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Transcriptome sequencing reveals two subtypes of cortisol-secreting adrenocortical tumors in dogs and identifies CYP26B1 as a potential new therapeutic target

ABSTRACT: Cushing’s syndrome (CS) is a serious endocrine disorder that is rare in humans, but relatively common in dogs. In ~15-20% of cases, CS is caused by a cortisol-secreting adrenocortical tumor (csACT). To identify differentially expressed genes that can improve prognostic predictions after surgery and represent novel treatment targets, we performed RNA sequencing on csACTs (n=48) and normal adrenal cortices (NACs; n=10) of dogs. A gene was declared differentially expressed when the adjusted P-value was <0.05 and the log2 fold change was >2 or <-2. Between NACs and csACTs, 98 genes were differentially expressed. Based on the principal component analysis (PCA) the csACTs were separated in two groups, of which group 1 had significantly better survival after adrenalectomy (P=0.002) than group 2. Between csACT group 1 and group 2, 77 genes were differentially expressed. One of these, cytochrome P450 26B1 (CYP26B1), was significantly associated with survival in both our canine csACTs and in a publicly available dataset of 33 human cortisol-secreting adrenocortical carcinomas. In the validation cohort, CYP26B1 was also expressed significantly higher (P=0.012) in canine csACTs compared to NACs. In future studies it would be interesting to determine whether CYP26B1 inhibitors could inhibit csACT growth in both dogs and humans.

ORGANISM(S): Canis lupus familiaris

PROVIDER: GSE196108 | GEO | 2022/02/11

REPOSITORIES: GEO

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Project description:This a model from the article: A mechanistic model of ACTH-stimulated cortisol secretion. Dempsher DP, Gann DS, Phair RD. Am J Physiol 1984 Apr;246(4 Pt 2):R587-96 6326602 , Abstract: Adrenal secretory rates of cortisol and arterial concentrations of adrenocorticotropin (ACTH) were measured in conscious trained dogs subjected to intravenous infusion of ACTH. To investigate the causal relation of ACTH to the secretion of cortisol, a mechanistic mathematical model based on current hypotheses of adrenocortical function was constructed and tested. It is widely believed that ACTH stimulates cortisol secretion through adenosine 3',5'-cyclic monophosphate (cAMP), which provides substrate cholesterol by activating cholesterol ester hydrolase and facilitating transport of cholesterol to the side-chain cleavage enzyme. In addition, cholesterol modulates its own synthesis by inhibiting beta-hydroxy-beta-methylglutaryl (HMG)-CoA reductase in the adrenocortical cell. These and other steps in the biosynthetic reaction sequence were described using differential equations subject to the additional constraints imposed by available measurements of intracellular quantities. The resulting model is consistent with many of the known characteristics of the canine adrenal response to ACTH. In this model, steady-state nonlinearities arise from cooperative binding of cAMP to its receptor protein and saturation of mitochondrial pregnenolone transport. The transient response is dominated by a depletable pool of intracellular free cholesterol. Other inferences based on the model are presented, and a quantifiable cellular basis for increased adrenal sensitivity to ACTH is proposed. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Dempsher DP, Gann DS, Phair RD. (1984) - version03 The original CellML model was created by: Lloyd, Catherine, May c.lloyd@aukland.ac.nz The University of Auckland The Bioengineering Institute This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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Transcriptome sequencing reveals two subtypes of cortisol-secreting adrenocortical tumors in dogs and identifies CYP26B1 as a potential new therapeutic target

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