Rubio-Manzanares-Dorado M, Antiñolo G, Borrego S. LncRNA LUCAT1 as a novel prognostic biomarker for patients with papillary thyroid cancer. Sci Rep 2019;9:14374.
DOI: https://doi.org/10.1038/s41598-019-50913-7
Stuchi LP, Castanhole-Nunes MMU, Maniezzo-Stuchi N, Biselli-Chicote PM, Henrique T, Padovani Neto JA, et al. VEGFA and NFE2L2 Gene expression and regulation by microRNAs in thyroid papillary cancer and colloid goiter. Genes 2020;11:954.
DOI: https://doi.org/10.3390/genes11090954
Greene FL. The American Joint Committee on Cancer: updating the strategies in cancer staging. Bull Am Coll Surg 2002;87:13-5.
Yu S, Liu Y, Wang J, Guo Z, Zhang Q, Yu F, et al. Circulating microRNA profiles as potential biomarkers for diagnosis of papillary thyroid carcinoma. J Clin Endocrinol Metab 2012;97:2084-92.
DOI: https://doi.org/10.1210/jc.2011-3059
Pupilli C, Pinzani P, Salvianti F, Fibbi B, Rossi M, Petrone L, et al. Circulating BRAFV600E in the diagnosis and follow-up of differentiated papillary thyroid carcinoma. J Clin Endocrinol Metab 2013;98:3359-65.
DOI: https://doi.org/10.1210/jc.2013-1072
Xu JY, Handy B, Michaelis CL, Waguespack SG, Hu MI, Busaidy N, et al. Detection and prognostic significance of circulating tumor cells in patients with metastatic thyroid cancer. J Clin Endocrinol Metab 2016;101:4461-7.
DOI: https://doi.org/10.1210/jc.2016-2567
Winkens T, Pachmann K, Freesmeyer M. Circulating epithelial cells in patients with thyroid carcinoma. Can they be identified in the blood? Nukl Nucl Med 2013;52:7-13.
DOI: https://doi.org/10.3413/Nukmed-0524-12-08
Tsuchida K, Tsujita T, Hayashi M, Ojima A, Keleku-Lukwete N, Katsuoka F, et al. Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation. Free Radic Biol Med 2017;103:236-47.
DOI: https://doi.org/10.1016/j.freeradbiomed.2016.12.041
Yamamoto M, Kensler TW, Motohashi H. The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol Rev 2018;98:1169-203.
DOI: https://doi.org/10.1152/physrev.00023.2017
Park JS, Kang DH, Bae SH. p62 prevents carbonyl cyanide m-chlorophenyl hydrazine (CCCP)-induced apoptotic cell death by activating Nrf2. Biochem Biophys Res Commun 2015;464:1139-44.
DOI: https://doi.org/10.1016/j.bbrc.2015.07.093
Jiang T, Harder B, Rojo de la Vega M, Wong PK, Chapman E, Zhang DD. p62 links autophagy and Nrf2 signaling. Free Radic Biol Med 2015;88:199-204.
DOI: https://doi.org/10.1016/j.freeradbiomed.2015.06.014
Jain A, Lamark T, Sjøttem E, Larsen KB, Awuh JA, Øvervatn A, et al. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J Biol Chem 2010;285:22576-91.
DOI: https://doi.org/10.1074/jbc.M110.118976
Ziros PG, Manolakou SD, Habeos IG, Lilis I, Chartoumpekis DV, Koika V, et al. Nrf2 is commonly activated in papillary thyroid carcinoma, and it controls antioxidant transcriptional responses and viability of cancer cells. J Clin Endocrinol Metab 2013;98:e1422-7.
DOI: https://doi.org/10.1210/jc.2013-1510
Chen GG, Liu ZM, Vlantis AC, Tse GMK, Leung BCH, Hasselt CA van. Heme oxygenase-1 protects against apoptosis induced by tumor necrosis factor-alpha and cycloheximide in papillary thyroid carcinoma cells. J Cell Biochem 2004;92:1246-56.
DOI: https://doi.org/10.1002/jcb.20157
Lyn-Cook BD, Yan-Sanders Y, Moore S, Taylor S, Word B, Hammons GJ. Increased levels of NAD(P)H: quinone oxidoreductase 1 (NQO1) in pancreatic tissues from smokers and pancreatic adenocarcinomas: A potential biomarker of early damage in the pancreas. Cell Biol Toxicol 2006;22:73-80.
DOI: https://doi.org/10.1007/s10565-006-0156-3
Cheng Y, Li J, Martinka M, Li G. The expression of NAD(P)H:quinone oxidoreductase 1 is increased along with NF-kappaB p105/p50 in human cutaneous melanomas. Oncol Rep 2010;23:973-9.
DOI: https://doi.org/10.3892/or_00000722
Awadallah NS, Dehn D, Shah RJ, Russell Nash S, Chen YK, Ross D, et al. NQO1 expression in pancreatic cancer and its potential use as a biomarker. Appl Immunohistochem Mol Morphol 2008;16:24–31.
DOI: https://doi.org/10.1097/PAI.0b013e31802e91d0
Ito Y, Jikuzono T, Higashiyama T, Asahi S, Tomoda C, Takamura Y, et al. Clinical significance of lymph node metastasis of thyroid papillary carcinoma located in one lobe. World J Surg 2006;30:1821-8.
DOI: https://doi.org/10.1007/s00268-006-0211-5
Lundgren CI, Hall P, Dickman PW, Zedenius J. Clinically significant prognostic factors for differentiated thyroid carcinoma: a population-based, nested case-control study. Cancer 2006;106:524-31.
DOI: https://doi.org/10.1002/cncr.21653
Podnos YD, Smith D, Wagman LD, Ellenhorn JDI. The implication of lymph node metastasis on survival in patients with well-differentiated thyroid cancer. Am Surg 2005;71:731-4.
DOI: https://doi.org/10.1177/000313480507100907
Ho AS, Luu M, Barrios L, Chen I, Melany M, Ali N, et al. Incidence and Mortality risk spectrum across aggressive variants of papillary thyroid carcinoma. JAMA Oncol 2020;6:706-13.
DOI: https://doi.org/10.1001/jamaoncol.2019.6851
Feng R, Morine Y, Ikemoto T, Imura S, Iwahashi S, Saito Y, et al. Nrf2 activation drive macrophages polarization and cancer cell epithelial-mesenchymal transition during interaction. Cell Commun Signal 2018;16:54.
DOI: https://doi.org/10.1186/s12964-018-0262-x
Gañán-Gómez I, Wei Y, Yang H, Boyano-Adánez MC, García-Manero G. Oncogenic functions of the transcription factor Nrf2. Free Radic Biol Med 2013;65:750-64.
DOI: https://doi.org/10.1016/j.freeradbiomed.2013.06.041
Cernigliaro C, D’Anneo A, Carlisi D, Giuliano M, Marino Gammazza A, Barone R, et al. Ethanol-mediated stress promotes autophagic survival and aggressiveness of colon cancer cells via activation of Nrf2/HO-1 pathway. Cancers 2019;11:505.
DOI: https://doi.org/10.3390/cancers11040505
Liu J, Liu M, Wang S, He Y, Huo Y, Yang Z, et al. Alantolactone induces apoptosis and suppresses migration in MCF‑7 human breast cancer cells via the p38 MAPK, NF‑κB and Nrf2 signaling pathways. Int J Mol Med 2018;42:1847-56.
DOI: https://doi.org/10.3892/ijmm.2018.3751
Fan H, Paiboonrungruan C, Zhang X, Prigge JR, Schmidt EE, Sun Z, et al. Nrf2 regulates cellular behaviors and Notch signaling in oral squamous cell carcinoma cells. Biochem Biophys Res Commun 2017;493:833-9.
DOI: https://doi.org/10.1016/j.bbrc.2017.08.049
Danilovic DLS, Mello ES de, Frazzato EST, Wakamatsu A, Lima Jorge AA de, Hoff AO, et al. Oncogenic mutations in KEAP1 disturbing inhibitory Nrf2-Keap1 interaction: Activation of antioxidative pathway in papillary thyroid carcinoma. Head Neck 2018;40:1271-8.
DOI: https://doi.org/10.1002/hed.25105
Mikami K, Naito M, Ishiguro T, Yano H, Tomida A, Yamada T, et al. Immunological quantitation of DT-diaphorase in carcinoma cell lines and clinical colon cancers: advanced tumors express greater levels of DT-diaphorase. Jpn J Cancer Res Gann 1998;89:910-5.
DOI: https://doi.org/10.1111/j.1349-7006.1998.tb00648.x
Furfaro AL, Traverso N, Domenicotti C, Piras S, Moretta L, Marinari UM, et al. The Nrf2/HO-1 axis in cancer cell growth and chemoresistance. Oxid Med Cell Longev 2016;2016:1958174.
DOI: https://doi.org/10.1155/2016/1958174
Abi-Raad R, Prasad ML, Zheng J, Hui P, Ustun B, Schofield K, et al. Prognostic assessment of BRAF mutation in preoperative thyroid fine-needle aspiration specimens. Am J Clin Pathol 2021;156:100-8.
DOI: https://doi.org/10.1093/ajcp/aqaa213
Ding Z, Tao X, Deng X, Guo B, Kang J, Wu B, et al. Genetic analysis and clinicopathologic features of locally advanced papillary thyroid cancers: a prospective observational study. J Cancer Res Clin Oncol 2023 Online ahead of print.
DOI: https://doi.org/10.1007/s00432-022-04541-w
Ivković I, Limani Z, Jakovčević A, Gajović S, Seiwerth S, Đanić Hadžibegović A, et al. Prognostic significance of BRAF V600E mutation and CPSF2 protein expression in papillary thyroid cancer. Biomedicines 2023;11:53.
DOI: https://doi.org/10.3390/biomedicines11010053
Xin Y, Guan D, Meng K, Lv Z, Chen B. Diagnostic accuracy of CK-19, Galectin-3 and HBME-1 on papillary thyroid carcinoma: a meta-analysis. Int J Clin Exp Pathol 2017;10:8130-40.
Cho BY, Choi HS, Park YJ, Lim JA, Ahn HY, Lee EK, et al. Changes in the clinicopathological characteristics and outcomes of thyroid cancer in Korea over the past four decades. Thyroid 2013;23:797-804.
DOI: https://doi.org/10.1089/thy.2012.0329
Rojo de la Vega M, Chapman E, Zhang DD. NRF2 and the hallmarks of cancer. Cancer Cell 2018;34:21-43.
DOI: https://doi.org/10.1016/j.ccell.2018.03.022
Ethics Approval
This study was approved by the Research Ethics Committee of the General Hospital of Central Theater Command, Wuhan, Hubei, China (N. [2021]005-02)Supporting Agencies
Hubei Province Key Laboratory of Occupational Hazard Identification and Control, Wuhan University of Science and Technology, China International Medical FoundationHow to Cite
Wang, Z., Li, J., Liu, Z., & Yue, L. (2023). Nrf2 as a novel diagnostic biomarker for papillary thyroid carcinoma. European Journal of Histochemistry, 67(2). https://doi.org/10.4081/ejh.2023.3622
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