HSD17B4, ACAA1, and PXMP4 in Peroxisome Pathway Are Down-Regulated and Have Clinical Significance in Non-small Cell Lung Cancer.

Xiuzhi Zhang,Liping Dai,Hongmei Yang,Jinzhong Zhang,Fenglan Gao

doi:10.3389/fgene.2020.00273

Abstract

To explore the potential functions and clinical significances of peroxisomes during lung cancer development and progression, we investigated the expressional profiles of peroxisome pathway genes and their correlations with clinical features in non-small cell lung cancer (NSCLC). The RNA-seq data of NSCLC including lung squamous carcinoma (LUSC) and lung adenocarcinoma (LUAD) patients with their clinical information were downloaded from The Cancer Genome Atlas (TCGA). Gene expression comparisons between tumor and normal samples were performed with edgeR package in R software and the results of the 83 peroxisome pathway genes were extracted. Through Venn diagram analysis, 38 common differentially expressed peroxisome pathway genes (C-DEPGs) in NSCLC were identified. Principal components analysis (PCA) was performed and the 38 C-DEPGs could discriminate NSCLC tumors from the non-tumor controls well. Through Kaplan-Meier survival and Cox regression analyses, 11 of the C-DEPGs were shown to have prognostic effects on NSCLC overall survival (OS) and were considered as key C-DEPGs (K-DEPGs). Through Oncomine, Human Protein Atlas (HPA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), three K-DEPGs (HSD17B4, ACAA1, and PXMP4) were confirmed to be down-regulated in NSCLC at both mRNA and protein level. Their dy-regulation mechanisms were revealed through their correlations with their copy number variations and methylation status. Their potential functions in NSCLC were explored through their NSCLC-specific co-expression network analysis, their correlations with immune infiltrations, immunomodulator gene expressions, MKI67 expression and their associations with anti-cancer drug sensitivity. Our findings suggested that HSD17B4, ACAA1, and PXMP4 might be new markers for NSCLC diagnosis and prognosis and might provide new clues for NSCLC treatment.

Highlights

Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death worldwide, with about 2.1 million new lung cancer cases and 1.8 million lung cancer deaths every year (Bray et al, 2018)
With the deepening understanding of the important functions of the peroxisomes, more and more attention were paid to the peroxisomes research (Tanner et al, 2013; El Hassouni et al, 2019) and they were demonstrated to be implicated in innate immunity (Ferreira et al, 2019), signal transduction (Schrul and Schliebs, 2018), aging (Deori et al, 2018), and cancer (Dahabieh et al, 2018)
Was shown to have prognostic effects on lung squamous carcinoma (LUSC) overall survival (OS) while 10 other genes (Figures 2B–K) were indicated to have significant prognostic effects on lung adenocarcinoma (LUAD) OS while no significance was shown for the other common differentially expressed peroxisome pathway genes (C-differentially expressed peroxisome pathway genes (DEPGs)) (Supplementary Figures S1, S2)

Summary

Introduction

Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death worldwide, with about 2.1 million new lung cancer cases and 1.8 million lung cancer deaths every year (Bray et al, 2018). For the NSCLC patients at an early stage (stage I–II), surgery is the recommended treatment and the 5-year survival is about 53–92% (Vansteenkiste et al, 2014; Goldstraw et al, 2016). Peroxisomes are ubiquitous cellular organelles which can be found in most eukaryotic cells. They were first described by Johannes Rhodin in 1954 and termed as “microbodies.” As there were a lot of hydrogen peroxide metabolizing enzymes in the microbodies, they were called “peroxisomes” functionally (De Duve and Baudhuin, 1966). With the deepening understanding of the important functions of the peroxisomes, more and more attention were paid to the peroxisomes research (Tanner et al, 2013; El Hassouni et al, 2019) and they were demonstrated to be implicated in innate immunity (Ferreira et al, 2019), signal transduction (Schrul and Schliebs, 2018), aging (Deori et al, 2018), and cancer (Dahabieh et al, 2018)

Methods

Results

Conclusion