Ferroptosis-related gene SLC1A5 is a novel prognostic biomarker and correlates with immune infiltrates in stomach adenocarcinoma

Dandan Zhu; Sifan Wu; Yafang Li; Yu Zhang; Jierong Chen; Jianhong Ma; Lixue Cao; Zejian Lyu; Tieying Hou

doi:10.1186/s12935-022-02544-8

Ferroptosis-related gene SLC1A5 is a novel prognostic biomarker and correlates with immune infiltrates in stomach adenocarcinoma

Cancer Cell Int. 2022 Mar 19;22(1):124. doi: 10.1186/s12935-022-02544-8.

Authors

Dandan Zhu^#^{1

2}, Sifan Wu^#^{1

3}, Yafang Li^#^{2

3}, Yu Zhang⁴, Jierong Chen³, Jianhong Ma³, Lixue Cao^#⁵, Zejian Lyu^#⁶, Tieying Hou^#^{7

8

9

10}

Affiliations

¹ School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China.
² Guangdong Clinical Laboratory Center, Guangdong Provincial People's Hospital; Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China.
³ Department of Laboratory Medicine, Guangdong Provincial People's Hospital; Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China.
⁴ Medical Department, Guangdong Provincial People's Hospital; Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China.
⁵ Research Center of Medical Sciences, Guangdong Provincial People's Hospital; Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China. caolx5@mail3.sysu.edu.cn.
⁶ Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital; Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China. lvzejian@gdph.org.cn.
⁷ School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China. houtieying@gdph.org.cn.
⁸ Guangdong Clinical Laboratory Center, Guangdong Provincial People's Hospital; Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China. houtieying@gdph.org.cn.
⁹ The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China. houtieying@gdph.org.cn.
¹⁰ Medical Department, Guangdong Provincial People's Hospital; Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China. houtieying@gdph.org.cn.

^# Contributed equally.

Abstract

Background: Stomach adenocarcinoma (STAD) is associated with high morbidity and mortality rates. Ferroptosis is an iron-dependent form of cell death, which plays an important role in the development of many cancers. Tumor-associated competing endogenous RNAs (ceRNAs) regulate tumorigenesis and development. Our study aimed to construct ceRNA networks and explore the relationship between ferroptosis-related genes in the ceRNA network and immune infiltration in STAD.

Methods: Based on the interactions among long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs), a ceRNA network was constructed to illustrate the relationships among lncRNAs, miRNAs, and mRNAs. Subsequently, gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) functional enrichment analyses were carried out to explore the functions and interactions of the differentially expressed (DE) mRNAs related to the ceRNA network. Differential expression and prognostic analysis of ferroptosis-related genes in the ceRNA network were performed using the R package "limma" and "survminer." The correlation between ferroptosis-related genes and tumor-infiltrating immune cells was analyzed using Spearman correlation analysis and CIBERSORT. Quantitative real-time PCR (qRT-PCR) was used to validate the expression of ferroptosis-related genes in STAD cells lines.

Results: A ceRNA network consisting of 29 DElncRNAs, 31 DEmiRNAs, and 182 DEmRNAs was constructed. These DEmRNAs were significantly enriched in pathways related to the occurrence and development of STAD. The ferroptosis-related gene SLC1A5 was upregulated in STAD (P < 0.001) and was associated with better prognosis (P = 0.049). The CIBERSORT database and Spearman correlation analysis indicated that SLC1A5 was correlated with eight types of tumor-infiltrating immune cells and immune checkpoints, including PD-L1(CD-274) and PD-1(PDCD1). The SLC1A5 mRNA was found to be highly expressed in STAD cells lines.

Conclusions: Our study provides insights into the function of ceRNAs in STAD and identifies biomarkers for the development of therapies for STAD. The ferroptosis-related gene SLC1A5 in the ceRNA network was associated with both tumor-infiltrating immune cells and immune checkpoints in the tumor microenvironment, suggesting that SLC1A5 may be a novel prognostic marker and a potential target for STAD immunotherapy in the future.

Keywords: Biomarker; CeRNA; Ferroptosis; Immune checkpoints; Stomach adenocarcinoma; Tumor-infiltrating immune cells.