E26 transformation (ETS)-specific related transcription factor-3 (ELF3) orchestrates a positive feedback loop that constitutively activates the MAPK/Erk pathway to drive thyroid cancer

Abstract

Thyroid cancer is the most commonly diagnosed malignancy of the endocrine system, the incidence of which has increased rapidly in the last 30 years. Genetic alterations in pathways, including the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathways, are the driving force behind the development of differentiated thyroid cancer cases into aggressive and undifferentiated forms of thyroid cancer. E26 transformation (ETS)-specific related transcription factor-3 (ELF3) belong to the epithelial-specific subfamily of ETS transcription factors and has recently been reported to be involved in various pathophysiological processes. However, the role of ELF3 in thyroid cancer has not yet been investigated. In the present study, data from The Cancer Genome Atlas (TCGA) were analyzed, and it was revealed that ELF3 was overexpressed in patients with papillary thyroid cancer (PTC). Furthermore, the expression of ELF3 was found to be higher in thyroid cancer tissues with a B-Raf proto-oncogene (BRAF) mutation as determined by western blot analysis and IHC staining. Additionally, ELF3 overexpression predicted a poor prognosis in patients with PTC. The MAPK signaling pathway inhibitor PLX4032 was demonstrated to strongly attenuate ELF3 protein levels in BRAF-mutant thyroid cancer cell lines. Knockdown of ELF3 with small interfering RNA (siRNA) inhibited the growth, clone formation, migration and invasion of BRAF mutant thyroid cancer cells. Mechanistically, ELF3 modulated the activity of the MAPK/Erk pathway via transcriptional regulation of the human epidermal growth factor receptor 2 family of receptors as determined by RT-qPCR. In conclusion, the present study demonstrated ELF3 to be a potential prognostic marker for patients with thyroid cancer. Notably, ELF3 was demonstrated to form a positive feedback loop with MAPK pathways leading to the progression of BRAF-mutant thyroid cancer.