The Molecular Mechanism Of Cushing’s Disease

Cushing’s disease,caused by pituitary corticotroph adenomas hypersecting adrenocorticotroph,is the most common endogenous hypercortisolism;the patients were faced with a double blow-endocrine disorders and tumor growth,which seriously threatened their normal life and survival.Currently,the pathogenesis of Cushing’s disease is still unclear and there is no effective targeted medical therapy.This study was designed to gain insights into molecular mechanism underlying Cushing’s tumorigenesis.1)By using RNA sequencing approach,we compared gene expression profiles between ACTH-secreting pituitary adenoma and normal pituitary tissue.Among 99920 detected genes,there are 241 genes changed with 2 fold in tumor tissues,the function of which are related to extracelluar matrix,cell proliferation,cell metabolism and hormone production,etc.Of note is that secreted frizzled-related protein 2(SFRP2),the inhibitor of Wnt pathway,was remarkablely decreased in human pituitary ACTH-secreting adenoma.We hence hypothesized that SFRP2 reducion might associate with the tumorigenesis of Cushing’s disease.In mouse AtT20 pituitary corticotroph cells,forced expression of SFRP2 could inhibited cell proliferation,migration and ACTH secretion.Importantly,we observed β-catenin was inactivated in SFRP2 transfected cells.These results suggest that downregulated SFRP2 may promote Cushing’s tumorigenesis by activating canonical Wnt signaling pathway.In addition,we compare the SFRP2 expression level between Cushing’s patients and normal human,establishing the correlation between SFRP2 and tumor size and invasion.This study will provide a new tumor suppressive factor for the pathogenesis and therapy of Cushing’s disease.2)In AtT20 cells,inhibition of USP8 activity with 9-ehtyloxyimino9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile leads to a suppression of cell growth and ACTH secretion.Also,treatment with USP8 inhibitor markedly induced cell apoptosis.These results indicate that inhibition of USP8 activity might be an effective strategy for Cushing’s disease.3)Here,we showed that cold inducible RNA binding protein(CIRP)was markedly elevated in corticotroph tumors Forced overexpression of CIRP in murine AtT20 pituitary corticotroph cell line increased corticotroph precursor hormone proopiomelanocortin(POMC)transcription,ACTH secretion and cellular proliferation.In vivo,CIRP overexpression promotes murine corticotroph tumor growth and enhances ACTH production.Mechanistically,we show that CIRP could promote AtT20 cells proliferation by inducing cyclinDl and decreasing p27 expression via Erk1/2 signaling pathway.Clinically,CIRP overexpression is significantly correlated with Cushing’s disease recurrence.CIRP appears to play a critical tumorigenesis function in Cushing’s disease and its expression might be a useful biomarker for tumor recurrence.