AUTHOR=Gu Xinyu , Zhou Haibo , Chu Qingfei , Zheng Qiuxian , Wang Jing , Zhu Haihong 

TITLE=Uncovering the Association Between m5C Regulator-Mediated Methylation Modification Patterns and Tumour Microenvironment Infiltration Characteristics in Hepatocellular Carcinoma

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=9

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.727935

DOI=10.3389/fcell.2021.727935

ISSN=2296-634X

ABSTRACT=<p><bold>Background:</bold> 5-Methylcytosine (m<sup>5</sup>C) plays essential roles in hepatocellular carcinoma (HCC), but the association between m<sup>5</sup>C regulation and immune cell infiltration in HCC has not yet been clarified.</p><p><bold>Methods:</bold> In this study, we analysed 371 patients with HCC from The Cancer Genome Atlas (TCGA) database, and the expression of 13 m<sup>5</sup>C regulators was investigated. Additionally, gene set variation analysis (GSVA), unsupervised clustering analysis, single-sample gene set enrichment analysis (ssGSEA), correlation analysis, and immunohistochemical (IHC) staining were performed.</p><p><bold>Results:</bold> Among the 371 patients, 41 had mutations in m<sup>5</sup>C regulators, the frequency of which was 11.26%. Compared with normal hepatic tissues, the expression of m<sup>5</sup>C regulators with copy number variations (CNVs) expansion was significantly higher than that in HCC tissues. Then, we identified three m<sup>5</sup>C modification patterns that had obvious tumour microenvironment (TME) cell infiltration characteristics. The prognostic analysis of the three major m<sup>5</sup>C modification subtypes showed that Cluster-2 had a clear survival advantage over the others. In addition, we found that DNMT1 was highly expressed in tumour tissues compared with normal tissues in a tissue microarray (TMA) and that it was positively correlated with many TME-infiltrating immune cells. High expression of the m<sup>5</sup>C regulator DNMT1 was related to a poor prognosis in patients with HCC. Furthermore, we developed three distinct Immu-clusters. Importantly, mRNAs related to the transcription of growth factor β (TGF-β)/EMT pathway were significantly up-regulated in Immu-cluster 2, indicating that this cluster is considered to be the immune rejection phenotype. Immu-cluster 3 showed elevated expression of mRNAs related to immune checkpoint genes.</p><p><bold>Conclusion:</bold> Our work revealed the association between m<sup>5</sup>C modification and immune regulators in the TME. These findings also suggest that DNMT1 has great potential as a prognostic biomarker and therapeutic target for HCC.</p>