Steroid-dependent ACTH-produced thymic carcinoid: regulation of POMC gene expression by cortisol via methylation of its promoter region.
OBJECTIVE
Metyrapone causes a decrease in the serum cortisol level without affecting ACTH production in ectopic tumors. We report a case who presented with Cushing's syndrome due to an ectopic ACTH-producing thymic carcinoid. In the present case, it was demonstrated that metyrapone administration resulted in a significant decrease in the plasma ACTH and serum cortisol levels. We hypothesized that the steroid hormone may promote proopiomelanocortin (POMC) gene expression in the carcinoid cells.


METHODS
An 11-year-old boy presented with Cushing's syndrome. Prior to the detection of a thymic tumor, metyrapone was administered to ameliorate the symptoms of Cushing's syndrome. Interestingly, plasma ACTH as well as serum cortisol levels immediately decreased after metyrapone administration. The levels of cortisol and ACTH were observed to be normal after complete surgical resection of the tumor. Biological characterization of the tumor cells was by in vitro analysis.


RESULTS
Thein vitro culture of the tumor cells showed an increased expression of POMC in the presence of cortisol. A CpG methylation assay showed that the demethylation of the POMC promoter was induced by a steroid hormone.


CONCLUSIONS
These findings suggest that the ectopic ACTH-producing tumor may partly be regulated by the elevated levels of cortisol.
Mizoguchi
Yoko
Y
Department of Pediatrics, Hiroshima University, Hiroshima, Japan.
Kajiume
Teruyuki
T
Miyagawa
Shin-ichiro
S
Okada
Satoshi
S
Nishi
Yoshikazu
Y
Kobayashi
Masao
M
D000182:ACTH Syndrome, Ectopic / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000963:Antimetabolites / Q000627:therapeutic use; D002276:Carcinoid Tumor / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D002648:Child; D019175:DNA Methylation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008797:Metyrapone / Q000627:therapeutic use; D008954:Models, Biological; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D011859:Radiography; D013953:Thymus Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000963:Antimetabolites; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone; D008797:Metyrapone