DNA hypermethylation of the vimentin gene inversely correlates with vimentin expression in intestinal- and diffuse-type gastric cancer

Abstract

Abstract. T he vimentin gene is a hallma rk of epithelial-to-mesenchymal transition and has been observed to be overexpressed in various types of tumor cell line and tissue. Previous studies have reported correlations between vimentin DNA methylation levels and subsequent vimentin expression levels in solid tumors, including breast and colorectal cancer; however, to the best of our knowledge, such a correlation has not been reported for gastric cancer (GC) using Lauren classification. Therefore, the present study aimed to quantify DNA methylation levels of the vimentin gene using quantitative (q) methylation-specific polymerase chain reaction (PCR) in intestinal-type GC cell lines (MKN-28, AGS and MKN-1), diffuse-type GC cell lines (SGC-7901, SNU-5 and KATO III), the GES-1 immortalized human non-neoplastic gastric epithelial cell line, as well as in tumor and paratumor normal tissue samples. Furthermore, the present study analyzed the messenger RNA expression of the vimentin gene in these cell lines and tissues by reverse transcription-qPCR. A comparison of the clinicopathological features was conducted between patients, grouped according to the Lauren classification. The present study identified that the vimentin promoter region was hypermethylated in all GC cell lines and tumor tissue samples when compared with immortalized normal gastric epithelial cells and paratumor normal tissues. In addition, vimentin promoter methylation levels were observed to be higher in intestinal-type cell lines when compared with those of diffuse-type lines and tissues. Correspondingly, vimentin expression levels were lower in intestinal-type gastric cell lines compared with those of diffuse-type cell lines and tissues, and were lowest in the non-neoplastic gastric cell line and paratumor normal tissues. Patients with diffuse-type GC were on average younger (P=0.023), and exhibited higher tumor (P=0.020), node (P= 0.032) and TNM classification of malignant tumor stage (P=0.039) than those with intestinal-type GC. Following treatment of AGS cells (which demonstrated the highest methylation level of the vimentin gene) with 5-aza-2'-deoxycytidine, vimentin expression was restored significantly. Thus, the present study revealed that vimentin promoter methylation levels are inversely correlated with vimentin expression levels in GC (according to Lauren classification). High levels of methylation in the vimentin gene promoter region may be involved in carcinogenesis and the development of GC, and may provide a novel molecular classification for GC.

Vimentin Intermediate Filaments as Potential Target for Cancer Treatment

“…Epigenetic regulation of vimentin expression has also been shown to play an important role in EMT and cancer progression. It has been demonstrated that vimentin promoter methylation inversely correlates with vimentin expression and disease progression in gastric cancer [25].…”

“…Moreover, vimentin expression is also transactivated by β-catenin/TCF binding to the Vim promoter, thus promoting tumor cell migration/invasion [24].Epigenetic regulation of vimentin expression has also been shown to play an important role in EMT and cancer progression. It has been demonstrated that vimentin promoter methylation inversely correlates with vimentin expression and disease progression in gastric cancer [25].Apart from transcriptional regulation of vimentin expression by EMT-related transcriptional drivers, vimentin expression can be regulated also by non-coding microRNAs (miRs). It has been proposed that the HIF-1a-HDAC1 complex transcriptionally inhibits miR-548an expression during hypoxia, resulting in the upregulation of vimentin that facilitates pancreatic tumorigenesis [26].…”

Vimentin as a target for the treatment of COVID-19

“…In particular, the methylation level of the vimentin promoter inversely correlates with the expression of vimentin in gastric Open access cancer. 54 Finally, vimentin expression is also regulated by post-transcriptional mechanisms including that of noncoding microRNAs. 12 Vimentin actively participates in inflammation and immune response Targeting vimentin could have additional effects against the progression of COVID-19 by directly modulating the inflammatory response of patients with COVID-19.…”

“…In particular, the methylation level of the vimentin promoter inversely correlates with the expression of vimentin in gastric cancer. 54 Finally, vimentin expression is also regulated by post-transcriptional mechanisms including that of non-coding microRNAs. 12 …”

<p>Research on the establishment of a TPM3 monoclonal stable transfected PANC-1 cell line and the experiment of the EMT occurrence in human pancreatic cancer</p>

“…It is found in this study that the expressions of vimentin at both the gene and protein levels were significantly upregulated with the downregulation of TPM3 expression ( p <0.05), and the monoclonal stable transfected PANC-1 cell line showed the interstitial cell morphology. It has been demonstrated that35 in breast cancer,36 liver cancer,37 gastric cancer, and38 prostate cancer, the upregulated expression of vimentin enhances the proliferation, invasion, and migration of cancer cells;39 in colon cancer, the downregulation of vimentin gene expression might lower the adhesive and invasive properties of the cancer cells.During the study process, it was found that the expressions of EMT-related transcription factors (such as Snail) were upregulated after the TPM3 gene downregulation ( p <0.05), but the Twist expression was downregulated in an insignificant way ( p >0.05). Numerous studies have shown that the transcription factor Snail can bind to the E-box of the E-cadherin promoter (the core sequence is CAGGTG), downregulating the expression of E-cadherin and inducing EMT.…”