RESUMO
Filamin-A (FLNA) plays a crucial role in somatostatin receptor (sst) subtype-2 signaling in somatotropinomas. Our objective was to investigate the in vivo association between FLNA and sst2 expression, sst5 expression, dopamine receptor subtype-2 (D2) expression, somatostatin receptor ligand (SRL) responsiveness and tumor invasiveness in somatotropinomas. Quantitative real-time PCR was used to evaluate the absolute mRNA copy numbers of FLNA/sst2/sst5/D2 in 96 somatotropinomas. FLNA, sst2 and sst5 protein expression levels were also evaluated using immunohistochemistry. The Knosp-Steiner criteria were used to evaluate tumor invasiveness. Median FLNA, sst2, sst5 and D2 copy numbers were 4,244, 731, 156 and 3,989, respectively. Thirty-one of the 35 available tumors (89%) were immune positive for FLNA in the cytoplasm and membrane but not in the nucleus. FLNA and sst5 expression were positively correlated at the mRNA and protein levels (p < 0.001 and p = 0.033, respectively). FLNA was positively correlated with sst2 mRNA in patients who were responsive to SRL (p = 0.014, R = 0.659). No association was found between FLNA and tumor invasiveness. Our findings show that in somatotropinomas FLNA expression positively correlated with in vivo sst5 and D2 expression. Notably, FLNA was only correlated with sst2 in patients who were controlled with SRL. FLNA was not associated with tumor invasiveness.
Assuntos
Acromegalia/genética , Adenoma/tratamento farmacológico , Antineoplásicos/administração & dosagem , Filaminas/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Receptores de Dopamina D2/genética , Receptores de Somatostatina/genética , Acromegalia/etiologia , Acromegalia/metabolismo , Adenoma/complicações , Adenoma/genética , Adenoma/metabolismo , Adolescente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Membrana Celular/genética , Membrana Celular/metabolismo , Núcleo Celular/genética , Núcleo Celular/metabolismo , Citoplasma/genética , Citoplasma/metabolismo , Feminino , Filaminas/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Octreotida/administração & dosagem , Octreotida/uso terapêutico , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/uso terapêutico , Receptores de Dopamina D2/metabolismo , Receptores de Somatostatina/metabolismo , Somatostatina/administração & dosagem , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Carga Tumoral , Adulto JovemRESUMO
ß-arrestins seem to have a role in endocytosis and desensitization of somatostatin receptor subtype 2 (sst2) and could be associated with the responsiveness to somatostatin receptor ligands (SRL) in patients with acromegaly. To investigate the in vivo correlation between ß-arrestins 1 and 2 with sst2, sst5 and dopamine receptor subtype 2 (D2) expressions, and the association of ß-arrestins with response to first-generation SRL and invasiveness in somatotropinomas. ß-arrestins 1 and 2, sst2, sst5 and D2 mRNA expressions were evaluated by quantitative real-time RT-PCR on tumoral tissue of 96 patients. Moreover, sst2 and sst5 protein expressions were also evaluated in 40 somatotropinomas by immunohistochemistry. Response to SRL, defined as GH <1 µg/l and normal IGF-I levels, was assessed in 40 patients. The Knosp-Steiner criteria were used to define invasiveness. Median ß-arrestin 1, ß-arrestin 2, sst2, sst5 and D2 mRNA copy numbers were 478; 9375; 731; 156; and 3989, respectively. There was a positive correlation between ß-arrestins 1 and 2 (R = 0.444, P < 0.001). However, no correlation between ß-arrestins and sst2, sst5 (mRNA and protein levels) or D2 was found. No association was found between ß-arrestins expression and SRL responsiveness or tumour invasiveness. Although previous data suggest a putative correlation between ß-arrestins and sst2, our data clearly indicated that no association existed between ß-arrestins and sst2, sst5 or D2 expression, nor with response to SRL or tumour invasiveness. Therefore, further studies are required to clarify whether ß-arrestins have a role in the response to treatment with SRL in acromegaly.