Nrf2 Is Commonly Activated in Papillary Thyroid Carcinoma, and It Controls Antioxidant Transcriptional Responses and Viability of Cancer Cells

Abstract

The high activity of Nrf2 in PTC warrants further exploration of this pathway's potential diagnostic, prognostic, and/or therapeutic utility in PTC.

Frequent concerted genetic mechanisms disrupt multiple components of the NRF2 inhibitor KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex in thyroid cancer

“…Consistent with previous reports, activating mutations or copy number gains/amplifications targeting NFE2L2 are uncommon in PTC [4]. Moreover, while BRAF V600E mutations were common, these were not associated with increased NRF2 expression in PTC, as described for other cancers [8], indicating that NRF2 pathway activation in PTC likely occurs through other mechanisms (Figure 1B).…”

“…Moreover, these results provide a plausible DNA level mechanism for recent findings by others describing NRF2 pathway activation in PTC [4]. …”

“…Paradoxically, the NRF2 pathway, which is responsible for protecting cells against ROS damage, is constitutively activated in multiple cancer types and associated with many cancer hallmarks [11,12]. Over-activation of this pathway has recently been described in PTC [4]. Given recent findings and the importance of ROS to normal thyroid hormonogensis, elucidation of the molecular mechanisms underlying NRF2 deregulation in PTC is relevant.…”

“…Paradoxically, constitutive activation of this pathway occurs in several tumor types affecting multiple oncogenic functions [3] (Figure 1A). Recently, the NRF2 pathway was found activated in papillary thyroid carcinoma (PTC) [4]. …”

“…Activating mutations in the NRF2 gene, NFE2L2 , are not common in PTC and genetic mechanisms underlying NRF2 activation remain to be elucidated for this tumor type [4]. NRF2 protein levels are negatively regulated by the KEAP1/CUL3/RBX1 E3 ubiquitin-ligase complex [5] (Figure 1A).…”