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Impact of gsp Oncogene on the Expression of Genes Coding for G_s, Pit-1, G_i2, and Somatostatin Receptor 2 in Human Somatotroph Adenomas: Involvement in Octreotide Sensitivity¹

Interactions Cellulaires Neuroendocriniennes, UMR 6544, Centre National de la Recherche Scientifique, Université de la Méditerranée, Institut Jean Roche, Faculté de Médecine Nord (A.B., I.P.-B., G.G., A.J.Z., P.J., A.E.), 13916 Marseille Cedex 20; Service d’Endocrinologie, Centre Hospitalo-Universitaire Timone (P.J.), 13385 Marseille, France

Address all correspondence and requests for reprints to: Dr. Anne Barlier, Interactions Cellulaires Neuroendocriniennes, UMR 6544, Centre National de la Recherche Scientifique, Université de la Méditerranée, Institut Fédératif Jean Roche, Faculté de Médecine Nord, boulevard P. Dramard, 13916 Marseille Cedex 20, France. E-mail: barlier.a{at}jean-roche.univ-mrs.fr

The impact of the gsp oncogene on the expression of genes engaged in the somatotroph cell phenotype remains poorly understood in human somatotroph adenomas. As the gsp oncogene is associated with an increased octreotide (somatostatin agonist) sensitivity, a group of 8 somatotroph adenomas bearing the gsp mutation (gsp+) and another group of 16 adenomas without the mutation (gsp-) were analyzed, all of them presenting variable octreotide sensitivities. The expressions of genes encoding for G_s, Pit-1, G_i2, and SSTR2, involved in the regulation of secretory activity in somatotroph cells, were assessed by Northern blot. A decreased expression of the G_s gene was found in gsp+ tumors, suggesting the existence of a negative feedback of the oncogenic protein upon its own messenger ribonucleic acid (mRNA). In contrast, G_i2, Pit-1, and GH messengers were not significantly different in the groups. A positive correlation between the in vitro and in vivo GH octreotide-induced secretory inhibition and the expression of SSTR2 mRNA was found. However, the expression of the gene for SSTR2 appeared not to be different between gsp+ and gsp-, even when the octreotide sensitivity was significantly higher in the adenomas carrying the mutation. Interestingly, the SSTR2 gene expression was significantly correlated to those of G_i2 and Pit-1. In the same way, the G_s mRNA expression was positively correlated with those of G_i2 and Pit-1. Such correlations strongly suggest a concerted dysregulation of the expression of these genes in both categories of adenomas. The loss of the octreotide sensitivity represents one aspect of the dysregulation process that partially results from the decreased SSTR2 expression. However, the improvement of the sensitivity associated with the presence of the gsp oncogene seems to proceed in a way different from SSTR2 expression.

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