Introduction: The silencing mechanisms of corticotroph tumors (CT) remain unclear. The most feasible hypothesis lies in a post-transcriptional deregulation of the POMC gene, precursor of ACTH. Micro RNAs (miRNAs) are small non-coding RNA molecules involved in the epigenetic regulation of gene expression through their inhibitory action on messenger RNA. miRNAs capable of inhibiting the expression of POMC have been described at the level of neurons of the hypothalamus, which gives us a basis to advance in the knowledge of CT.
Aim: The aim of the present study was to determine if epigenetic regulation by miRNAs is involved in the silencing mechanisms of CT.
Methods: We have quantified the relative gene expression of 8 factors (PKA, MAP3K8, MEK, MAPK3, NGFIB, NURR1, PITX1, STAT3) and 5 miRNAs (miR375, miR383, miR488, miR200a, miR103) related with the expression of POMC by qRT-PCR with TaqMan probes in 24 functioning CT (fCT) and 23 silent CT (sCT).
Results: sCT were significantly higher than fCT (maximum tumor diameter mean ± standard deviation: 22.44 mm ±10.26 vs 13.76 mm ±9.99, P=0.003). The expression of miR200a and miR103 was higher in sCT than in fCT (P=0.007 and P=0.011, respectively). No statistically significant data were found when we evaluated the correlations between gene expression of factors and miRNAs in fCT. Conversely, we observed a strong negative correlation between miR488, miR200a and miR103 and the expression of MAP3K8 (rho =−0.747, P<0.001, rho =−0.686, P=0.001 and rho =−0.782, P<0.001, respectively); between miR488 and miR103 and MEK expression (rho =−0.605, P=0.006 and rho =−0.665, P=0.002, respectively) and between miR383 and the expression of STAT3 (rho =−0.544, P=0.016) in sCT. Finally, the maximum tumor diameter was positively correlated with the expression of miR488 (rho=0.521, P=0.027) in sCT.
Conclusions: The inhibition of transcription factors (STAT3) and kinases related with proliferation, differentiation and transcription regulation (MAP3K8 and MEK) could participate in the silencing of CT.
18 - 21 May 2019
European Society of Endocrinology