Clinical significance of filamin A in patients with acromegaly and its association with somatostatin and dopamine receptor profiles

Maria Caroline Alves Coelho,Leila Chimelli,Liana Lumi Ogino,Marina Lipkin Vasquez,Mônica R Gadelha,Luiz Eduardo Wildemberg,Raul M Luque,Luciana Bitana,Rafael Sánchez-Sánchez,Leandro Kasuki,Débora Silva,Aline Helen Da Silva Camacho,Nina Ventura,Mari C Vázquez-Borrego

doi:10.1038/s41598-018-37692-3

Abstract

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.

Highlights

Three drug classes are used for the treatment of patients with acromegaly to reduce hormone secretion: somatostatin receptor ligands (SRLs), dopamine agonists (DA) and antagonists of growth hormone (GH) receptor[1,2]
The aim of this study was to analyze filamin A (FLNA) expression levels and its association with sst[2], sst[5] and dopamine receptor subtype-2 (D2) expression in human somatotropinoma samples and to investigate the association of FLNA expression with SRL responsiveness and tumor invasiveness in patients with acromegaly
Tumor invasiveness was evaluated in 33 tumors, and 14 (42%) tumors were invasive adenomas based on MRI findings

Summary

Introduction

Three drug classes are used for the treatment of patients with acromegaly to reduce hormone secretion: somatostatin receptor ligands (SRLs), dopamine agonists (DA) and antagonists of growth hormone (GH) receptor[1,2]. FLNA is encoded by a gene located in chromosomal region Xq28, and it is a cytoskeletal protein that organizes actin filaments into stress fibers and networks[10] This process is important for conformational changes at the cell membrane, where it acts as a key mediator of cytoskeleton reorganization[11]. Peverelli and et al.[7] demonstrated an association between FLNA expression and response to pharmacological therapy in somatotropinomas and suggested that a reduction of FLNA expression was another mechanism of resistance to SRLs, at least in vitro. The aim of this study was to analyze FLNA expression levels and its association with sst[2], sst[5] and D2 expression in human somatotropinoma samples and to investigate the association of FLNA expression with SRL responsiveness and tumor invasiveness in patients with acromegaly

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