NRG1 regulates redox homeostasis via NRF2 in papillary thyroid cancer

Abstract

Thyroid cancer is a common endocrine cancer, of which papillary thyroid cancer (PTC) is the most common type. Neuregulin 1 (NRG1), a glycoprotein mediating cell-cell signaling, plays vital roles in cellular activities; however, its role in PTC progression remains poorly understood. In this study, we performed immunohistochemistry in 196 samples from patients and found that NRG1, a potential prognostic marker is highly expressed in PTC compared with adjacent normal tissues. Cell Counting kit-8 (CCK-8) and clone formation assays indicated that NRG1 is essential for PTC cell viability and proliferation, probably by regulating redox homeostasis, which was implied by ROS generation analysis and intracellular GSH activity assay. Western blot analysis and RT-qPCR revealed that NRG1 regulates ERK pathway and the pivotal regulator of cellular redox status, nuclear factor E2-related factor 2 (NRF2), which maintains moderate reactive oxygen species (ROS) levels through a set of antioxidant response element (ARE)-containing genes. The immuno-histochemical scoring of 196 PTC samples and the analysis of the data of 490 patients from The Cancer Genome Atlas (TCGA) reveled a positive association between the expression of NRG1 and NRF2. Since the presence of NRG1 regulates redox homeostasis through NRF2, protecting PTC cells from the accumulation of ROS and ROS-induced cell death, NRG1 may thus prove to be a potential therapeutic target in the treatment of thyroid cancer.

Keap1/Nrf2 Signaling: A New Player in Thyroid Pathophysiology and Thyroid Cancer

“…Among PTC samples with strong expression of Nrf2, the BRAF V600E mutation was not more frequent compared to a general PTC cohort, suggesting that Nrf2 activation is not exclusively associated with BRAF mutation (42). Another study focused on neuregulin 1 (NRG1), a member of the epidermal growth factor-like family, which was found to be overexpressed in PTC (58, 59). NRG1 positively impacts Nrf2 protein levels in PTC and stimulates the upregulation of its target genes, including NQO1, GCLC , and GCLM (glutamate cysteine ligase, modulatory subunit) (58).…”

“…Another study focused on neuregulin 1 (NRG1), a member of the epidermal growth factor-like family, which was found to be overexpressed in PTC (58, 59). NRG1 positively impacts Nrf2 protein levels in PTC and stimulates the upregulation of its target genes, including NQO1, GCLC , and GCLM (glutamate cysteine ligase, modulatory subunit) (58). The latter genes improve redox balance, as reflected in a higher ratio of reduced to oxidized glutathione (GSH/GSSG, GSH being the most abundant intracellular antioxidant), and this additional protection against ROS confers a survival advantage to the tumor cells (58).…”

“…NRG1 positively impacts Nrf2 protein levels in PTC and stimulates the upregulation of its target genes, including NQO1, GCLC , and GCLM (glutamate cysteine ligase, modulatory subunit) (58). The latter genes improve redox balance, as reflected in a higher ratio of reduced to oxidized glutathione (GSH/GSSG, GSH being the most abundant intracellular antioxidant), and this additional protection against ROS confers a survival advantage to the tumor cells (58). Similar to experimental knock-down of Nrf2 (42), knock-down of NRG1 abolished the survival advantage of PTC cells, suggesting that NRG1 may be a potential therapeutic target (58).…”

Current and future markers for the diagnosis of thyroid cancer

“…Moreover, when TROP-2 were combined to CD56, the sensitivity and NPV increased to 100% and had a better diagnostic accuracy, further supporting the interest for CD56 [20]. Again, NRG1 was also recently reported to be highly expressed in PTC compared with adjacent normal tissues [21].…”

lncRNA CASC9 regulates cell migration and invasion in hemangioma endothelial cells by targeting miR-125a-3p/Nrg1

“…To deeply investigate the mechanism by which CASC9 exerted its tumorigenesis role in HAs, the target of miR-125a-3p was also predicted. NRG1 was confirmed as a target of miR-125a-3p, which is recognized as an oncogene in gastric cancer,19 colon cancer,20 lung cancer,21 and papillary thyroid cancer 22. Yin et al23 reported that miR-125a-3p affected cell apoptosis and invasion through regulating Nrg1 in human glioma cells.…”