Abstract
The pathogenesis of Cushing's disease, which is caused by pituitary corticotroph adenoma, remains to be studied. Secreted angioinhibitory factor thrombospondin‐1 (TSP‐1) is an adhesive glycoprotein that mediates cell‐to‐cell and cell‐to‐matrix interactions and is associated with platelet aggregation, angiogenesis and tumorigenesis. We have found that the expression of TSP‐1 is significantly lower in human pituitary corticotroph tumours compared with normal adenohypophysis. This study aims to elucidate the role of TSP‐1 in regulating the tumour function of pituitary adenomas. Forced overexpression of TSP‐1 in a murine AtT20 pituitary corticotroph tumour cell line decreased corticotroph precursor hormone proopiomelanocortin (POMC) transcription and adrenocorticotropic hormone (ACTH) secretion. Functional studies showed that TSP‐1 overexpression in pituitary adenoma cells suppressed proliferation, migration and invasion. We have demonstrated that TSP‐1 is a direct target of miR‐449c. Further study showed that miR‐449c activity enhanced tumorigenesis by directly inhibiting TSP‐1 expression. Low expression of lncTHBS1, along with low expression of TSP‐1, was associated with the high expression of miR‐449c in Cushing's disease patients. Furthermore, RNA‐immunoprecipitation associates miR‐449c with lncTHBS1 suggesting that lncTHBS1 might be a negative regulator of miR‐449c. Taken together, this study has demonstrated that lncTHBS1 might function as competing endogenous RNA for miR‐449c, which could suppress the development of Cushing's disease.
Highlights
Cushing's disease is a consequence of the chronic hypercortisolism associated with the oversecretion of the adrenocorticotropic hormone (ACTH) and is the most common cause of corticotrophin‐dependentCushing's syndrome, accounting for up to 80% of cases.[1-4]
POMC expression and ACTH secretion were increased in AtT20 cells transfected with miR‐449c but decreased when TSP‐1 was overexpressed in the cells
The present study aimed to elucidate the mechanistic role of TSP‐1 in regulating the tumour function of pituitary adenomas
Summary
Cushing's disease is a consequence of the chronic hypercortisolism associated with the oversecretion of the adrenocorticotropic hormone (ACTH) and is the most common cause of corticotrophin‐dependent. Secreting pituitary adenomas that cause Cushing's disease are usually benign slow‐growing tumours originating from pituitary corticotroph cells.[5]. It is known that the downregulation of the TGF beta signalling pathway and activation of the TGF pathway may decrease the secretion of ACTH and tumour cell proliferation in pituitary corticotrophinomas.[31,32]. TSP‐1 induced by TGFB1 is reported to promote the migration of oral squamous cell carcinoma and stimulate the expression of matrix metalloproteinases (MMPs) through integrin signalling.[35]. Loss‐ and gain‐of‐function assays showed that CCAT2 positively regulated pituitary adenoma cell proliferation, migration and invasion, and interacted with PTTG1 to promote its stability. To investigate dysregulated lncRNAs and miRNAs in Cushing's disease we selected miR‐449c and lncTHBS1 and compared their expression in ACTH‐secreting adenoma and normal pituitary tissue. We investigated the expression of TSP‐1 in ACTH‐secreting adenoma and its effects on the expression of POMC, VEGF, Ki67 and MMP9
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