MDM2 Knockdown Reduces the Oncogenic Activities and Enhances NIS Protein Abundance in Papillary Thyroid Cancer

Abstract

Background/aim: Despite the excellent prognosis post thyroidectomy and radioiodine therapy, papillary thyroid cancer (PTC) patients still undergo dismal outcomes, especially when tumors undergo de-differentiation and thus progress to radioiodine refractory status. Our knowledge on the pathogenesis mechanisms of PTC and NIS protein (responsible for iodine uptake) activity is still behind satisfaction. To increase our knowledge on these issues, we conducted this study.

Materials and methods: We analyzed microarray data to identify the genes differentially expressed between normal and tumor thyroid tissues. Next, pathway enrichment analysis was conducted to derive candidate genes and pathways involved in PTC oncogenesis and NIS activity. The expression of candidate genes was confirmed by an independent TCGA dataset. Then, we used siRNA to knockdown the MDM2 gene to examine the potential pathogenesis mechanisms of MDM2 and MDM2-P53-NIS axis in cells. Also, we examined whether oncogenic activities, including cell proliferation, colony formation, cell migration and cell invasion, were altered with MDM2 knockdown. Moreover, NIS protein intensity in cell membrane was also investigated.

Results: Through analyzing microarray data, pathway enrichment and correlation analyses, we focused on MDM2 since it could be involved in the MDM2-P53-NIS axis. Knockdown of MDM2 significantly reduced the mRNA levels and protein abundance of MDM2. In addition, P53 protein was also elevated with MDM2 knockdown. With MDM2 knockdown, cell proliferation and colony formation were repressed. And, both cell migration and invasion abilities were interfered. Moreover, MDM2 knockdown also enhanced the intensity of membrane NIS protein.

Conclusion: MDM2 knockdown not only reduced the oncogenic activities of thyroid cancer but also enhanced the intensity of NIS protein responsible for iodine intake in thyroid gland. Therefore, MDM2 could serve as a prognosis indicator in thyroid cancer.

Keywords: MDM2; NIS protein; Thyroid cancer; oncogenesis.