title: Targeting growth hormone receptor in human melanoma cells attenuates tumor progression and epithelial mesenchymal transition via suppression of multiple oncogenic pathways.
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.
authors.affiliation: Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA.|Molecular and Cell Biology Program, Ohio University, Athens, Ohio, USA.
authors.forename: Reetobrata
authors.initials: R
authors.lastname: Basu
authors.affiliation: Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA.|Molecular and Cell Biology Program, Ohio University, Athens, Ohio, USA.
authors.forename: Shiyong
authors.initials: S
authors.lastname: Wu
authors.affiliation: Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA.|Molecular and Cell Biology Program, Ohio University, Athens, Ohio, USA.|Ohio University Heritage College of Osteopathic Medicine, Athens, Ohio, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Kopchick
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011986:Receptors, Somatotropin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D011986:Receptors, Somatotropin; D019382:Human Growth Hormone
keywords: IGF-1; cancer; growth hormone (GH); growth hormone receptor (GHR); melanoma