PRRX1 Is a Novel Prognostic Biomarker and Facilitates Tumor Progression Through Epithelial-Mesenchymal Transition in Uveal Melanoma.

Zhishang Meng,Bin Yan,Lusi Zhang,Youling Liang,Yongan Meng,Yanzhu Chen,Jing Luo,Wenyi Wu,Xiaoxi Yao,Huihui Chen

doi:10.3389/fimmu.2022.754645

Abstract

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. UM develops and is sustained by inflammation and immunosuppression from the tumor microenvironment (TME). This study sought to identify a reliable TME-related biomarker that could provide survival prediction and new insight into therapy for UM patients. Based on clinical characteristics and the RNA-seq transcriptome data of 80 samples from The Cancer Genome Atlas (TCGA) database, PRRX1 as a TME- and prognosis-related gene was identified using the ESTIMATE algorithm and the LASSO–Cox regression model. A prognostic model based on PRRX1 was constructed and validated with a Gene Expression Omnibus (GEO) dataset of 63 samples. High PRRX1 expression was associated with poorer overall survival (OS) and metastasis-free survival (MFS) in UM patients. Comprehensive results of the prognostic analysis showed that PRRX1 was an independent and reliable predictor of UM. Then the results of immunological characteristics demonstrated that higher expression of PRRX1 was accompanied by higher expression of immune checkpoint genes, lower tumor mutation burden (TMB), and greater tumor cell infiltration into the TME. Gene set enrichment analysis (GSEA) showed that high PRRX1 expression correlated with angiogenesis, epithelial–mesenchymal transition (EMT), and inflammation. Furthermore, downregulation of PRRX1 weakened the process of EMT, reduced cell invasion and migration of human UM cell line MuM-2B in vitro. Taken together, these findings indicated that increased PRRX1 expression is independently a prognostic factor of poorer OS and MFS in patients with UM, and that PRRX1 promotes malignant progression of UM by facilitating EMT, suggesting that PRRX1 may be a potential target for UM therapy.

Highlights

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, with no effective treatments currently available for metastatic UM [1]
40 samples each were classified into the high and low score groups based on the median scores, and overall survival (OS) was compared in The Cancer Genome Atlas (TCGA)-uveal melanoma (UVM) cohort (n = 80)
The area under the ROC curve (AUC) of the time-dependent receiver operating characteristic (ROC) curves for 1, 2, and 3-year metastasis-free survival (MFS) were 0.677, 0.748, and 0.696, respectively (Figure 6E), and the AUC of PRRX1 expression for predicting MFS was 0.718 (Figure 6F), greater than that for all other factors. These results indicate that PRRX1 expression was an independent prognostic factor that could effectively predict the prognosis of UM patients

Summary

Introduction

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, with no effective treatments currently available for metastatic UM [1]. UM arises from the uveal tract of the eye, which contains the ciliary body, choroid, and iris. The clinical and biologic features of UM differ from cutaneous melanoma [2]. Up to 50% of UM are aggressive malignancies, giving rise to liver metastases, with liver metastasis being a frequent cause of morbidity and mortality in patients with UM. The average overall survival (OS) time of untreated patients has been reported to be approximately 2 months [7, 8], whereas the median OS time with aggressive treatment ranged from 6 to 12 months [8,9,10]

Methods

Results

Conclusion