Targeting growth hormone receptor in human melanoma cells attenuates tumor progression and epithelial mesenchymal transition via suppression of multiple oncogenic pathways.

Reetobrata Basu,Shiyong Wu,John J Kopchick

doi:10.18632/oncotarget.15375

Abstract

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.

Highlights

In the current year, melanoma is considered the most aggressive and treatment-resistant form of human skin cancer with an annual incidence of 76,380 in 2016 [1] and a total of approximately 1,000,000 patients in the USA
Our RT-qPCR analysis of RNA confirmed high levels of growth hormone receptor (GHR) RNA in all four melanoma cells which were reduced by almost 90% following GHR knock-down (GHRKD) (Supplementary Figure 1a)
As well as previous reports of abundant expression of GHR and readily detectable RNA levels of GH in all four melanoma cells [13,14,15,16,17,18,19], in addition to our observation of distinct growth hormone regulation of JAK2, SRC, STAT5, STAT3, AKT, mTOR and ERK1/2 pathways [56,57,58,59,60] – all converge upon initiation and progression of epithelial mesenchymal transition (EMT) in several forms of cancer

Summary

Introduction

Melanoma is considered the most aggressive and treatment-resistant form of human skin cancer with an annual incidence of 76,380 in 2016 [1] and a total of approximately 1,000,000 patients in the USA. GH action is mediated by binding to a pre-dimerized cognate receptor [GH receptor (GHR)], and may involve direct or indirect activation of well-known intracellular signaling pathways downstream of JAK2 as well as the SRC family kinases [23,24,25,26,27,28,29,30,31,32,33,34].

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Results

Conclusion