Targeting growth hormone receptor in human melanoma cells attenuates tumor progression and epithelial mesenchymal transition via suppression of multiple oncogenic pathways.
Targeting growth hormone receptor in human melanoma cells attenuates tumor progression and epithelial mesenchymal transition via suppression of multiple oncogenic pathways.
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DOI：
10.18632/oncotarget.15375
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发表时间：
2017-03-28
期刊：
影响因子：
--
通讯作者：
Kopchick JJ
中科院分区：
文献类型：
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作者：
Basu R;Wu S;Kopchick JJ
最近的报道证实，黑色素瘤中生长激素(GH)受体(GHR)转录水平最高，黑色素瘤是人类最具侵袭性的癌症之一。然而，生长激素在黑色素瘤中的作用机制大多仍不清楚。在这里，我们利用人恶性黑色素瘤细胞，研究了GH过量或siRNA介导的GHR基因敲除(GHRKD)对肿瘤增殖、迁移和侵袭的影响。GH促进黑色素瘤进展，而GHRKD抑制黑色素瘤进展。Western印迹分析显示，加入GH或GHRKD后，多种致癌信号通路(JAK2、STAT1、STAT3、STAT5、AKT、mTOR、SRC和ERK1/2)发生了剧烈的变化。此外，我们还发现，在人类黑色素瘤中，GH过量上调了上皮间充质转化标志物的表达，而GHRKD则逆转了这种作用。有趣的是，我们观察到在黑色素瘤细胞中GH转录本的持续表达，以及IGF受体和结合蛋白(IGF1R、IGF2R、IR、IGFBP2、IGFBP3)和致癌HGF-MET mRNA的显著调节，以响应过量的GH或GHRKD。因此，我们的研究确定了GH-GHR在人类黑色素瘤中作用的机制模型，并验证了它是干预的重要药理靶点。
Recent reports have confirmed highest levels of growth hormone (GH) receptor (GHR) transcripts in melanoma, one of the most aggressive forms of human cancer. Yet the mechanism of GH action in melanoma remains mostly unknown. Here, using human malignant melanoma cells, we examined the effects of GH excess or siRNA mediated GHR knock-down (GHRKD) on tumor proliferation, migration and invasion. GH promoted melanoma progression while GHRKD attenuated the same. Western blot analysis revealed drastic modulation of multiple oncogenic signaling pathways (JAK2, STAT1, STAT3, STAT5, AKT, mTOR, SRC and ERK1/2) following addition of GH or GHRKD. Further, we show that GH excess upregulates expression of markers of epithelial mesenchymal transition in human melanoma, while the effects were reversed by GHRKD. Interestingly, we observed consistent expression of GH transcript in the melanoma cells as well as marked modulation of the IGF receptors and binding proteins (IGF1R, IGF2R, IR, IGFBP2, IGFBP3) and the oncogenic HGF-MET mRNA, in response to excess GH or GHRKD. Our study thus identifies the mechanistic model of GH-GHR action in human melanoma and validates it as an important pharmacological target of intervention.