Unraveling the Relevance of ARL GTPases in Cutaneous Melanoma Prognosis through Integrated Bioinformatics Analysis.

Cheila Brito,Bruno Costa-Silva,Duarte C Barral,Marta Pojo

doi:10.3390/ijms22179260

Abstract

Cutaneous melanoma (CM) is the deadliest skin cancer, whose molecular pathways underlying its malignancy remain unclear. Therefore, new information to guide evidence-based clinical decisions is required. Adenosine diphosphate (ADP)-ribosylation factor-like (ARL) proteins are membrane trafficking regulators whose biological relevance in CM is undetermined. Here, we investigated ARL expression and its impact on CM prognosis and immune microenvironment through integrated bioinformatics analysis. Our study found that all 22 ARLs are differentially expressed in CM. Specifically, ARL1 and ARL11 are upregulated and ARL15 is downregulated regardless of mutational frequency or copy number variations. According to TCGA data, ARL1 and ARL15 represent independent prognostic factors in CM as well as ARL11 based on GEPIA and OncoLnc. To investigate the mechanisms by which ARL1 and ARL11 increase patient survival while ARL15 reduces it, we evaluated their correlation with the immune microenvironment. CD4+ T cells and neutrophil infiltrates are significantly increased by ARL1 expression. Furthermore, ARL11 expression was correlated with 17 out of 21 immune infiltrates, including CD8+ T cells and M2 macrophages, described as having anti-tumoral activity. Likewise, ARL11 is interconnected with ZAP70, ADAM17, and P2RX7, which are implicated in immune cell activation. Collectively, this study provides the first evidence that ARL1, ARL11, and ARL15 may influence CM progression, prognosis, and immune microenvironment remodeling.

Highlights

Cutaneous melanoma (CM) is the most invasive type of skin cancer, accounting for 60% to 75% of the mortality rate related to skin neoplasms [1,2]
Considering the lack of data on ADP-ribosylation factor-like (ARL) function in CM, we evaluated their transcriptional levels in primary and metastatic CM samples using the Cancer Genome Atlas (TCGA) and Genotype tissue expression (GTEx) data, obtained from the University of California, Santa Cruz (UCSC) Xena project and processed using a uniform bioinformatic pipeline
Since CM is a highly immunogenic type of tumor, after discovering that ARL1, ARL11, and ARL15 expression may have a significant impact on CM patients’ prognosis, we investigated whether the immune microenvironment could be involved in the mechanisms associated with ARL prognostic value

Summary

Introduction

Cutaneous melanoma (CM) is the most invasive type of skin cancer, accounting for 60% to 75% of the mortality rate related to skin neoplasms [1,2]. CM often shows the ability to metastasize even when primary lesions are thinner than 1 mm, presenting high aggressiveness and poor prognosis [3,4]. According to the melanoma research alliance statistics, stage IV CM is characterized by a 5-year survival rate of only 22.5% and there is evidence showing that patients with three or more sites of metastatic disease die within 1 year [5,6]. Efforts have been made toward the early diagnosis of CM, as early-stage CM presents a 5-year survival rate of around 90% [7]. The metastatic ability and mechanisms of resistance to therapy render the treatment of this disease challenging

Methods

Results

Discussion

Conclusion