Journal of Advanced Research

Journal of Advanced Research

Volume 40, September 2022, Pages 153-166
Journal of Advanced Research

Original Article
Prognostic value of JAK3 promoter methylation and mRNA expression in clear cell renal cell carcinoma

https://doi.org/10.1016/j.jare.2021.11.016Get rights and content
Under a Creative Commons license
open access

Research highlight

  • JAK3 promoter methylation was correlated with JAK3 expression in ccRCC.

  • JAK3 promoter methylation was associated with clinicopathological characteristics in ccRCC.

  • JAK3 promoter methylation was associated with overall survival in ccRCC.

  • JAK3 promoter methylation was correlated with immune cell infiltration in ccRCC.

  • JAK3 promoter methylation was correlated with the expression of immune checkpoint molecules in ccRCC.

  • JAK3 promoter methylation was a potential biomarker for predicting responses to immune checkpoint inhibitors in ccRCC.

Abstract

Introduction

Janus kinase 3 (JAK3) is a well-established oncogene in clear cell renal cell carcinoma (ccRCC). The methylation status of oncogene promoters has emerged as biomarkers for cancer diagnosis and prognosis.

Objective

This study aims to investigate the biological and clinical significance of JAK3 promoter methylation in ccRCC.

Methods

We analyzed the relationship of JAK3 promoter methylation with its mRNA expression, overall survival, and immune cell infiltration in a cohort obtained from The Cancer Genome Atlas (TCGA), which was further validated by another independent cohort. We further validated correlations of JAK3 promoter methylation with JAK3 expression, overall survival, and immune cell infiltration in an independent ccRCC cohort (Sun Yat-sen University Cancer Center (SYSUCC) cohort) by methods of immunohistochemistry (IHC) and pyrosequencing.

Results

We found JAK3 promoter was significantly hypomethylated in tumor tissues compared to normal adjacent tissues in ccRCC, and JAK3 promoter hypomethylation was strongly correlated with high JAK3 mRNA expression in all three ccRCC cohorts we examined. JAK3 promoter hypomethylation predicted advanced clinicopathological characteristics and shorter overall survival (TCGA cohort and SYSUCC cohort). Furthermore, we found that JAK3 promoter methylation was significantly associated with immune cell infiltration and expression of immune checkpoint molecules (TCGA cohort and CPTAC cohort). Finally, our SYSUCC cohort validated that JAK3 promoter methylation was correlated with CD4+ and CD8+ T cell infiltration in ccRCC tumor tissues.

Conclusion

Our data demonstrated that the crucial role of JAK3 promoter methylation in its expression regulation and tumor microenvironment. JAK3 promoter methylation and expression are associated with clinicopathological characteristics, overall survival, and immune cell infiltration in ccRCC. We propose a rationale for further validation of JAK3 promoter methylation as a molecular biomarker for predicting responses to immune checkpoint inhibitors in ccRCC.

Keywords

Janus kinase 3
Renal cell carcinoma
Epigenetic biomarker
Tumor immune microenvironment
Tumor immune cell infiltration

Abbreviations

JAK3
Janus kinase 3
ccRCC
clear cell renal cell carcinoma
TCGA
The Cancer Genome Atlas
SYSUCC
Sun Yat-sen University Cancer Center
RCC
Renal cell carcinoma
CPTAC
The National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium
JAK-STAT
Janus kinase-signal transducer and activator of transcription
TPM
transcripts per million
GEO
Gene Expression Omnibus
IHC
immunohistochemistry
ssGSEA
single-sample gene-set enrichment analysis
EMT
epithelial mesenchymal transition
Pan-FTBRS
pan-fibroblast TGFβ response signature

Cited by (0)

Peer review under responsibility of Cairo University.

1

These authors contributed equally to this article.