NRG1 regulates redox homeostasis via NRF2 in papillary thyroid cancer

Int J Oncol. 2018 Aug;53(2):685-693. doi: 10.3892/ijo.2018.4426. Epub 2018 May 31.

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 immunohistochemical 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.

MeSH terms

  • Carcinoma, Papillary / genetics
  • Carcinoma, Papillary / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Female
  • Gene Expression Regulation, Neoplastic
  • Homeostasis
  • Humans
  • Male
  • NF-E2-Related Factor 2 / genetics*
  • NF-E2-Related Factor 2 / metabolism*
  • Neuregulin-1 / genetics
  • Neuregulin-1 / metabolism*
  • Oxidation-Reduction
  • Prognosis
  • Thyroid Cancer, Papillary
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / metabolism*
  • Up-Regulation*

Substances

  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • NRG1 protein, human
  • Neuregulin-1