Prognostic Significance and Tumor Immune Microenvironment Heterogenicity of m5C RNA Methylation Regulators in Triple-Negative Breast Cancer.

Zhidong Huang,Xianqiang Du,Junfan Pan,Zhitang Wang,Helin Wang,Yusheng Xu,Debo Chen

doi:10.3389/fcell.2021.657547

Zhidong Huang, Xianqiang Du + Show 5 more

Open Access

https://doi.org/10.3389/fcell.2021.657547

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Abstract

PurposeThe m5C RNA methylation regulators are closely related to tumor proliferation, occurrence, and metastasis. This study aimed to investigate the gene expression, clinicopathological characteristics, and prognostic value of m5C regulators in triple-negative breast cancer (TNBC) and their correlation with the tumor immune microenvironment (TIM).MethodsThe TNBC data, Luminal BC data and HER2 positive BC data set were obtained from The Cancer Genome Atlas and Gene Expression Omnibus, and 11 m5C RNA methylation regulators were analyzed. Univariate Cox regression and the least absolute shrinkage and selection operator regression models were used to develop a prognostic risk signature. The UALCAN and cBioportal databases were used to analyze the gene characteristics and gene alteration frequency of prognosis-related m5C RNA methylation regulators. Gene set enrichment analysis was used to analyze cellular pathways enriched by prognostic factors. The Tumor Immune Single Cell Hub (TISCH) and Timer online databases were used to explore the relationship between prognosis-related genes and the TIM.ResultsMost of the 11 m5C RNA methylation regulators were differentially expressed in TNBC and normal samples. The prognostic risk signature showed good reliability and an independent prognostic value. Prognosis-related gene mutations were mainly amplified. Concurrently, the NOP2/Sun domain family member 2 (NSUN2) upregulation was closely related to spliceosome, RNA degradation, cell cycle signaling pathways, and RNA polymerase. Meanwhile, NSUN6 downregulation was related to extracellular matrix receptor interaction, metabolism, and cell adhesion. Analysis of the TISCH and Timer databases showed that prognosis-related genes affected the TIM, and the subtypes of immune-infiltrating cells differed between NSUN2 and NSUN6.ConclusionRegulatory factors of m5C RNA methylation can predict the clinical prognostic risk of TNBC patients and affect tumor development and the TIM. Thus, they have the potential to be a novel prognostic marker of TNBC, providing clues for understanding the RNA epigenetic modification of TNBC.

Highlights

Despite advances in treatment, breast cancer remains a leading cause of cancer-related mortality among women worldwide, accounting for 6.6% of all deaths in 2018 (Bray et al, 2018)
To study the relationship between m5C RNA methylation regulators and BC, we analyzed the expression of m5C RNA methylation regulators in Triple-negative breast cancer (TNBC) samples, Luminal BC samples, and human epidermal growth factor receptor 2 (HER2) positive BC samples compared with normal tissue samples from the The Cancer Genome Atlas (TCGA) databases
RNA modifications have already been reported to be associated with disease pathogenesis and cancer tumorigenesis (Tang et al, 2019; Tian et al, 2020; Zhao et al, 2020), the potential relationships between TNBC and m5C are still unclear

Summary

Introduction

Breast cancer remains a leading cause of cancer-related mortality among women worldwide, accounting for 6.6% of all deaths in 2018 (Bray et al, 2018). Unlike the estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2) positive subtype, the biology of TNBC includes a high proliferation activity, a high degree of immune infiltration, basallike or mesenchymal phenotypes, and insufficient homologous recombination (Denkert et al, 2017); its characteristics, including the risk factors, molecular and pathological characteristics, disease course, and sensitivity to chemotherapy, are distinct from those of other breast cancer subtypes (Borri and Granaglia, 2020). Recent studies have presented RNA modification as an emerging mechanism in gene regulation. This reversible post-transcriptional modification is regulated by “writers” (methyltransferases), “readers,” and “erasers” (demethylase) and affects various molecular functions, such as RNA-protein interaction (Liu et al, 2015), RNA stability (Wang et al, 2014; Yang X. et al, 2017), and translation efficiency (Wang et al, 2015; Schumann et al, 2020). Dysregulation of RNA modifications has been linked to several diseases including cancers, such as leukemia (Paris et al, 2019), breast cancer (Marcel et al, 2013), and prostate cancer (Chen et al, 2017)

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