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首页> 外文期刊>Frontiers in neuroendocrinology >The biology of gonadotropin hormone-releasing hormone: role in the control of tumor growth and progression in humans.
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The biology of gonadotropin hormone-releasing hormone: role in the control of tumor growth and progression in humans.

机译：促性腺激素释放激素的生物学：在控制人类肿瘤生长和进展中的作用。

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It is now well known that different forms of GnRH coexist in the same vertebrate species. In humans, two forms of GnRH have been identified so far. The first form corresponds to the hypophysiotropic decapeptide, and is now called GnRH-I. The second form has been initially identified in the chicken brain, and it is referred to as GnRH-II. GnRH-I binds to and activates specific receptors, belonging to the 7 transmembrane (7TM) domain superfamily, present on pituitary gonadotropes. These receptors (type I GnRH receptors) are coupled to the Gq/11/PLC intracellular signalling pathway. A receptor specific for GnRH-II (type II GnRH receptor) has been identified in non-mammalian vertebrates as well as in primates, but not yet in humans. In the last 10-15 years experimental evidence has been accumulated indicating that GnRH-I is expressed, together with its receptors, in tumors of the reproductive tract (prostate, breast, ovary, and endometrium). In these hormone-related tumors, activation of type I GnRH receptors consistently decreases cell proliferation, mainly by interfering with the mitogenic activity of stimulatory growth factors (e.g., EGF, IGF). Recent data seem to suggest that GnRH-I might also reduce the migratory and invasive capacity of cancer cells, possibly by affecting the expression and/or activity of cell adhesion molecules and of enzymes involved in the remodelling of the extracellular matrix. These observations point to GnRH-I as an autocrine negative regulatory factor on tumor growth progression and metastatization. Extensive research has been performed to clarify the molecular mechanisms underlying the peculiar antitumor activity of GnRH-I. Type I GnRH receptors in hormone-related tumors correspond to those present at the pituitary level in terms of cDNA nucleotide sequence and protein molecular weight, but do not share the same pharmacological profile in terms of binding affinity for the different synthetic GnRH-I analogs. Moreover, the classical intracellular signalling pathway mediatingthe stimulatory activity of the decapeptide on gonadotropin synthesis and secretion is not involved in its inhibitory activity on hormone-related tumor growth. In these tumors, type I GnRH receptors are coupled to the Gi-cAMP, rather than the Gq/11-PLC, signal transduction pathway. Recently, we have reported that GnRH-I and type I GnRH receptors are expressed also in tumors not related to the reproductive system, such as melanoma. Also in melanoma cells, GnRH-I behaves as a negative regulator of tumor growth and progression. Interestingly, the biochemical and pharmacological profiles of type I GnRH receptors in melanoma seem to correspond to those of the receptors at pituitary level. The data so far reported on the expression and on the possible functions of GnRH-II in humans are still scanty. The decapeptide has been identified, together with a 'putative' type II GnRH receptor, both in the central nervous system and in peripheral structures, such as tissues of the reproductive tract (both normal and tumoral). The specific biological functions of GnRH-II in humans are presently under investigation.
机译：现在众所周知，同一脊椎动物物种中共存在不同形式的GnRH。迄今为止，在人类中已鉴定出两种形式的GnRH。第一种形式对应于促生理上的十肽，现在称为GnRH-1。第二种形式已在鸡脑中初步鉴定，称为GnRH-II。 GnRH-1与垂体促性腺激素上存在的7个跨膜（7TM）域超家族的特定受体结合并激活它们。这些受体（I型GnRH受体）与Gq / 11 / PLC细胞内信号传导途径偶联。已在非哺乳动物脊椎动物以及灵长类动物中鉴定出了对GnRH-II特异的受体（II型GnRH受体），但尚未在人类中发现。在最近的10-15年中，积累了实验证据，表明GnRH-1及其受体在生殖道（前列腺癌，乳腺癌，卵巢癌和子宫内膜癌）中表达。在这些激素相关的肿瘤中，主要通过干扰刺激性生长因子（例如，EGF，IGF）的促有丝分裂活性，I型GnRH受体的激活持续降低细胞增殖。最近的数据似乎表明，GnRH-1可能还可能通过影响细胞粘附分子和参与细胞外基质重塑的酶的表达和/或活性来降低癌细胞的迁移和侵袭能力。这些观察结果表明GnRH-1是肿瘤生长进程和转移的自分泌负调控因子。已经进行了广泛的研究以阐明GnRH-1特有的抗肿瘤活性的分子机制。激素相关肿瘤中的I型GnRH受体对应于垂体水平的cDNA核苷酸序列和蛋白质分子量，但就不同的合成GnRH-1类似物的结合亲和力而言，并不共有相同的药理学特征。此外，介导十肽对促性腺激素合成和分泌的刺激活性的经典细胞内信号转导途径不涉及其对激素相关肿瘤生长的抑制活性。在这些肿瘤中，I型GnRH受体与Gi-cAMP而非Gq / 11-PLC信号转导途径偶联。最近，我们报道了GnRH-1和I型GnRH受体也在与生殖系统无关的肿瘤（例如黑素瘤）中表达。同样在黑素瘤细胞中，GnRH-1充当肿瘤生长和进展的负调节剂。有趣的是，黑色素瘤中I型GnRH受体的生化和药理学特征似乎与垂体水平的受体相对应。迄今为止，有关GnRH-II在人类中的表达及其可能功能的报道数据仍然很少。在中枢神经系统和外周结构（例如生殖道组织（正常组织和肿瘤组织））中，已鉴定出十肽以及“公认的” II型GnRH受体。目前正在研究GnRH-II在人类中的特定生物学功能。

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