The Dysregulation of SOX Family Correlates with DNA Methylation and Immune Microenvironment Characteristics to Predict Prognosis in Hepatocellular Carcinoma

Abstract

Background. Due to the molecular heterogeneity of hepatocellular carcinoma (HCC), majority of patients respond poorly among various of therapy. This study is aimed at conducting a comprehensive analysis about roles of SOX family in HCC for obtaining more therapeutic targets and biomarkers which may bring new ideas for the treatment of HCC. Methods. UALCAN, Kaplan Meier plotter, cBioPortal, STRING, WebGestalt, Metascape, TIMER 2.0, DiseaseMeth, MethSurv, HPA, CCLE database, and Cytoscape software were used to comprehensively analyze the bioinformatic data. Results. SOX2, SOX4, SOX8, SOX10, SOX11, SOX12, SOX17, and SOX18 were significantly differentially expressed in HCC and normal tissues and were valuable for the grade and survival of HCC patients. In addition, the gene alterations of SOX family happened frequently, and SOX4 and SOX17 had the highest mutation rate. The function of SOX family on HCC may be closely correlated with the regulation of angiogenesis-related signaling pathways. Moreover, SOX4, SOX8, SOX11, SOX12, SOX17, and SOX18 were correlation with 8 types of immune cells (including CD8+ T cell, CD4+ T cell, B cell, Tregs, neutrophil, macrophage, myeloid DC, and NK cell), and we found that most types of immune cells had a positive correlation with SOX family. Notably, CD4+ T cell and macrophage were positively related with all these SOX family. NK cells were negatively related with most SOX family genes. DNA methylation levels in promoter area of SOX2, SOX4, and SOX10 were lower in HCC than normal tissues, while SOX8, SOX11, SOX17, and SOX18 had higher DNA methylation levels than normal tissues. Moreover, higher DNA methylation level of SOX12 and SOX18 demonstrated worse survival rates in patients with HCC. Conclusion. SOX family genes could predict the prognosis of HCC. In addition, the regulation of angiogenesis-related signaling pathways may participate in the development of HCC. DNA methylation level and immune microenvironment characteristics (especially CD4+ T cell and macrophage immune cell infiltration) could be a novel insight for predicting prognosis in HCC.

Computed tomography-detected extramural venous invasion-related gene signature: a potential negative biomarker of immune checkpoint inhibitor treatment in patients with gastric cancer

“…In addition to CXC12, SOX17 was also at the core of the PPI network. The SOX family is correlated with multiple clusters of immune cells and is involved in the regulation of the angiogenesis-related signaling pathway [ 26 ]. In one study, SOX17 was found to promote high-grade glioma by increasing vascular endothelial growth factor (VEGF) mediated vascular abnormality [ 27 ].…”

Systematic Investigation of the Multifaceted Role of SOX11 in Cancer

“…Additionally, SOX11 could promote brain metastasis in triple-negative breast cancer (TNBC) [ 41 ]. In hepatic cell carcinoma (HCC), higher mRNA transcript levels of SOX11 were associated with shorter OS and PFS [ 42 ]. However, it was reported that the upregulation of SOX11 expression might be a good prognostic factor for patients with MCL [ 18 ].…”

“…Clinical studies also showed that SOX11 -positive MCL patients with lymph node involvement had a poorer prognosis [ 47 ]. In addition, high mRNA levels of SOX11 in HCC were closely associated with the high grade of the tumor [ 42 ]. In our study, SOX11 expression levels in ACC, COAD, ESCA, TGCT and UVM showed an increasing trend with increasing tumor stage, but the trend was more pronounced mainly in tumor stages I-III which might be due to the small sample size of stage IV patients.…”

“…SOX11 mutations were reported to occur frequently in the hotspot(D233 del/2_D233 del) in esophageal, gastric and lung cancers, while amplification was the major form of genetic alteration in neuroendocrine prostate cancer (NEPC), OV, PRAD, BRCA and UCEC [ 48 ]. A study explored the genetic alterations of the SOX family in patients with HCC and found that all genes in the SOX family had some genetic alterations, including missense mutations, truncating mutations, amplifications, deep deletions and high mRNA [ 42 ]. It was important to note that SOX11 amplification or mutation was uncommon in primary cancers [ 49 ], but SOX11 amplification and upregulation of expression were found in metastatic brain cancers [ 50 ], which was consistent with the results of our study.…”

The Prognostic Value of AT-Rich Interaction Domain (ARID) Family Members in Patients with Hepatocellular Carcinoma

“…Tumor Immune Estimation Resource (TIMER, https://cistrome.shinyapps.io/timer/ ), an online tool for comprehensive analysis of tumor-infiltrating immune cells [ 24 ], was used to assess the correlation between ARID family genes and immune infiltrates. We followed the methods of Qin et al to perform the immune infiltrates correlation analysis [ 25 ]. The relationships of ARIDs expression with tumor-infiltrating immune cells (B cell, CD4 + T cell, CD8 + cell, macrophage, neutrophil, and dendritic cell) were identified by purity-corrected partial Spearman's correlation (partial-cor) and statistical significance, and the results were shown in scatterplots provided by TIMER.…”