ARMC5 mutations are associated with high levels of proliferating cell nuclear antigen and the presence of the serotonin receptor 5HT4R in PMAH nodules

Autor(es)

Barbara Brito da Conceição ^[1] ; Isadora Pontes Cavalcante ^[2] ; Jean Lucas Kremer ^[3] ; Thais Barabba Auricino ^[4] ; Eduarda Corrêa Bento ^[5] ; Maria Claudia Nogueira Zerbini ^[6] ; Maria Candida Barisson Villares Fragoso ^[7] ; Claudimara Ferini Pacicco Lotfi ^[8]

Afiliação do(s) autor(es)

^[1] Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Anatomia - Brasil

^[2] Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Anatomia - Brasil

^[3] Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Anatomia - Brasil

^[4] Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Anatomia - Brasil

^[5] Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Anatomia - Brasil

^[6] Universidade de São Paulo. Departamento de Patologia - Brasil

^[7] Universidade de São Paulo. Laboratório de Hormônios e Genética Molecular LIM/42 - Brasil

^[8] Universidade de São Paulo. Instituto de Ciências Biomédicas. Departamento de Anatomia - Brasil

• Tipo de documento: Artigo Científico
• Fonte: ARCHIVES OF ENDOCRINOLOGY METABOLISM; v. 64, n. 4, p. 390-401, 2020-04-06.

Resumo

ABSTRACT Objective To analyze the morphological and functional characteristics of primary macronodular adrenal hyperplasia (PMAH) nodules carrying or not carrying ARMC5 mutations and the consequences of the presence of mutations in terms of the pattern of macronodule composition and functional state. Subjects and methods The analyses were performed by hematoxylin-eosin staining, immunohistochemistry, microdissection of spongiocyte tissue and RT-qPCR of histological sections from 16 patients diagnosed with PMAH with germline (5) or germline/somatic mutations (5) and without mutations (6) in the ARMC5 gene. Results Hyperplastic nodules were predominantly composed of spongiocytes in mutated and nonmutated sections. ARMC5 mRNA expression in spongiocytes was higher in ARMC5-mutated nodules than in ARMC5-nonmutated nodules, and homogenous ARMC5 protein distribution was observed. The presence of arginine-vasopressin receptor (AVP1AR) and ectopic ACTH production were observed in both cell populations regardless of ARMC5 mutations; the numbers of serotonin receptor (5HT4R)- and proliferating cell nuclear antigen (PCNA)-positive cells were higher in macronodules carrying ARMC5 mutations than in those without mutations. Conclusions Our results suggest that the presence of ARMC5 mutations does not interfere with the pattern of distribution of spongiocytes and compact cells or with the presence of AVP1AR, gastric-inhibitory polypeptide receptor (GIPR) and ectopic ACTH. Nevertheless, the higher numbers of PCNA-positive cells in mutated nodules than in nonmutated nodules suggest that mutated ARMC5 can be related to higher proliferation rates in these cells. In conclusion, our results provide more information about the crosstalk among abnormal GPCRs, ectopic ACTH in steroidogenesis and the ARMC5 gene, which may be relevant in understanding the pathogenesis and diagnosis of patients with PMAH. (AU)

• Processo FAPESP: 15/50192-9 - Avanços na compreensão da fisiopatologia da hiperplasia macronodular adrenocortical primária - PMAH (GP-PMAH)
• Beneficiário: Maria Candida Barisson Villares Fragoso
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 15/14199-9 - Estudo da expressão do fator de transcrição Pod-1/TCF21 em tumores adrenocorticais, identificação de novos alvos de regulação de Pod-1 e seu papel na migração celular de células tumorais
• Beneficiário: Claudimara Ferini Pacicco Lotfi
• Modalidade de apoio: Auxílio à Pesquisa - Regular