Programmed Cell Death-Related Gene Signature Associated with Prognosis and Immune Infiltration and the Roles of HMOX1 in the Proliferation and Apoptosis were Investigated in Uveal Melanoma.

Abstract

Background: Uveal melanoma (UVM) is the most common primary ocular malignancy, with a wide range of symptoms and outcomes. The programmed cell death (PCD) plays an important role in tumor development, diagnosis, and prognosis. There is still no research on the relationship between PCD-related genes and UVM. A novel PCD-associated prognostic model is urgently needed to improve treatment strategies.

Objective: We aim to screen PCD-related prognostic signature and investigate its proliferation ability and apoptosis in UVM cells.

Methods: The clinical information and RNA-seq data of the UVM patients were collected from the TCGA cohort. All the patients were classified using consensus clustering by the selected PCD-related genes. After univariate Cox regression and PPI network analysis, the prognostic PCD-related genes were then submitted to the LASSO regression analysis to build a prognostic model. The level of immune infiltration of 8-PCD signature in high- and low-risk patients was analyzed using xCell. The prediction on chemotherapy and immunotherapy response in UVM patients was assessed by GDSC and TIDE algorithm. CCK-8, western blot and Annexin V-FITC/PI staining were used to explore the roles of HMOX1 in UVM cells.

Results: A total of 8-PCD signature was constructed and the risk score of the PCD signature was negatively correlated with the overall survival, indicating strong predictive ability and independent prognostic value. The risk score was positively correlated with CD8 Tcm, CD8 Tem and Th2 cells. Immune cells in high-risk group had poorer overall survival. The drug sensitivity demonstrated that cisplatin might impact the progression of UVM and better immunotherapy responsiveness in the high-risk group. Finally, Overespression HMOX1 (OE-HMOX1) decreased the cell viability and induced apoptosis in UVM cells. Recuse experiment results showed that ferrostatin-1 (fer-1) protected MP65 cells from apoptosis and necrosis caused by OE-HMOX1.

Conclusion: The PCD signature may have a significant role in the tumor microenvironment, clinicopathological characteristics, prognosis and drug sensitivity. More importantly, HMOX1 depletion greatly induced tumor cell growth and inhibited cell apoptosis and fer-1 protected UVM cells from apoptosis and necrosis induced by OE-HMOX1. This work provides a foundation for effective therapeutic strategy in tumour treatment.