Pan-cancer characterization of PAFAH1B3 expression and its role in esophageal cancer

Abstract

Globally, esophageal cancer is one of the main reasons of deaths from cancer. The initiation and progression of this malignancy is the result of complex interactions between alterations in genes, epigenetic processes and components of the tumor microenvironment. Esophageal squamous cell carcinoma (ESCC) is the most frequent histological type of esophageal carcinoma in human being, which is associated with high incidence, poor prognosis and few therapeutic options. Recent investigations suggest that an enzyme that is related to lipid metabolism, namely, Platelet activating factor acetylhydrolase 1B subunit 3 (PAFAH1B3) plays a crucial role in the development of tumours among various types of cancer. Nevertheless, the exact role played by this factor in ESCC so far has not been clarified in detail. The aim of this investigation was on providing a comprehensive characterization of PAFAH1B3 expression patterns in several cancers along with its associations with survival outcomes of patients and the immune components of tumor microenvironments. Such efforts aimed to improve the understanding of the functional contributions and probable pathways of the action of this enzyme in esophageal carcinoma (ESC) particularly ESCC. Moreover, the research has focused on its value as a candidate for predicting or as the focus for interventions. Bioinformatic analyses were performed by several public databases (e.g., The Cancer Genome Atlas [TCGA] and cBioPortal). These analyses focused on the study of the expression of PAFAH1B3, copy number alterations (CNV), DNA methylation status, immune cell infiltration, and clinical outcomes in several different cancer types. Additionally, clinical ESCC tissues and in vitro assays were used to investigate the role of PAFAH1B3 in ESCC cell behavior and its potential involvement in FGFR1–PI3K/AKT signaling, and reciprocal Co-IP assays were performed to confirm the endogenous interaction between PAFAH1B3 and FGFR1. Pan-cancer analyses showed that PAFAH1B3 was overexpressed in various types of tumors, and was expressed in close correlation with copy number amplification and DNA methylation changes. Elevated expression of PAFAH1B3 was significantly associated with unfavorable clinical outcomes in a number of cancers. In ESCC, PAFAH1B3 expression correlated with clinicopathological features such as the higher expression of PAFAH1B3 was noted in advanced-stage tumors. Functional and pathway related studies showed that silencing of PAFAH1B3 significantly inhibited ESCC cell proliferation, migration and invasion. Reciprocal Co-IP assays demonstrated an endogenous interaction between PAFAH1B3 and FGFR1 in ESCC cells.Additionally, Immune landscape analysis showed a negative correlation between the expression of PAFAH1B3 and immune cell infiltration, as well as immune-related scores. Overexpression of PAFAH1B3 in ESCC may promote tumor progression through its association with FGFR1-PI3K/AKT signaling.It is also strongly associated with alterations of the tumor immune milieu. These findings suggest that PAFAH1B3 may serve as a potential biomarker and therapeutic target for ESCC, although further mechanistic and clinical validation is required.