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Role of ACTH receptor in adrenocortical tumor formation
1Unidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular, Disciplina de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil. anacl@usp.br
Abstract:
Adrenocorticotrophin (ACTH) is the major regulatory hormone of steroid synthesis and secretion by adrenocortical cells. The actions of ACTH are mediated by its specific membrane receptor (ACTH-R). The human ACTH-R gene was recently cloned, allowing systematic determination of its sequence, expression and function in adrenal tumorigenesis. The presence of oncogenic mutations of the ACTH-R gene in adrenocortical tumors has been reported. Direct sequencing of the entire coding region of the ACTH-R gene of sporadic adrenocortical adenomas and carcinomas did not reveal constitutive activating mutations, indicating that this mechanism is not frequent in human adrenocortical tumorigenesis. Recent studies demonstrated allelic loss of the ACTH-R gene in a subset of sporadic adrenocortical tumors using a PstI polymorphism located in the promoter region of the ACTH-R gene. Loss of heterozygosity of the ACTH-R was analyzed in 20 informative patients with a variety of benign and malignant adrenocortical tumors. Three of them showed loss of heterozygosity of the ACTH-R gene. In addition, Northern blot experiments demonstrated reduced expression of ACTH-R mRNA in these three tumors with loss of heterozygosity, suggesting the functional significance of this finding at the transcriptional level. Deletion of the ACTH-R gene seems to be involved in a subset of human adrenocortical tumors, contributing to cellular dedifferentiation.
Insights
Deletion of the adrenocorticotrophin receptor (ACTH-R) gene occurs in some adrenal tumors. This loss of heterozygosity correlates with reduced ACTH-R mRNA expression, suggesting a role in tumor development.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Adrenocorticotrophin (ACTH) regulates steroid synthesis via its receptor (ACTH-R).
- The human ACTH-R gene's sequence, expression, and function in adrenal tumorigenesis are areas of active research.
- Previous reports suggested oncogenic mutations in the ACTH-R gene in adrenal tumors.
Purpose of the Study:
- To investigate the role of ACTH-R gene alterations in human adrenocortical tumorigenesis.
- To determine if constitutive activating mutations in the ACTH-R gene are frequent in sporadic adrenocortical tumors.
- To analyze loss of heterozygosity (LOH) of the ACTH-R gene in a subset of adrenocortical tumors.
Main Methods:
- Direct sequencing of the ACTH-R gene coding region in sporadic adrenocortical adenomas and carcinomas.
- Analysis of ACTH-R gene LOH using a PstI polymorphism in the promoter region.
- Northern blot experiments to assess ACTH-R mRNA expression levels in tumors with LOH.
Main Results:
- Constitutive activating mutations of the ACTH-R gene were not found to be frequent in human adrenocortical tumorigenesis.
- Loss of heterozygosity of the ACTH-R gene was identified in 3 out of 20 informative patients with adrenocortical tumors.
- Reduced ACTH-R mRNA expression was observed in tumors exhibiting LOH, indicating functional significance at the transcriptional level.
Conclusions:
- Deletion of the ACTH-R gene appears to be involved in a subset of human adrenocortical tumors.
- ACTH-R gene LOH may contribute to cellular dedifferentiation in adrenocortical tumors.
- The findings suggest a role for ACTH-R gene alterations beyond mutations in adrenal tumor development.