Epigenome-wide DNA methylation profiling of portal vein tumor thrombosis (PVTT) tissues in hepatocellular carcinoma patients

Abstract

Aberrant methylation is a hallmark of hepatocellular carcinoma and plays an important role in tumor initiation and progression. However, the epigenome-wide methylation patterns of portal vein tumor thrombosis (PVTTs) have not been fully explored. Here, we performed epigenome-wide DNA methylation of adjacent normal tissues (ANTs), paired tumor tissues and paired PVTTs using an Infinium HumanMethylation450 array ( n = 11) and conducted the Sequenom EpiTYPER assays to confirm the aberrantly methylated genes. MTS and apoptosis assay were used to assess the synergistic effect of two drugs on the HCC cell lines. We found the mean global methylation levels of HCC tissues and PVTTs were significantly lower than ANTs ( P < 0.01). A total of 864 differentially methylated CpG sites annotated in 532 genes were identified between HCC tissues and paired PVTTs (|mean methylation difference|>10%, P < 0.005). The pathway analysis based on hypermethylated genes in PVTT tissues was interestingly enriched in regulation of actin cytoskeleton pathway ( P = 4.48E−5). We found 23 genes whose methylation levels were gradually alternated in HCC tissues and PVTTs. Aberrant methylation status of TNFRSF10A, ZC3H3 and SLC9A3R2 were confirmed in a validation cohort ( n = 48). The functional experiments demonstrated the combination of decitabine (DAC) and tumor necrosis factor-related apoptosis-inducing ligand (rh-TRAIL) could synergistically suppress the proliferation and induce apoptosis in SK-Hep-1 and Huh7 cell lines. Together, our findings indicated that DNA methylation plays an important role in the PVTT formation through regulating the metastasis-related pathways. The combination of DAC and rh-TRAIL might be a promising treatment strategy for HCC.

Identification of prognostic biomarkers associated with the occurrence of portal vein tumor thrombus in hepatocellular carcinoma

“…The results of alternation occurrence analysis and intergenic correlation analysis implied the DEGs correlated with each other closely ( Figure 7A and Supplementary Table 3 ). And the DEGs’ co-expressive genes were mostly involved in ECM organization, focal adhesion, along with the binding of integrin and collagen ( Figure 7 ), which was consistent with the previous studies [ 14 , 16 ]. As we know, the TME is formed by cellular components (stroma cells, immune cells, and endothelial cells, etc.…”

“…These genes participated in focal adhesion and xenobiotics metabolism, and many of them could regulate the invasion of HCC cells [ 13 ]. Besides, genomic variations [ 12 ], non-coding RNAs [ 10 , 15 ], DNA methylation [ 16 ], cancer stem cells [ 17 ], along with the immune cells [ 18 ] and vascular endothelial cells [ 19 ] in the tumor microenvironment (TME) have been reported to contribute to the development of PVTT.…”

C8orf76 Modulates Ferroptosis in Liver Cancer via Transcriptionally Up-Regulating SLC7A11

“…Notably, patients with increased C8orf76 had worse OS in the TCGA dataset (Figure 1C). Moreover, we also found that C8orf76 was highly expressed in tumor and portal vein tumor thrombosis (PVTT) tissues compared to adjacent benign tissues according to our previous RNA-seq analysis [24] (Figure 1D).…”

Portal Vein Tumor Thrombosis and Hepatocellular Carcinoma – The Changing Tides

“…37 Other factors such as the vascular endothelial cells, immune cells in the tumor microenvironment, genomic irregularities, sequential alterations of mRNA expression, DNA methylation of differentially expressed genes, cancer stem cells, dysregulation of extracellular matrix organization, and focal adhesion have all been proposed to contribute to the development of PVTT. [38][39][40][41] HBV infection and active replication has also been implicated in the vascular invasion in HCC patients. 42 Figure 1 Management of advanced hepatocellular carcinoma according to different guidelines.…”