Kola Blerina, Korbonits Márta, Diaz-Cano Salvador, Kaltsas Gregory, Morris Damian G, Jordan Suzanne, Metherell Lou, Powell Michael, Czirják Sándor, Arnaldi Giorgio, Bustin Stephen, Boscaro Marco, Mantero Franco, Grossman Ashley B
Departments of Endocrinology and Histopatholgy, St Bartholomew's Hospital and National Institute of Neurology and Neurosurgery, London, UK.
Clin Endocrinol (Oxf). 2003 Sep;59(3):328-38. doi: 10.1046/j.1365-2265.2003.01851.x.
Clinical acromegaly is characterized by elevated GH secretion in the presence of high circulating IGF-I levels. We hypothesized that the physiological IGF-I/GH negative feedback loop may be reset in somatotroph adenomas, specifically in terms of the level of expression of these receptors or mutations of the GH receptor (GH-R) in such tumours.
We therefore investigated the full coding sequence of the GH-R in a series of somatotroph and other pituitary adenomas. We also investigated the mRNA expression of these putative feedback receptors in a series of pituitary adenomas and normal pituitary tissue, and their protein expression by immunostaining. Real-time RT-PCR assay was used for the quantification of the type 1 IGF receptor (IGF-R) and GH receptor (GH-R) mRNA, and sequence analysis was performed on the coding region of the GH-R gene.
No somatic mutations of the GH-R mRNA were detected in 18 GH-secreting tumours or two nonfunctioning pituitary adenomas (NFPAs). However, the levels of GH-R mRNA were significantly lower in both somatotroph tumours and NFPAs compared to the normal pituitary (P < 0.05 for both). Immunostaining for GH-R also showed significantly less GH-R expression in somatotroph adenomas compared to normal pituitary tissue (P < 0.0001). IGF-R mRNA levels were significantly lower in somatotroph tumours compared to normal pituitary (P = 0.005), and trended lower in corticotroph tumours (P = 0.07), while the other tumour types showed no significant difference from normal pituitary. Immunostaining for IGF-R also showed less IGF-R protein in the somatotroph adenomas compared to the normal pituitary tissue (P < 0.01).
Our findings suggest that decreased feedback inhibition of GH because of somatic mutations of the coding region of the GH-R are unlikely to be a common factor in the pathogenesis of these tumours. Nevertheless, decreased expression of the GH-R and of IGF-R in somatotroph tumours (both at the mRNA and protein level) may, at least in part, help explain the continuous secretion of GH from the tumour despite the high circulating levels of IGF-I and GH.
临床肢端肥大症的特征是在循环中胰岛素样生长因子-I（IGF-I）水平升高的情况下生长激素（GH）分泌增加。我们推测，在生长激素细胞腺瘤中，生理上的IGF-I/GH负反馈回路可能会重置，特别是在这些受体的表达水平或此类肿瘤中生长激素受体（GH-R）的突变方面。
因此，我们研究了一系列生长激素细胞腺瘤和其他垂体腺瘤中GH-R的完整编码序列。我们还研究了一系列垂体腺瘤和正常垂体组织中这些假定的反馈受体的mRNA表达，并通过免疫染色研究了它们的蛋白表达。实时逆转录聚合酶链反应（RT-PCR）检测用于定量1型胰岛素样生长因子受体（IGF-R）和生长激素受体（GH-R）mRNA，对GH-R基因的编码区进行序列分析。
在18例分泌GH的肿瘤或2例无功能垂体腺瘤（NFPA）中未检测到GH-R mRNA的体细胞突变。然而，与正常垂体相比，生长激素细胞肿瘤和NFPA中GH-R mRNA的水平均显著降低（两者P均<0.05）。与正常垂体组织相比，生长激素细胞腺瘤中GH-R的免疫染色也显示GH-R表达明显减少（P<0.0001）。与正常垂体相比，生长激素细胞肿瘤中IGF-R mRNA水平显著降低（P = 0.005），促肾上腺皮质激素细胞肿瘤中IGF-R mRNA水平呈下降趋势（P = 0.07），而其他肿瘤类型与正常垂体无显著差异。与正常垂体组织相比，生长激素细胞腺瘤中IGF-R的免疫染色也显示IGF-R蛋白减少（P<0.01）。
我们的研究结果表明，由于GH-R编码区的体细胞突变导致的GH反馈抑制降低不太可能是这些肿瘤发病机制中的常见因素。然而，生长激素细胞肿瘤中GH-R和IGF-R表达的降低（在mRNA和蛋白水平）可能至少部分有助于解释尽管循环中IGF-I和GH水平较高，但肿瘤仍持续分泌GH的现象。
