Dysregulated Mitogen-Activated Protein Kinase Pathway Mediated Cell Cycle Disruption in Sporadic Parathyroid Tumors

J Endocrinol Invest. 2020 Feb;43(2):247-253. doi: 10.1007/s40618-019-01098-3. Epub 2019 Sep 18.

Abstract

Objectives: The study was designed to evaluate expression profiling of mitogen-activated protein kinase (MAPK) signalling pathway genes in sporadic parathyroid adenoma.

Methods: Expression of MAPK signalling pathway genes including activated transcription factors and cell cycle regulatory genes was analysed by real-time PCR- based array in parathyroid adenoma (N = 20) and normal parathyroid tissue (N = 4).

Results: MAPK signalling pathway as studied by PCR array revealed that a total of 22 genes were differentially expressed (≥ twofold change, p ≤ 0.05) in parathyroid adenoma. Up-regulated genes were ARAF, MAPK12, CREBBP, MYC, HSPB1, HRAS, CDK4, CCND1, and E2F1, and down-regulated genes were MAP4K1, DLK1, MAP3K4, MAPK10, MAPK8, ATF2, SMAD4, MEF2C, LAMTOR3, FOS, CDKN2A CDKN2B, and RB1. The present study revealed that ERK1/2 signalling pathway with up-regulation of HRAS, ARAF, and MEK1 genes and up-regulation of positive regulators of cell cycle (CCND1, CDK4, and E2F1) and down-regulation negative regulators of cell cycle (CDKN2A, CDKN2B, and RB1) made highly dysregulated MAPK signalling pathway in parathyroid adenoma. Expression of CDK4 was positively associated with plasma PTH level (r = 0.60, p = 0.04) and tumor weight (r = 0.80, p = 0.02) of the adenoma patients, respectively. Expression of CDKN2A was correlated negatively with PTH level (r = - 0.52, p = 0.04) of the adenoma patients.

Conclusion: The current study revealed that ERK pathway and associated cell cycle regulator genes are dysregulated in sporadic parathyroid adenoma.

Keywords: Cell cycle regulation; Hypercalcemia; MAPK signalling pathway; Parathyroid adenoma.