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 mediating the 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.

中文翻译：

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促性腺激素释放激素的生物学特性：在控制人类肿瘤生长和进展中的作用

现在众所周知，不同形式的 GnRH 共存于同一脊椎动物物种中。在人类中，迄今已鉴定出两种形式的 GnRH。第一种形式对应于垂体十肽，现在称为 GnRH-I。第二种形式最初是在鸡脑中发现的，它被称为 GnRH-II。GnRH-I 结合并激活特定受体，属于 7 跨膜 (7TM) 结构域超家族，存在于垂体促性腺激素上。这些受体（I 型 GnRH 受体）与 Gq/11/PLC 细胞内信号通路偶联。GnRH-II（II 型 GnRH 受体）特异性受体已在非哺乳类脊椎动物和灵长类动物中得到鉴定，但尚未在人类中得到鉴定。在过去的 10-15 年中，积累的实验证据表明 GnRH-I 表达，连同其受体，在生殖道肿瘤（前列腺、乳腺、卵巢和子宫内膜）中。在这些激素相关肿瘤中，I 型 GnRH 受体的激活持续降低细胞增殖，主要是通过干扰刺激性生长因子（例如，EGF、IGF）的促有丝分裂活性。最近的数据似乎表明 GnRH-1 也可能降低癌细胞的迁移和侵袭能力，可能是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。这些观察结果表明 GnRH-I 是肿瘤生长进展和转移的自分泌负调节因子。已经进行了广泛的研究，以阐明 GnRH-I 独特的抗肿瘤活性背后的分子机制。激素相关肿瘤中的 I 型 GnRH 受体在 cDNA 核苷酸序列和蛋白质分子量方面对应于垂体水平上存在的那些，但在对不同合成 GnRH-I 类似物的结合亲和力方面不具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通路不参与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 信号转导通路偶联。最近，我们报道了 GnRH-I 和 I 型 GnRH 受体也在与生殖系统无关的肿瘤中表达，例如黑色素瘤。同样在黑色素瘤细胞中，GnRH-I 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受体的特征一致。迄今为止，关于 GnRH-II 在人类中的表达和可能功能的报告仍然很少。在中枢神经系统和外周结构中，如生殖道组织（正常和肿瘤组织）中，已鉴定出十肽以及“推定的”II 型 GnRH 受体。目前正在研究 GnRH-II 在人体中的特定生物学功能。迄今为止，关于 GnRH-II 在人类中的表达和可能功能的报告仍然很少。在中枢神经系统和外周结构中，如生殖道组织（正常和肿瘤组织）中，已鉴定出十肽以及“推定的”II 型 GnRH 受体。目前正在研究 GnRH-II 在人体中的特定生物学功能。迄今为止，关于 GnRH-II 在人类中的表达和可能功能的报告仍然很少。在中枢神经系统和外周结构中，如生殖道组织（正常和肿瘤组织）中，已鉴定出十肽以及“推定的”II 型 GnRH 受体。目前正在研究 GnRH-II 在人体中的特定生物学功能。