Endocrine Abstracts

Introduction: E-cadherins are found in epithelial tissue. Reduced expression in somatotroph pituitary adenomas has been demonstrated to correlate with dedifferentiated phenotype; reduced tumour size, increased invasiveness, and reduced somatostatin analog response. Recently, correlations between corticotroph tumour dedifferentiation and both E-cadherin immunostaining and reduced E-cadherin gene (CDH1) mRNA was demonstrated.

Glucocorticoids induces transcription of some genes, and inhibit others. Corticotroph adenomas are characterised by a relative resistance to the normal inhibitory effect of glucocorticoids on proopiomelanocortin (POMC) gene expression and ACTH secretion.

Our aims were to explore if glucocorticoid resistance in corticotrophs was associated with both positively and negatively regulated genes, and if the resistance correlated with level of tumour dedifferentiation.

Methods/design: Twenty patients with verified Cushing’s disease or Nelson’s syndrome, operated at Rikshospitalet, Oslo, were included. RT-qPCR of CDH1, growth arrest-specific 5 (GAS5), POMC, the reference gene GAPDH and the normally glucocorticoid stimulated genes GILZ and thioredoxin-interacting protein (TXNIP), as well as immunohistochemical analysis of E-cadherin, were performed. Correlations between expression of the POMC, GILZ and TXNIP genes in different stages of corticotroph adenomas, defined clinically (microadenomas, macroadenomas or Nelson tumours), by CDH1 gene expression, and by E-cadherin immunoreactivity (nuclear, intermediate or membranous), were evaluated. Expression of the glucocorticoid regulated genes, GAS5 expression and preoperative 24-h urinary cortisol excretion were investigated.

Results: TXNIP and GILZ expressions were positively correlated to CDH1 expression, and were highest in microadenomas and in tumours with high membranous E-cadherin reactivity. In contrast, POMC expression was not significantly different between the groups. No correlations to GAS5 expression or urinary cortisol were found.

Conclusions: The expression of the glucocorticoid responsive genes POMC, GILZ and TXNIP in corticotroph adenomas shows a remarkable variation. The pattern and mechanism of glucocorticoid resistance in corticotroph adenomas seem dynamic, and covariate with loss of epithelial phenotype associated with corticotroph tumour dedifferentiation.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.