Heme oxygenase-1 promotes uveal melanoma growth and migration both in vitro and in vivo

Abstract

Purpose : Uveal melanoma is the most common primary intraocular tumor in adults, with about 1200-1500 new cases occurring per year in the U.S. Metastasis is a frequent occurrence in uveal melanoma, and outcomes are poor once distant spread occurs. Heme Oxygenase (HO) catalyzes the enzymatic degradation of heme with the simultaneous release of carbon monoxide (CO), ferrous iron (Fe²⁺), and biliverdin. In some cancer cells, HO-1 is considered to play a major role as an essential survival factor that protects against chemotherapy-induced increases in reactive oxygen species (ROS). The aim of the present study was to evaluate the biological significance of the HO system in uveal melanoma with particular regard to cell (92.1 cell line) proliferation and migration and to confirm such findings into a clinical setting.

Methods : Cell proliferation and colony formation capacity was evaluated by cytofluorimetric assay, Xcelligence technology, clonogenic and wound healing assay. Such analyses were also performed in separate set of experiments following Hemin (5 and 10 μM) treatment, a well-established pharmacological inducer of HO-1 and CO.

Results : Our results showed that hemin significantly increased HO-1 gene and protein expression. Interestingly, such upregulation resulted in a significant increase in cell proliferation, wound healing and colony unit formation. These results were further confirmed by CO releasing molecules (CORM-3 and CORMA1), which showed the same effects of the pharmacological induction of HO-1. Finally, immunohistochemical analysis showed that HO-1 was significantly upregulated in biopsies from patients with uveal melanoma with increased proliferative phenotype.

Conclusions : Our results suggest that HO-1 plays a major role in uveal melanoma growth and may represent a good candidate to be exploited as a target for new chemotherapic agents.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.