Methylation of RUNX3 in various types of human cancers and premalignant stages of gastric carcinoma

Abstract

Accumulating evidence has identified a mechanism potentially responsible for the inactivation of tumor suppressor genes, namely transcriptional silencing by aberrant methylation of CpG islands. A previous study has shown the loss of RUNX3 expression, due to aberrant methylation of its CpG island, in gastric cancer cell lines, suggesting that RUNX3 is a target for epigenetic gene silencing in gastric carcinogenesis. However, there are limited data on the methylation status of RUNX3 in the neoplastic and non-neoplastic tissues in various types of human cancers, including gastric cancer. Here, we report that 60% of gastric cancer cell lines and 64% of primary gastric carcinomas (n ¼ 75) were methylated at the RUNX3 CpG island. RUNX3 methylation was also detected in hepatocellular carcinomas (73%, n ¼ 48), larynx cancers (62%, n ¼ 37), lung cancers (46%, n ¼ 24), breast cancers (25%, n ¼ 25), prostate cancers (23%, n ¼ 44), endometrial cancers (12.5%, n ¼ 24), colon cancers (4.9%, n ¼ 61) and uterine cervical cancers (2.5%, n ¼ 40), showing that RUNX3 methylation is not restricted to gastric cancer. Interestingly, the RUNX3 methylation was especially frequent in tumors from tissues of a foregut derivative, that is, the stomach, liver, larynx and lung. Next, the methylation status of RUNX3 in various nonneoplastic tissues was examined, including the premalignant lesions of gastric carcinomas. The RUNX3 methylation was found in 8.1% of chronic gastritis (n ¼ 99), 28.1% of intestinal metaplasia (n ¼ 32), 27.3% of gastric adenomas (n ¼ 77) and 64% of gastric carcinomas (n ¼ 75), but not in chronic hepatitis B, normal prostate and colon mucosa, even though in cases of chronic hepatitis, the methylation frequency of its neoplastic tissues was very high. In conclusion, RUNX3 methylation is frequently found in human cancers, including gastric cancer, and is mostly cancer specific, with the exception of the stomach, and thus, might be useful as a potential diagnostic biomarker of cancer.

Frequent loss of RUNX3 gene expression in remnant stomach cancer and adjacent mucosa with special reference to topography

“…In the remnant stomach mucosa, chronic gastritis and intestinal metaplasia were intensively observed with downregulation of RUNX3. Our previous study and others indicate that RUNX3 downregulation is frequently observed in chronic gastritis, intestinal metaplasia, and gastric adenoma in the GCI group (Li et al, 2002;Kim et al, 2004), which are thought to be precancerous (SafatleRibeiro et al, 1996;Tanigawa et al, 2000;Nishizawa et al, 2002). In our study, 19.5% of adjacent mucosa of the GCI group had downregulation of RUNX3 expression.…”

Intragenic DNA Methylation Concomitant with Repression of ATP4B and ATP4A Gene Expression in Gastric Cancer is a Potential Serum Biomarker

“…Some of the applications include oncogene mutations, oncogene amplification, and tumor related viral DNA. Several studies have used circulating DNA to study aberrant methylation in genes (RUNX3 (Kim et al, 2004), DAP-kinase, E-cadherin, GSTP1, p15, and p16 (Lee et al, 2002) specific to tumor tissue and correlate it with clinical outcome. In the present study we have demonstrated the detection of DNA methylation of ATP4B gene in circulating cell free DNA in plasma samples of gastric cancer patients.…”

MicroRNA-148a Can Regulate Runt-Related Transcription Factor 3 Gene Expression via Modulation of DNA Methyltransferase 1 in Gastric Cancer

“…The bisulfite conversion was performed using an EpiTect Bisulfite (Qiagen) in accordance with the product manual. The methylation status of RUNX3 was analyzed by methylation-specific PCR (MSP) as described previously (Kim et al, 2004). MSP assays were repeated at least twice to verify the reproducibility of the assay.…”

“…Several cancer-associated genes, such as adenomatous polyposis coli (APC), E-cadherin (CDH1), cyclindependent kinase 4 inhibitor B (p15/INK4B), cyclin-dependent kinase inhibitor 2A (p16/INK4A), and RUNX3, may be inactivated in gastric carcinogenesis due to hypermethylation (Sato and Meltzer, 2006), and hypermethylation of the RUNX3 promoter region in particular is frequently found in gastric cancer and other human cancers (Kim et al, 2004;Li et al, 2002). However, it is not clear what causes aberrant methylation of RUNX3.…”