Renaud Cedric O, Ziros Panos G, Chartoumpekis Dionysios V, Bongiovanni Massimo, Sykiotis Gerasimos P
Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of Patras, Patras, Greece.
Front Endocrinol (Lausanne). 2019 Aug 2;10:510. doi: 10.3389/fendo.2019.00510. eCollection 2019.
The Keap1/Nrf2 pathway is a key mediator of general redox and tissue-specific homeostasis. It also exerts a dual role in cancer, by preventing cell transformation of normal cells but promoting aggressiveness, and drug resistance of malignant ones. Although Nrf2 is well-studied in other tissues, its roles in the thyroid gland are only recently emerging. This review focuses on the involvement of Keap1/Nrf2 signaling in thyroid physiology, and pathophysiology in general, and particularly in thyroid cancer. Studies in mice and cultured follicular cells have shown that, under physiological conditions, Nrf2 coordinates antioxidant defenses, directly increases thyroglobulin production and inhibits its iodination. Increased Nrf2 pathway activation has been reported in two independent families with multinodular goiters due to germline loss-of-function mutations in . Nrf2 pathway activation has also been documented in papillary thyroid carcinoma (PTC), due to somatic mutations, or epigenetic modifications in , or other pathway components. In PTC, such Nrf2-activating mutations have been associated with tumor aggressiveness. Furthermore, polymorphisms in the prototypical Nrf2 target genes and have been associated with extra-thyroidal extension and metastasis. More recently, mutations in the Nrf2 pathway have also been found in Hürthle-cell (oncocytic) thyroid carcinoma. Finally, in , and models of poorly-differentiated, and undifferentiated (anaplastic) thyroid carcinoma, Nrf2 activation has been associated with resistance to experimental molecularly-targeted therapy. Thus, Keap1/Nrf2 signaling is involved in both benign and malignant thyroid conditions, where it might serve as a prognostic marker or therapeutic target.
Keap1/Nrf2信号通路是全身氧化还原和组织特异性稳态的关键调节因子。它在癌症中也发挥着双重作用，既能阻止正常细胞的转化，又能促进恶性细胞的侵袭性和耐药性。尽管Nrf2在其他组织中已得到充分研究，但其在甲状腺中的作用直到最近才逐渐显现。本综述重点关注Keap1/Nrf2信号通路在甲状腺生理学和一般病理生理学中的作用，特别是在甲状腺癌中的作用。对小鼠和培养的滤泡细胞的研究表明，在生理条件下，Nrf2协调抗氧化防御，直接增加甲状腺球蛋白的产生并抑制其碘化。据报道，在两个独立的多结节性甲状腺肿家族中，由于种系功能丧失突变，Nrf2信号通路的激活增加。在乳头状甲状腺癌（PTC）中，也有文献记载Nrf2信号通路的激活，这是由于体细胞突变、或其他通路成分的表观遗传修饰所致。在PTC中，这种激活Nrf2的突变与肿瘤侵袭性有关。此外，典型的Nrf2靶基因和的多态性与甲状腺外扩展和转移有关。最近，在许特莱细胞（嗜酸性）甲状腺癌中也发现了Nrf2信号通路的突变。最后，在低分化和未分化（间变性）甲状腺癌的模型中，Nrf2激活与对实验性分子靶向治疗的耐药性有关。因此，Keap1/Nrf2信号通路参与了甲状腺的良性和恶性疾病，它可能作为一种预后标志物或治疗靶点。
