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首页> 外文期刊>Molecular and Cellular Endocrinology >Growth hormone (GH) receptors in prostate cancer: gene expression in human tissues and cell lines and characterization, GH signaling and androgen receptor regulation in LNCaP cells.
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Growth hormone (GH) receptors in prostate cancer: gene expression in human tissues and cell lines and characterization, GH signaling and androgen receptor regulation in LNCaP cells.

机译：前列腺癌中的生长激素（GH）受体：人类组织和细胞系中的基因表达以及LNCaP细胞中的特征，GH信号传导和雄激素受体调节。

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摘要

Various hormones and growth factors have been implicated in progression of prostate cancer, but their role and the underlying molecular mechanism(s) involved remain poorly understood. In this study, we investigated the role of human growth hormone (GH) and its receptor (GHR) in human prostate cancer. We first demonstrated mRNA expression of GHR and of its exon 9-truncated isoform (GHR(tr)) in benign prostate hyperplasia (BPH) and prostate adenocarcinoma patient tissues, as well as in LNCaP, PC3 and DU145 human prostate cancer cell lines. GHR mRNA levels were 80% higher and GHR(tr) only 25% higher, in the carcinoma tissues than in BPH. Both isoforms were also expressed in LNCaP and PC3 cell lines and somewhat less so in DU145 cells. The LNCaP cell GHR protein was further characterized, on the basis of its M(r) of 120kDa, its binding to two different GHR monoclonal antibodies, its high affinity and purely somatogenic binding to (125)I-hGH and its ability to secrete GH binding protein, all characteristic of a functional GHR. Furthermore, GH induced rapid, time- and dose-dependent signaling events in LNCaP cells, including phosphorylation of JAK2 tyrosine kinase, of GHR itself and of STAT5A (JAK2-STAT5A pathway), of p42/p44 MAPK and of Akt/PKB. No effect of GH (72h) could be shown on basal or androgen-induced LNCaP cell proliferation nor on PSA secretion. Interestingly, however, GH caused a rapid (2-12h) though transient striking increase in immunoreactive androgen receptor (AR) levels (< or =5-fold), followed by a slower (24-48h) reduction (< or = 80%), with only modest parallel changes in serine-phosphorylated AR. In conclusion, the GH-induced activation of signaling pathways, its effects on AR protein in LNCaP cells and the isoform-specific regulation of GHR in prostate cancer patient tissues, suggest that GH, most likely in concert with other hormones and growth factors, may play an important role in progression of human prostate cancer.
机译：各种激素和生长因子已被认为与前列腺癌的进展有关，但是它们的作用和涉及的潜在分子机制仍然知之甚少。在这项研究中，我们调查了人类生长激素（GH）及其受体（GHR）在人类前列腺癌中的作用。我们首先在良性前列腺增生（BPH）和前列腺腺癌患者组织以及LNCaP，PC3和DU145人前列腺癌细胞系中证明了GHR及其外显子9截短同工型（GHR（tr））的mRNA表达。在癌组织中，GHR mRNA水平比BPH高80％，而GHR（tr）仅高25％。两种同工型也都在LNCaP和PC3细胞系中表达，而在DU145细胞中则略少表达。根据LNCaP细胞GHR蛋白的120kDa M（r），与两种不同GHR单克隆抗体的结合，与（125）I-hGH的高亲和力和纯生体结合及其分泌GH的能力，进一步表征LNCaP细胞GHR蛋白结合蛋白，是功能性GHR的所有特征。此外，GH诱导LNCaP细胞发生快速，时间和剂量依赖性的信号转导事件，包括JAK2酪氨酸激酶，GHR自身和STAT5A（JAK2-STAT5A途径），p42 / p44 MAPK和Akt / PKB的磷酸化。 GH（72h）对基础或雄激素诱导的LNCaP细胞增殖或PSA分泌均无影响。有趣的是，尽管免疫反应性雄激素受体（AR）水平短暂升高（<或= 5倍），但GH引起的快速（2-12h）升高，随后降低（24-48h）（<或= 80％ ），丝氨酸磷酸化AR的变化很小。总之，GH诱导的信号通路激活，其对LNCaP细胞中AR蛋白的作用以及前列腺癌患者组织中GHR的同工型特异性调节，表明GH最有可能与其他激素和生长因子协同作用在人类前列腺癌的进展中起重要作用。

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