Abstract
BackgroundAs essential components of cycle growth, the cell division cycle-associated family genes (CDCAs) have crucial roles in tumor development and progression, especially in hepatocellular carcinoma (HCC). However, due to the tumor heterogeneity of HCC, little is known about the methylation variability of CDCAs in mediating phenotypic changes (e.g., immune infiltrates) in HCC. Presently, we aim to comprehensively explore the expression and prognosis of CDCAs methylation with regard to immune infiltrates of HCC.MethodsWe first identified the correlating differentially expressed genes (co-DEGs) among 19 different types of cancer cohorts (a total of 7,783 patients) and then constructed the weighted gene co-expressed and co-methylated networks. Applying the clustering analysis, significant modules of DEGs including CDCAs were selected and their functional bioinformatics analyses were performed. Besides, using DiseaseMeth and TIMER, the correlation between the methylation levels of CDCAs and tumor immune infiltrates was also analyzed. In final, to assess the influence of CDCAs methylation on clinical prognosis, Kaplan-Meier and Cox regression analysis were carried out.ResultA total of 473 co-DEGs are successfully identified, while seven genes of CDCAs (CDCA1–3 and CDCA5–8) have significant over-expression in HCC. Co-expressed and co-methylated networks reveal the strong positive correlations in mRNA expression and methylation levels of CDCAs. Besides, the biological enrichment analysis of CDCAs demonstrates that they are significantly related to the immune function regulation of infiltrating immune cells in HCC. Also, the methylation analysis of CDCAs depicts the strong association with the tumor immunogenicity, i.e., low-methylation of CDCA1, CDCA2, and CDCA8 dramatically reduced the immune infiltrate levels of T cells and cytotoxic lymphocytes. Additionally, CDCA1–6 and CDCA8 with low-methylation levels significantly deteriorate the overall survival of patients in HCC.ConclusionsThe co-expressed and co-methylated gene networks of CDCAs show a powerful association with immune function regulation. And the methylation levels of CDCAs suggesting the prognostic value and infiltrating immune differences could be a novel and predictive biomarker for the response of immunotherapy.
Highlights
In accordance with the global cancer statistics released in 2018, hepatocellular carcinoma (HCC) has become the sixth most common cancer worldwide and the second leading cause of cancer-related death in men [1]
Through constructing the co-expressed and co-methylated networks, we explored the biological enrichment of cell division cycle-associated family genes (CDCAs) and found that they are significantly related to immune function
All the results demonstrate that the methylation levels of CDCAs could be served as predictive biomarkers for determining prognosis and immune infiltration in HCC
Summary
In accordance with the global cancer statistics released in 2018, hepatocellular carcinoma (HCC) has become the sixth most common cancer worldwide and the second leading cause of cancer-related death in men [1]. The cell division cycle-associated family genes (CDCAs), consisting of eight members (CDCA1–8), are essential components of cell cycle growth, and they have been found malfunctions in various cancers, including HCC [3,4,5,6]. Through enhancing cell proliferation with the prevention of G1 phase arrest, the upregulation of CDCA3 promoted cancer progression [9]. CDCA8, as the key mediator of estrogen-stimulated cell proliferation in cancer cells, could inhibit cancer cell survival and growth by cell cycle G1 phase arrest [11]. As essential components of cycle growth, the cell division cycle-associated family genes (CDCAs) have crucial roles in tumor development and progression, especially in hepatocellular carcinoma (HCC).
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