The frequencies of high-level methylation in GC tissues for the seven genes were: 48% for APC, 57.33% for WIF-1, 56% for RUNX-3, 50.67% for DLC-1, 52% for SFRP-1, 54.67% for DKK, and 48% for E-cad.
Although RUNX1 is similar to RUNX3 in both the expression pattern in the stomach and its cell growth-inhibition activity, RUNX1 is not involved in most cases of gastric cancers.
These findings suggest that RUNX1 and CBFBeta in addition to RUNX3 play some roles in gastric cancers and that roles of RUNX gene family in gastric cancer are more widespread and complex than previously realized.
A great number of genes with promoter methylation have been observed in gastric cancer (GC), among which p16INK4A (p16), Mut L homologue 1 (MLH1), Epithelial-cadherin (E-cadherin), Runt-related transcription factor 3 (RUNX3), adenomatous polyposis coli (APC), O(6)-methylguanine-DNA methyltransferase (MGMT), Ras association domain family 1A (RASSF1A) and Death-associated protein kinase (DAPK) have been extensively studied.
In addition to the deregulation of mechanisms controlling gene expression, there would also seem to be at least one other mechanism controlling nuclear translocation of RUNX3 that is impaired frequently in gastric cancer.
We found no statistically significant associations between RUNX3rs6672420 polymorphism and risk of gastric atrophy, nor between these two RUNX3 polymorphisms and the risk of gastric cancer relative to the subjects with gastric atrophy.
The pooled data showed that expression of RUNX3 was significant correlated with tumor's differentiation (OR = 0.387; 95%CI: 0.237-0.633; P = 0.000), depth of invasion (OR = 0.443; 95%CI: 0.273-0.717; P = 0.001), lymph node metastasis (OR = 0.394; 95%CI: 0.259-0.598; P = 0.000), distant metastasis (OR = 0.403; 95%CI: 0.213-0.764; P = 0.005) and TNM stage (OR = 0.461; 95%CI, 0.322-0.659; P = 0.000) in GC.
RUNX3 showed protein silencing in cancer and normal mucosa, compared to inflammatory peritumoural infiltrate in almost all cases, showing a non-lymphocytic predominant pattern and being correlated with epigenetic silencing.Our results show aberrant promoter's methylation in APC, CDH1, CDKN2A, MLH1 and RUNX3 associated with GC, as well as a non-lymphocytic predominant infiltrate with high expression of RUNX3.
In addition to gene mutation and promoter hypermethylation, cytoplasmic mislocalization has emerged as another major manifestation of RUNX3 dysfunction in malignancies including breast, colorectal and gastric cancers.
A significant association was observed between RUNX3 promoter methylation and gastric cancer, with an aggregated odds ratio (OR) of 5.63 (95%CI 3.15, 10.07).
Overall, 55% of GC demonstrated methylation of the RUNX3 promoter; 82% of GC was classified as stable microsatellite instability, 5% as low-level microsatellite instability and 13% as high-level microsatellite instability (MSI-H); mtMSI was detected in 11% of GC.
Finally, via long-term culture of gastric tumour epithelium, we revealed that de novo methylation of the RUNX3 canonical CGI promoter is a bystander effect of oncogenic immortalization and not likely causal in GC pathogenesis as previously argued.
Furthermore, the expression of miR‑130a in plasma in gastric cancer patients was upregulated and diagnostic value for gastric cancer of miR-130a is more effective than the tumor markers carcinoembryonic antigen (CEA) and CA-199. miR-130a directly targeted runt‑related transcription factor 3 (RUNX3) and promoted gastric cancer tumorigenesis by targeting RUNX3. miR-130a may therefore be a useful marker for the diagnosis and prognosis of gastric cancer.
In addition to epigenetic changes in the RUNX3 proximal promoter, genetic changes in the distal promoter may be associated with susceptibility to intestinal-type gastric cancer by increasing promoter activity.
Runt-related transcription factor 3 (RUNX3) is reported as a tumor suppressor gene for gastric cancer, and may be important in the development of hepatocellular carcinoma (HCC).
Among samples obtained from patients with stomach cancer, methylation was observed in both the neoplastic and the corresponding non-neoplastic gastric epithelia; 43% (40/93) and 73% (68/93) for DAP-kinase, and 45% (42/93) and 8% (7/93) for RUNX3, respectively.
The negative correlation of RUNX3 and Akt expression and downstream β-catenin/cyclin D1 effectors was further confirmed in AGS and GES-1 cell lines, as well as clinical specimens of gastric cancer.