Advisory Committee Chair
Stuart J Frank
Advisory Committee Members
Mohammad Athar
Doug Hurst
Andrew Paterson
Lalita Shevde-Samant
Document Type
Dissertation
Date of Award
2018
Degree Name by School
Doctor of Philosophy (PhD) College of Arts and Sciences
Abstract
Melanoma is less common than basal and squamous cell skin cancers, but is the most aggressive form of skin cancer. ~90% of melanomas carry a mutation in the RAS-RAF pathway, which promotes progression by constitutive activation of the extracellular sig-nal-regulated kinase (ERK) signaling cascade. BRAF inhibition is an effective line of therapy for advance melanoma, but patients often progress due to the development of several forms of treatment resistance. Therapeutic resistance often results in increased invasion and migration of the cancer into proximal and distant tissues leading to the formation of metastasis. Examination of various cancer genomics data sets using cBi-oPortal and the NCI60 database revealed that melanoma isolates are enriched, compared to other cancers, for expression of growth hormone receptor (GHR) mRNA. Our survey of eight human melanoma cell lines (a few – WM35 and SK-MEL 119 – not included in either database; SK-MEL5 and SK-MEL 28) confirmed these findings, in that GHR was detected by immunoblotting in four of the eight. In each, growth hormone (GH) induced dose-and time-dependent GHR, JAK2 and STAT5 phosphorylation. Not surprisingly, ERK was constitutively activated in each, as revealed by anti-pERK immunoblotting and GH caused little change in ERK phosphorylation status. GH excess also causes en-hanced melanoma cell invasion and migration, which can be inhibited by a GHR-specific GH antagonist. Furthermore, we are able to confirm the presence of immunore-active GH in melanoma conditioned media by ELISA and with a bioreactive reporter cell line 32D-GHR. Lastly, independent of exogenously added GH we are able to inhibit basal melanoma invasion and migration. We conclude that GH promotes melanoma progression while a GHR-specific GH antagonist attenuates the same. These studies suggest that the GH axis can be therapeutically targeted in concert with other growth mediating pathways in melanoma.
Recommended Citation
Buckels, Ashiya, "The Effects Of Growth Hormone In Human Melanoma Cell Lines" (2018). All ETDs from UAB. 1280.
https://digitalcommons.library.uab.edu/etd-collection/1280