Abstract
Purpose :
The tumor microenvironment (TME) is crucial in controlling and influencing the behavior of UM. HIF-1α is one factor that regulates the TME in the presence of hypoxia. HIF-1α is the upstream regulator of Yes-associated protein (YAP) which is a major effector of the Hippo-signaling pathway and plays an important role in tumorigenesis. Knockdown of YAP inhibits melanoma cells invasiveness. HIF-1α also upregulates the expression of PAX3 (Paired-box homeotic gene transcription factor), which is a transcription factor and well-established in advanced metastatic melanomas. Its knockdown in melanoma cells leads to cell growth inhibition and apoptosis. We aim to detect the expression of HIF-1α, YAP, and PAX3 at mRNA and protein levels, as well as its association with the expression of BAP1 in UM tissues and clinicopathological parameters.
Methods :
Expression levels of HIF-1α, YAP, PAX3, and BAP1 proteins were assessed in 34 prospective cases of uveal melanoma by immunohistochemistry which was validated by western blot. mRNA expression of HIF-1α, YAP, and PAX3 was measured by quantitative real-time PCR. The protein and mRNA expression were correlated with clinicopathological parameters.
Results :
In 20% of cases, there was evidence of HIF-1α immunoexpression. Nuclear YAP (nYAP) and nuclear PAX3 (nPAX3) immunoexpression were detected in 17.6% and 23.5% of cases, respectively, and demonstrated a statistically significant association with HIF-1α immunoexpression and distant metastasis. HIF-1α mRNA expression was present in 25% of cases. YAP and PAX3 gene upregulation occurred in 26.5% and 44.1% of cases, respectively, showing statistical significance with high pigmentation, distant metastasis, and HIF-1α immunoexpression. PAX3 mRNA expression also exhibited a significant correlation with the loss of nBAP1 (p=0.02). Furthermore, UM patients displaying high HIF-1α immunoexpression experienced reduced metastasis-free survival which was statistically significant.
Conclusions :
We conclude that HIF-1α has a crucial role in the upregulation of YAP and PAX3 expression, suggesting their prognostic significance in the development of uveal melanoma. This association may contribute to an elevated risk of metastasis. Nevertheless, additional translational research on a larger cohort is essential to enhance our understanding and pave the way for improved therapeutic interventions in patients with uveal melanoma.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.