Integrated analysis of gene expression and DNA methylation changes induced by hepatocyte growth factor in human hepatocytes

Abstract

Hepatocellular carcinoma (HCC) is the one of most common malignant tumors. The tumor microenvironment has a role in not only supporting growth and survival of tumor cells, but also triggering tumor recurrence and metastasis. Hepatocyte growth factor (HGF), one of the important growth factors in the tumor microenvironment, has an important role in angiogenesis, tumorigenesis and regeneration. However, the exact mechanism by which HGF regulates HCC initiation and development via epigenetic reprogramming has remained elusive. The present study focused on the epigenetic modification and target tumor-suppressive genes of HGF treatment in HCC. Expression profiling and DNA methylation array were performed to investigate the function of HGF and examine global genomic DNA methylation changes, respectively. Integrated analysis of gene expression and DNA methylation revealed potential tumor suppressor genes (TSGs) in HCC. The present study showed the multiple functions of HGF in tumorous and nontumorous pathways and global genomic DNA methylation changes. HGF treatment upregulated the expression of DNA methyltransferase 1 (DNMT1). Overexpression of DNMT1 in HCC patients correlated with the malignant potential and poor prognosis of HCC. Furthermore, integration analysis of gene expression and DNA methylation changes revealed novel potential tumor suppressor genes TSGs including MYOCD, PANX2 and LHX9. The present study has provided mechanistic insight into epigenetic repression of TSGs through HGF-induced DNA hypermethylation.

Connexin and pannexin channels in cancer

“…Downregulated in human tumours and positive correlation with patient survival [ 179 , 183 ] Panx2 Hepatocellular carcinoma Potential tumour suppressor. Methylated in cancer samples [ 184 ] Panx2 Neuroblastoma Knockdown in Neuro2a cells increases differentiation [ 21 ] Panx1, Panx3 Basal and squamous skin cell carcinoma Downregulated in BCC and SCC tumours compared to normal skin [ 152 ] …”

“…Consistent with a potential role as tumour suppressor, a recent publication listed PANX2 as one of the methylated genes identified by expression profiling and DNA methylation arrays in hepatocellular carcinomas (HCC) [ 184 ]. In HCC, the hepatocyte growth factor (HGF) upregulates the expression of DNA methyltransferase 1 that results in the hypermethylation and epigenetic repression of potential tumour suppressor genes, including PANX2 .…”

Impact of seasonality, storage of semen, and sperm head‐shape on whole tissue methylation and expression of methylation responsive candidate genes in swine placenta and fetal livers from summer and winter breedings

“…The fetal liver can be compared to a malignant tumor, in the fact that there is rapid changes and growth occurring. It has been shown that HGF treatment of liver cell lines induced alterations in global methylation levels in support of tumorigenesis (Xie et al, ). Investigators reported a hypermethylation of tumor suppressor genes in conjunction with a hypomethylation of several other genes within HGF‐treated cell lines.…”

“…The fetal liver can be compared to a malignant tumor, in the fact that there is rapid changes and growth occurring. It has been shown that HGF treatment of liver cell lines induced alterations in global methylation levels in support of tumorigenesis (Xie et al, 2015).…”

Pannexin hemichannels: A novel promising therapy target for oxidative stress related diseases

“…Using brain cancer gene expression database REMBRANDT shows that pannexin‐2 expression levels acts as a post diagnosis survival in patients with glial tumors (Litvin, Tiunova, Connell‐Alberts, Panchin, & Baranova, ). Pannexin‐2 is reported to may be tumor suppressor genes (TSGs) in hepatocellular carcinoma (HCC) (Xie, Sun, et al, ). Moreover, pannexin‐2 expression decreases in a human C6 glioma cell line (Lai et al, ).…”