人类转移性黑色素瘤细胞系表达高水平的生长激素受体,并对 GH 治疗有反应。
Human metastatic melanoma cell lines express high levels of growth hormone receptor and respond to GH treatment.
机构信息
Edison Biotechnology Institute, 1 Watertower Drive, Athens, OH, United States; Department of Biological Sciences, Ohio University, Athens, OH, United States.
出版信息
Biochem Biophys Res Commun. 2013 Nov 8;441(1):144-50. doi: 10.1016/j.bbrc.2013.10.023. Epub 2013 Oct 14.
Accumulating evidence implicates the growth hormone receptor (GHR) in carcinogenesis. While multiple studies show evidence for expression of growth hormone (GH) and GHR mRNA in human cancer tissue, there is a lack of quantification and only a few cancer types have been investigated. The National Cancer Institute's NCI60 panel includes 60 cancer cell lines from nine types of human cancer: breast, CNS, colon, leukemia, melanoma, non-small cell lung, ovarian, prostate and renal. We utilized this panel to quantify expression of GHR, GH, prolactin receptor (PRLR) and prolactin (PRL) mRNA with real-time RT qPCR. Both GHR and PRLR show a broad range of expression within and among most cancer types. Strikingly, GHR expression is nearly 50-fold higher in melanoma than in the panel as a whole. Analysis of human metastatic melanoma biopsies confirmed GHR gene expression in melanoma tissue. In these human biopsies, the level of GHR mRNA is elevated in advanced stage IV tumor samples compared to stage III. Due to the novel finding of high GHR in melanoma, we examined the effect of GH treatment on three NCI60 melanoma lines (MDA-MB-435, UACC-62 and SK-MEL-5). GH increased proliferation in two out of three cell lines tested. Further analysis revealed GH-induced activation of STAT5 and mTOR in a cell line dependent manner. In conclusion, we have identified cell lines and cancer types that are ideal to study the role of GH and PRL in cancer, yet have been largely overlooked. Furthermore, we found that human metastatic melanoma tumors express GHR and cell lines possess active GHRs that can modulate multiple signaling pathways and alter cell proliferation. Based on this data, GH could be a new therapeutic target in melanoma.
越来越多的证据表明生长激素受体(GHR)参与了致癌作用。虽然多项研究表明人类癌症组织中存在生长激素(GH)和 GHR mRNA 的表达,但缺乏定量分析,且仅对少数几种癌症类型进行了研究。美国国立卫生研究院(NIH)的 NCI60 细胞面板包括来自九种人类癌症类型的 60 种癌细胞系:乳腺癌、中枢神经系统癌、结肠癌、白血病、黑色素瘤、非小细胞肺癌、卵巢癌、前列腺癌和肾癌。我们利用该面板,通过实时 RT-qPCR 定量检测 GHR、GH、催乳素受体(PRLR)和催乳素(PRL)mRNA 的表达。GHR 和 PRLR 在大多数癌症类型中均表现出广泛的表达。令人惊讶的是,与整个面板相比,黑色素瘤中的 GHR 表达水平高出近 50 倍。对人类转移性黑色素瘤活检的分析证实了黑色素瘤组织中 GHR 基因的表达。在这些人类活检中,与 III 期相比,IV 期晚期肿瘤样本中 GHR mRNA 的水平升高。由于发现黑色素瘤中存在高 GHR,我们研究了 GH 对三种 NCI60 黑色素瘤细胞系(MDA-MB-435、UACC-62 和 SK-MEL-5)的治疗作用。GH 增加了三种细胞系中两种细胞系的增殖。进一步的分析表明,GH 以细胞系依赖性的方式诱导 STAT5 和 mTOR 的激活。总之,我们鉴定出了一些适合研究 GH 和 PRL 在癌症中作用的细胞系和癌症类型,但这些研究在很大程度上被忽视了。此外,我们发现人类转移性黑色素瘤肿瘤表达 GHR,并且细胞系具有活性的 GHR,可调节多种信号通路并改变细胞增殖。基于这些数据,GH 可能成为黑色素瘤的一个新的治疗靶点。