RUNX3

Gene Summary

Gene:RUNX3; runt-related transcription factor 3
Aliases: AML2, CBFA3, PEBP2aC
Location:1p36
Summary:This gene encodes a member of the runt domain-containing family of transcription factors. A heterodimer of this protein and a beta subunit forms a complex that binds to the core DNA sequence 5'-PYGPYGGT-3' found in a number of enhancers and promoters, and can either activate or suppress transcription. It also interacts with other transcription factors. It functions as a tumor suppressor, and the gene is frequently deleted or transcriptionally silenced in cancer. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:runt-related transcription factor 3
HPRD
Source:NCBIAccessed: 24 July, 2015

Ontology:

What does this gene/protein do?
Show (21)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 24 July 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Apoptosis
  • Cell Proliferation
  • Tumor Suppressor Gene
  • Epigenetics
  • Base Sequence
  • Microsatellite Instability
  • Cancer Gene Expression Regulation
  • Cancer DNA
  • Eye Cancer
  • Phenotype
  • Mutation
  • Case-Control Studies
  • Promoter Regions
  • CpG Islands
  • Neoplastic Cell Transformation
  • Immunohistochemistry
  • Neoplasm Proteins
  • Stomach Cancer
  • Polymerase Chain Reaction
  • Gene Silencing
  • Chromosome 1
  • Down-Regulation
  • Gene Expression Profiling
  • Loss of Heterozygosity
  • Disease Progression
  • Uveal Neoplasms
  • Squamous Cell Carcinoma
  • Staging
  • Oligonucleotide Array Sequence Analysis
  • Gastric Mucosa
  • Liver Cancer
  • Cohort Studies
  • RUNX3
  • Proto-Oncogene Proteins
  • Uterine Cancer
  • Adenocarcinoma
  • DNA Methylation
  • DNA-Binding Proteins
  • Tumor Burden
  • Colorectal Cancer
  • Messenger RNA
Tag cloud generated 24 July, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: RUNX3 (cancer-related)

Zhang X, He H, Zhang X, et al.
RUNX3 Promoter Methylation Is Associated with Hepatocellular Carcinoma Risk: A Meta-Analysis.
Cancer Invest. 2015; 33(4):121-5 [PubMed] Related Publications
Runt-related transcription factor 3 (RUNX3) has been reported to be a tumor-suppressing gene in hepatocellular carcinoma. Association between hepatocellular carcinoma and RUNX3 promoter methylation has been investigated in studies with specific ethnic backgrounds and small sample sizes. In this study, a meta-analysis was adopted to combine the data from 11 studies of association between RUNX3 promoter methylation and hepatocellular carcinoma. Pooled odds ratio for RUNX3 promoter methylation status in hepatocellular carcinoma versus control liver tissue was 24.37 (95%CI: 12.14, 48.92), p < .00001, indicates a strong association between methylation of the RUNX3 promoter and hepatocellular carcinoma.

Estécio MR, Maddipoti S, Bueso-Ramos C, et al.
RUNX3 promoter hypermethylation is frequent in leukaemia cell lines and associated with acute myeloid leukaemia inv(16) subtype.
Br J Haematol. 2015; 169(3):344-51 [PubMed] Related Publications
Correlative and functional studies support the involvement of the RUNX gene family in haematological malignancies. To elucidate the role of epigenetics in RUNX inactivation, we evaluated promoter DNA methylation of RUNX1, 2, and 3 in 23 leukaemia cell lines and samples from acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) and myelodysplatic syndromes (MDS) patients. RUNX1 and RUNX2 gene promoters were mostly unmethylated in cell lines and clinical samples. Hypermethylation of RUNX3 was frequent among cell lines (74%) and highly variable among patient samples, with clear association to cytogenetic status. High frequency of RUNX3 hypermethylation (85% of the 20 studied cases) was found in AML patients with inv(16)(p13.1q22) compared to other AML subtypes (31% of the other 49 cases). RUNX3 hypermethylation was also frequent in ALL (100% of the six cases) but low in MDS (21%). In support of a functional role, hypermethylation of RUNX3 was correlated with low levels of protein, and treatment of cell lines with the DNA demethylating agent, decitabine, resulted in mRNA re-expression. Furthermore, relapse-free survival of non-inv(16)(p13.1q22) AML patients without RUNX3 methylation was significantly better (P = 0·016) than that of methylated cases. These results suggest that RUNX3 silencing is an important event in inv(16)(p13.1q22) leukaemias.

Paluszczak J, Sarbak J, Kostrzewska-Poczekaj M, et al.
The negative regulators of Wnt pathway-DACH1, DKK1, and WIF1 are methylated in oral and oropharyngeal cancer and WIF1 methylation predicts shorter survival.
Tumour Biol. 2015; 36(4):2855-61 [PubMed] Free Access to Full Article Related Publications
The deregulation of Wnt signaling has recently emerged as one of the drivers of head and neck cancers. This is frequently related to the methylation of several antagonists of this pathway. This study aimed at the assessment of the profile of methylation of Wnt pathway antagonists and the determination of the prognostic value of the methylation of selected genes in oral carcinomas. The methylation of DACH1, DKK1, LKB1, PPP2R2B, RUNX3, SFRP2, and WIF-1 was analyzed in 16 oral squamous cell carcinoma cell lines using the methylation-specific polymerase chain reaction. The methylation of selected genes was further analyzed in tumor sections from 43 primary oral carcinoma patients. The analysis of oral carcinoma cell lines showed very frequent methylation of SFRP2 and WIF-1 and also a less frequent methylation of DACH1 and DKK1. On the other hand, RUNX3 was methylated only in one cell line, while LKB1 and PPP2R2B were not methylated in any of the cell lines. The biallelic methylation of DKK1 correlated with the low level of expression of this gene. Further evaluation of the methylation of DACH1, DKK1, and WIF1 in a clinical patient group confirmed the frequent methylation of WIF1 and intermediate or low frequency of methylation of DACH1 or DKK1, respectively. Importantly, the methylation of WIF-1 correlated with shorter survival in oral cancer patients. Overall, the methylation of the antagonists of Wnt pathway is frequently detected in oral squamous cell carcinomas. The methylation of WIF1 may be considered a prognostic marker in oral cancers.

Guo C, Ren F, Wang D, et al.
RUNX3 is inactivated by promoter hypermethylation in malignant transformation of ovarian endometriosis.
Oncol Rep. 2014; 32(6):2580-8 [PubMed] Related Publications
The aim of the present study was to investigate the role of epigenetic inactivation of the runt-related transcription factor 3 gene (RUNX3) in the malignant transformation of ovarian endometriosis. Samples obtained by microdissection and scraping included 30 malignant ovarian endometriotic cyst tissues and 30 corresponding eutopic endometrium tissues from the endometriosis-associated ovarian carcinoma (EAOC) group, 19 benign ovarian endometriotic cyst tissues and 22 corresponding eutopic endometrium tissues from the endometriosis (EM) group and 22 normal eutopic endometrium tissues from the control endometrium (CE) group. RUNX3 methylation status was determined by methylation-specific PCR and bisulfite sequencing, while levels of RUNX3 and ERα protein expression were evaluated using immunohistochemistry. The percentage of RUNX3 methylation and negative RUNX3 protein expression in the malignant ovarian endometriotic cysts from the EAOC group was significantly higher than that in the benign ovarian endometriotic cysts from the EM group. The percentage of RUNX3 methylation and negative RUNX3 protein expression in the eutopic endometrium from the EAOC group was significantly higher than that in the EM and CE groups. An inverse correlation between positive RUNX3 protein expression and methylation was observed and a positive correlation was shown between RUNX3 methylation and ERα protein expression. In the malignant ovarian endometriotic cysts from the EAOC group, there was no significant correlation between methylation frequency of the RUNX3 gene and histological type. However, the percentage of RUNX3 gene methylation was significantly higher in the tissue samples from patients with surgical stage IC EAOC than the percentage in patients with stage IA and IB disease. These results suggest that RUNX3 inactivation by promoter hypermethylation plays a role in the progression of malignant transformation of ovarian EM and is closely related to estrogen metabolism. Negative protein expression and abnormal RUNX3 methylation in the eutopic endometrium could be used as diagnostic markers in patients with ovarian EM who may be at an increased risk of developing EAOC.

Ren F, Wang DB, Li T, et al.
Identification of differentially methylated genes in the malignant transformation of ovarian endometriosis.
J Ovarian Res. 2014; 7:73 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Key roles for epigenetic mechanisms in tumorigenesis are well accepted, while the relationship between gene methylation and malignant transformation of ovarian endometriosis (EMS) was seldom reported. In this study, we aimed to screen for aberrantly methylated genes associated with the malignant transformation of ovarian EMS and to preliminarily verify the reliability of screened results by detecting the methylation status and protein expression of the candidate gene in a larger scale of formaldehyde-fixed and paraffin-embedded (FFPE) samples.
METHODS: Methylated CpG island amplification coupled with representational difference analysis (MCA-RDA) was performed on 3 couples of endometriosis-associated ovarian carcinoma (EAOC) fresh samples to identify differentially methylated candidate genes related to malignant transformation of ovarian EMS; Methylation-specific PCR (MSP) and immunohistochemistry were performed in 30 EAOC samples to detected the methylation status and protein expression of RASSF2 gene to verify the reliability of MCA-RDA results.
RESULTS: Nine differentially methylated genes were obtained by MCA-RDA as candidate genes for malignant transformation of EMS; Methylation frequency of RASSF2 in the neoplastic tissues of EAOC group was higher than that in the ectopic endometria (p < 0.05). While protein expression of RASSF2 in the neoplastic tissues was lower than that in the ectopic endometria of the EAOC group (p < 0.05) Absence of protein expression of RASSF2 was significantly correlated with the promoter methylation of the gene (p < 0.05).
CONCLUSIONS: RASSF2, RUNX3, GSTZ1, CYP2A, GBGT1, NDUFS1, SPOCK2, ADAM22, and TRIM36 were candidate genes for malignant transformation of ovarian EMS and epigenetic inactivation of RASSF2 by promoter hypermethylation is an early event in malignant transformation of ovarian EMS. The screen results were reliable and worthy of further study.

Li Y, Ji X, Su Z, et al.
Downregulation of Runx3 is closely related to the decreased Th1-associated factors in patients with gastric carcinoma.
Tumour Biol. 2014; 35(12):12235-44 [PubMed] Related Publications
Runt-related transcription factor 3 (Runx3) is a tumor-suppressor gene and plays an important role in immune regulation, whose reduced expression may play an important role in the development and progression of gastric carcinoma. The aim of this study was to investigate the role of Runx3 on the levels of transcription factors in patients with gastric carcinoma and analyze the relationship between the expression of Runx3 and Th1-type cytokines in peripheral blood mononuclear cells (PBMCs). Our results showed that the expression levels of Runx3, T-bet, and IFN-γ in patients with gastric carcinoma were obviously lower than those in control groups, and there was a positive correlation between the expression of Runx3 and T-bet or IFN-γ in patients (p < 0.01). In order to further confirm this result, the Runx3 gene was constructed into pIRES2-eGFP and the recombined plasmid was transfected into SGC-7901 cells with liposome in vitro, the results obtained from the reverse transcription PCR indicated that the mRNA of Runx3, T-bet, or IFN-γ was significantly upregulated individually in Runx3 gene-transfected SGC-7901 cells. It suggested that the Runx3 and Th1-associated factors including T-bet and IFN-γ synchronization declines in gastric carcinoma may contribute to the development of cancer.

Lu XX, Zhu LQ, Pang F, et al.
Relationship between RUNX3 methylation and hepatocellular carcinoma in Asian populations: a systematic review.
Genet Mol Res. 2014; 13(3):5182-9 [PubMed] Related Publications
Runt-related transcription factor 3 (RUNX3) is a potential tumor suppressor that is frequently hypermethylated in hepatocellular carcinoma (HCC). The present meta-analysis of case-control studies was carried out to determine whether RUNX3 hypermethylation is associated with HCC. The PubMed, Embase, and Chinese National Knowledge Infrastructure databases were searched for all relevant studies published between May 2000 and May 2012. A total of 11 studies were identified, and 8 studies involving 491 patients with HCC and 409 patients without tumors were found to satisfy the inclusion criteria for the meta-analysis. All tissue samples were from Asian populations. There was significant heterogeneity between the studies. Over the entire sample, the odds ratio (OR) of RUNX3 promoter methylation was 18.5 [95% confidence interval (CI), 11.6-29.6] for HCC tissues relative to control tissues. The ORs of RUNX3 methylation were 16.6 (95%CI = 6.5-42.4) for tumor tissues relative to tumor-adjacent tissues in patients with HCC, 67.3 (95%CI = 13.0-348.5) for tumor tissues from patients with HCC relative to liver tissues from patients with non-neoplastic liver diseases, and 3.26 (95%CI = 1.54-6.90) for tissues from patients with hepatitis C virus (HCV)- related HCC relative to liver tissues from patients with HCC unrelated to HCV. There was no association between RUNX3 methylation and age, gender, pathological stage, or hepatitis B virus infection in HCC tissues. Methylation of the RUNX3 promoter strongly correlated with HCC in Asian populations, especially in individuals with HCV-related HCC, and may be a useful marker for HCC diagnosis in these populations.

Yang Y, Ye Z, Zou Z, et al.
Clinicopathological significance of RUNX3 gene hypermethylation in hepatocellular carcinoma.
Tumour Biol. 2014; 35(10):10333-40 [PubMed] Related Publications
Emerging evidence indicates that RUNX3 is a candidate tumor suppressor in several types of human tumors including hepatocellular carcinoma (HCC). However, the correlation between RUNX3 hypermethylation and incidence of HCC remains unclear. Here, we conducted a systematic review and meta-analysis aiming to comprehensively assess the potential role of RUNX3 hypermethylation in the pathogenesis of HCC. A detailed literature search was made from PubMed, EMBASE, and ISI web of knowledge to identify studies for related research publications. Methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analysis of pooled data was performed. Odds ratio (OR) was calculated and summarized, respectively. Final analysis of 821 HCC patients from 14 eligible studies was performed. We observed that RUNX3 hypermethylation was significantly higher in HCC than in normal liver tissue, the pooled OR from eight studies including 382 HCC and 161 normal liver tissue (OR = 39.32, 95 % confidence interval (CI) = 13.72-112.7, p < 0.00001). The pooled analysis showed significantly increased OR of RUNX3 hypermethylation (OR = 5.4, 95 % CI = 2.06-14.17, p < 0.00001) in HCC tissues and non-tumor liver tissues. In addition, statistically significant OR of RUNX3 hypermethylation was obtained from non-tumorous liver tissue of HCC patients and normal liver tissue (OR = 12.57, 95 % CI = 3.56-44.35, p < 0.0001). The results of this meta-analysis suggest that RUNX3 hypermethylation may be implicated in the pathogenesis of HCC. Thus, detection of RUNX3 hypermethylation may be a helpful and valuable biomarker for diagnosis of HCC.

Xue LN, Bai FH, Wang XY, et al.
Expression of RUNX3 gene in pancreatic adenocarcinoma and its clinical significance.
Genet Mol Res. 2014; 13(2):3940-6 [PubMed] Related Publications
We investigated the clinical significance of RUNX3 gene expression in human pancreatic carcinoma. Five samples of pancreatic tissues and 30 samples of pancreatic cancer tissues and paracancerous tissues were collected. RUNX3 expression was detected by real-time PCR and immunohistochemistry. The relationships between clinicopathological findings and the expression of RUNX3 were analyzed. The relative quantification level of RUNX3 mRNA expression in human pancreatic carcinoma tissues and paracancerous tissues was 2.60 (0.42-12.82) and 1.02 (0.19-3.58), respectively (P < 0.05). The percentage of positive cells expressing RUNX3 protein in human pancreatic tissues and paracancerous tissues was 45.5 ± 26.2 and 6.9 ± 6.0%, respectively (P < 0.01). The high RUNX3 group (N = 9) with 45.5% or more of the cancer cells staining for RUNX3 and the low RUNX3 group (N = 21) with less than 45.5% cancer cells staining for RUNX3. Low expression of RUNX3 correlated significantly with an advanced TNM stage (χ(2) = 6.897, P = 0.045), lymph node metastasis (χ(2) = 4.739, P = 0.029) and neural invasion (χ(2) = 5.44, P = 0.020). On the other hand, no association could be found between RUNX3 expression and clinicopathological variables including age, gender, tumor location, tumor size, tumor differentiation or the serum concentration of CEA and CA199. The expression of RUNX3 in pancreatic cancer tissues was obviously higher than that in the paracancerous tissues. Low expression of RUNX3 may have an important role in aggressiveness, lymph node metastasis and neural invasion in pancreatic cancer. In pancreatic carcinoma tissues, low expression of RUNX3 may indicate a poor prognosis.

Shiovitz S, Bertagnolli MM, Renfro LA, et al.
CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer.
Gastroenterology. 2014; 147(3):637-45 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND & AIMS: The CpG island methylator phenotype (CIMP), defined by a high frequency of aberrantly methylated genes, is a characteristic of a subclass of colon tumors with distinct clinical and molecular features. Cohort studies have produced conflicting results on responses of CIMP-positive tumors to chemotherapy. We assessed the association between tumor CIMP status and survival of patients receiving adjuvant fluorouracil and leucovorin alone or with irinotecan (IFL).
METHODS: We analyzed data from patients with stage III colon adenocarcinoma randomly assigned to groups given fluorouracil and leucovorin or IFL after surgery, from April 1999 through April 2001. The primary end point of the trial was overall survival and the secondary end point was disease-free survival. DNA isolated from available tumor samples (n = 615) was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci. The effects of CIMP on survival were modeled using Kaplan-Meier and Cox proportional hazards; interactions with treatment and BRAF, KRAS, and mismatch repair (MMR) status were also investigated.
RESULTS: Of the tumor samples characterized for CIMP status, 145 were CIMP positive (23%). Patients with CIMP-positive tumors had shorter overall survival times than patients with CIMP-negative tumors (hazard ratio = 1.36; 95% confidence interval: 1.01-1.84). Treatment with IFL showed a trend toward increased overall survival for patients with CIMP-positive tumors, compared with treatment with fluorouracil and leucovorin (hazard ratio = 0.62; 95% CI: 0.37-1.05; P = .07), but not for patients with CIMP-negative tumors (hazard ratio = 1.38; 95% CI: 1.00-1.89; P = .049). In a 3-way interaction analysis, patients with CIMP-positive, MMR-intact tumors benefited most from the addition of irinotecan to fluorouracil and leucovorin therapy (for the interaction, P = .01). CIMP was more strongly associated with response to IFL than MMR status. Results for disease-free survival times were comparable among all analyses.
CONCLUSIONS: Patients with stage III, CIMP-positive, MMR-intact colon tumors have longer survival times when irinotecan is added to combination therapy with fluorouracil and leucovorin.

Bledsoe KL, McGee-Lawrence ME, Camilleri ET, et al.
RUNX3 facilitates growth of Ewing sarcoma cells.
J Cell Physiol. 2014; 229(12):2049-56 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Ewing sarcoma is an aggressive pediatric small round cell tumor that predominantly occurs in bone. Approximately 85% of Ewing sarcomas harbor the EWS/FLI fusion protein, which arises from a chromosomal translocation, t(11:22)(q24:q12). EWS/FLI interacts with numerous lineage-essential transcription factors to maintain mesenchymal progenitors in an undifferentiated state. We previously showed that EWS/FLI binds the osteogenic transcription factor RUNX2 and prevents osteoblast differentiation. In this study, we investigated the role of another Runt-domain protein, RUNX3, in Ewing sarcoma. RUNX3 participates in mesenchymal-derived bone formation and is a context dependent tumor suppressor and oncogene. RUNX3 was detected in all Ewing sarcoma cells examined, whereas RUNX2 was detected in only 73% of specimens. Like RUNX2, RUNX3 binds to EWS/FLI via its Runt domain. EWS/FLI prevented RUNX3 from activating the transcription of a RUNX-responsive reporter, p6OSE2. Stable suppression of RUNX3 expression in the Ewing sarcoma cell line A673 delayed colony growth in anchorage independent soft agar assays and reversed expression of EWS/FLI-responsive genes. These results demonstrate an important role for RUNX3 in Ewing sarcoma.

Li Q, Wang JX, He YQ, et al.
MicroRNA-185 regulates chemotherapeutic sensitivity in gastric cancer by targeting apoptosis repressor with caspase recruitment domain.
Cell Death Dis. 2014; 5:e1197 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Gastric cancer remains the second leading cause of cancer deaths worldwide. Resistance to chemotherapy is a significant barrier for effective cancer treatment. Here, we identified miR-185 to be a contributor to chemosensitivity in gastric cancer. We observed low levels of miR-185 in gastric cancer cell lines and clinical tissues, compared with gastric epithelium cell line and noncancerous tissues. Furthermore, enforced expression of miR-185 increased the sensitivity of gastric cancer cells to low-dose chemotherapeutic agents, which alone cannot trigger significant apoptosis. Conversely, knockdown of endogenous miR-185 prevented high-dose chemotherapy-induced apoptosis. In elucidating the molecular mechanism by which miR-185 participated in the regulation of chemosensitivity in gastric cancer, we discovered that apoptosis repressor with caspase recruitment domain (ARC) is a direct target of miR-185. The role of miR-185 was confirmed in gastric tumor xenograft model. The growth of established tumors was suppressed by a combination therapy using enforced miR-185 expression and a low dose of anticancer drugs. Finally, we found that RUNX3 (Runt-related transcription factor) was involved in the activation of miR-185 at the transcriptional level. Taken together, our results reveal that RUNX3, miR-185 and ARC regulate the sensitivity of gastric cancer cells to chemotherapy.

Bornschein J, Malfertheiner P
Helicobacter pylori and gastric cancer.
Dig Dis. 2014; 32(3):249-64 [PubMed] Related Publications
Infection with Helicobacter pylori is established as the major risk factor for gastric cancer development. Damage of the mucosal barrier due to H. pylori-induced inflammation enhances the carcinogenic effect of other risk factors such as salt intake or tobacco smoking. The genetic disposition of both the bacterial strain and the host can increase the potential towards gastric cancer formation. Genetic variance of the bacterial proteins CagA and VacA is associated with a higher gastric cancer risk, as are polymorphisms and epigenetic changes in host gene coding for interleukins (IL1β, IL8), transcription factors (CDX2, RUNX3) and DNA repair enzymes. Application of high-throughput assays for genome-wide assessment of either genetic structural variance or gene expression patterns may lead to a better understanding of the pathobiological background of these processes, including the underlying signaling pathways. Understanding of the stepwise alterations that take place in the transition from chronic atrophic gastritis, via metaplastic changes, to invasive neoplasia is vital to define the 'point of no return' before which eradication of H. pylori has the potential to prevent gastric cancer. Currently, eradication as preventive strategy is only recommended for high-incidence regions in Asia; large population studies with an adequate follow-up are required to demonstrate the effectiveness of such an approach in Western populations.

Oh JH, Rhyu MG, Jung SH, et al.
Slow overmethylation of housekeeping genes in the body mucosa is associated with the risk for gastric cancer.
Cancer Prev Res (Phila). 2014; 7(6):585-95 [PubMed] Related Publications
Helicobacter pylori infection increases age-related diverse overmethylation in gene-control regions, which increases the risk of gastric cancer. The H. pylori-associated overmethylation changes subsequently disappear when gastric atrophy and cancer develop. To identify cancer-risk epigenotypes, we traced dynamic methylation changes in the background mucosa of the stomach depending on the extent of gastric atrophy. Paired biopsy specimens were obtained from the noncancerous antrum and body mucosa of 102 patients with cancer and 114 H. pylori-positive and 112 H. pylori-negative controls. The grade of gastric atrophy was evaluated using the endoscopic atrophic border score. The methylation-variable sites at the CpG-island margins and near the transcriptional start sites lacking CpG islands were semiquantitatively analyzed by radioisotope-labeling methylation-specific PCR. We selected eight housekeeping genes adjacent to Alu (CDH1, ARRDC4, PPARG, and TRAPPC2L) or LTR retroelements (MMP2, CDKN2A, RUNX2, and RUNX3) and eight stomach-specific genes (TFF2, PGC, ATP4B, TFF1, TFF3, GHRL, PGA, and ATP4A). Analysis of age-related methylation in the H. pylori-positive controls revealed slow overmethylation in the body and in the LTR-adjacent genes. A high-frequency overmethylation defined based on the slowly overmethylated genes was frequently observed in the body of patients with gastric cancer with open-type atrophy (OR, 12.7; 95% confidence interval, 3.2-49.8). The rapidly changing methylation of Alu-adjacent genes was barely increased in the antrum of patients with gastric cancer. Among diverse methylation changes associated with H. pylori infection, an increase in slowly changing methylation could serve as a cancer-risk marker.

Chen HX, Wang S, Wang Z, et al.
Overexpression of RUNX3 inhibits malignant behaviour of Eca109 cells in vitro and vivo.
Asian Pac J Cancer Prev. 2014; 15(4):1531-7 [PubMed] Related Publications
Runt-related transcription factor 3 (RUNX3) is a tumor suppressor gene whose reduced expression may play an important role in the development and progression of esophageal squamous cell cancer (ESCC). The aim of this study was to investigate the clinical relevance of RUNX3 in ESCC patients and effects of overexpression on biological behaviour of Eca109 cells in vitro and in vivo. Immunohistochemistry was performed to detect the clinical relevance of RUNX3 and lymph node metastasis in 80 ESCC tissues and 40 non-cancerous tissues using the SP method. RT-PCR and Western blotting were applied to assess the RUNX3 level and verify the Eca109 cell line with stable overexpression. Localization of RUNX3 proteins was performed by cell immunofluorescence. CCK-8 and Scrape motility assays were used to determine proliferation and migration and the TUNEL assay to analyze cell apoptosis. Invasive potential was assessed in cell transwell invasion experiments. In nude mice, tumorigenesis in vivo was determined. Results showed decreased expression of RUNX3 in esophageal tissue to be significantly related to lymph node metastasis (LNM) (P<0.01). In addition, construction of a recombinant lentiviral vector and transfection into the human ESCC cell line Eca109 demonstrated that overexpression could inhibit cell proliferation, migration and invasion, and induce apoptosis. The in vivo experiments in mice showed tumorigenicity and invasiveness to be significantly reduced. Taken together, our studies indicate that underexpression of RUNX3 in human ESCC tissue is significantly correlated with progression. Restoration of RUNX3 expression significantly inhibits ESCC cells proliferation, migration, invasion and tumorigenesis.

Liu Z, Zhang X, Xu X, et al.
RUNX3 inhibits survivin expression and induces cell apoptosis in gastric cancer.
Eur J Cell Biol. 2014; 93(3):118-26 [PubMed] Related Publications
Transcription factor RUNX3 is associated with gastric tumorigenesis and progression through regulating the expression of its target genes. Survivin is a member of the inhibitor of apoptosis (IAP) family and has been shown to inhibit cell apoptosis and promote cell proliferation. Increased survivin expression has been found in various cancer types, including gastric cancer. In this study, we found that restoration of RUNX3 promotes cell apoptosis through inhibiting the survivin expression, while RUNX3 inhibition increases the expression of survivin in gastric cancer cell lines. Moreover, RUNX3 over-expression inhibits,whereas its inhibition increases, the promoter activity of survivin gene, respectively. RUNX3-R122C, a mutation located in the conserved Runt domain, has no effect on the promoter activity of survivin gene. We further identified a RUNX3-binding site in the promoter of survivin gene and the binding of RUNX3 on survivin promoter leads to significantly inhibition of survivin expression. Finally, we confirmed the negative correlation of RUNX3 and survivin expression in clinical specimens of gastric cancer. These findings reveal a novel mechanism of RUNX3 for the induction of cell apoptosis in human gastric cancer.

Wang L, Li D, Liu Y, et al.
Expression of RUNX3 and β-catenin in the carcinogenesis of sporadic colorectal tubular adenoma.
Tumour Biol. 2014; 35(6):6039-46 [PubMed] Related Publications
The aim of this study is to investigate the possible roles of runt-related transcription factor 3 (RUNX3) and β-catenin in the carcinogenesis of sporadic colorectal tubular adenomas. The expression of the RUNX3 and β-catenin proteins was evaluated by immunohistochemistry in 23 normal colorectal mucosa (NCM), 81 sporadic colorectal tubular adenomas with different dysplasias (SCTA-D) (mild n=33, moderate n=23, and severe n=25 dysplasia), and 48 sporadic colorectal tubular adenomas with cancerous changes (SCTA-Ca). RUNX3 methylation was assessed by methylation-specific polymerase chain reaction (MSP), combined with laser capture microdissection (LCM), in 17 NCM, 41 SCTA-D (mild n=15, moderate n=12, and severe n=14 dysplasia), and 17 SCTA-Ca tissues. Compared to NCM (82.6 %), RUNX3 in SCTA-D (54.3 %) and SCTA-Ca (27.1 %) was significantly downregulated (P<0.05). In NCM, SCTA-D, and SCTA-Ca, the incidence of positive expression for β-catenin was 13.0, 60.5, and 79.2 %, respectively. A statistically significant difference was observed (P<0.05). RUNX3 levels were markedly higher in adenoma with mild dysplasia (75.8 %) and moderate dysplasia (60.9 %) than in adenoma with severe dysplasia (20.0 %) (both with P<0.05). Likewise, the expression of β-catenin in severe dysplasia adenoma was 84.0 %, which was significantly higher than that in mild dysplasia adenoma (39.4 %). An inverse correlation was found between the protein expression of RUNX3 and β-catenin in SCTA-D and SCTA-Ca (P<0.05). MSP results showed that RUNX3 methylation in NCM, SCTA-D, and SCTA-Ca was 5.9, 17.1, and 41.2 %, respectively, with a statistically significant difference between NCM and SCTA-Ca (P<0.05). However, no significant difference of RUNX3 methylation was observed among different dysplasia groups. RUNX3 and β-catenin play important roles in the carcinogenesis of sporadic colorectal tubular adenomas. In addition, hypermethylation of RUNX3 can downregulate its expression.

García-Baquero R, Puerta P, Beltran M, et al.
Methylation of tumor suppressor genes in a novel panel predicts clinical outcome in paraffin-embedded bladder tumors.
Tumour Biol. 2014; 35(6):5777-86 [PubMed] Related Publications
DNA methylation of tumor suppressor genes (TSGs) represents a frequent and early epigenetic event with potential applications for cancer detection and disease evolution. Our aim was to examine the stratification and prognostic biomarker role of the methylation of a novel panel of TSGs in bladder cancer. The methylation status of 18 TSGs was evaluated in bladder cancer cells (n=14) and paraffin-embedded primary bladder tumors (n=61), using a methylation-specific multiplex ligation-dependent probe amplification assay (MS-MLPA). Recurrence, progression, and disease-specific survival were analyzed using univariate and multivariate Cox models. PRDM2, HLTF, ID4, DLC1, BNIP3, H2AFX, CACNA1G, TGIF, and CACNA1A were discovered methylated in bladder cancer. The methylation of RUNX3 (p=0.026), TWIST1 (p=0.009), SFRP4 (p=0.002), and CCND2 (p=0.027) correlated to tumor stage. Univariate analyses indicated prognostic associations for recurrence (DLC1, SFRP5, H2AFX, CACNA1G), progression (DLC1, SFRP5, CACNA1G), disease-specific (PRDM2, DLC1, SFRP5, CACNA1G, and TIMP3), and overall survival (SFRP5 and TIMP3). In multivariate analyses, several TSGs remained as independent prognosticators for recurrence (SFRP5, H2AFX), progression (CACNA1G), and disease-specific survival (SFRP5). Thus, a novel set of TSGs was identified, frequently methylated in bladder cancer cells and tumors. TSG methylation allowed histopathologic and outcome stratification using paraffin-embedded tumors. This is clinically relevant by offering a strategy for the management of patients affected with uroepithelial neoplasias in pathology routine laboratories.

Wang S, Liu H, Wang Z, Chen HX
Effects of 5-azacytidine on RUNX3 gene expression and the biological behavior of esophageal carcinoma cells.
Mol Med Rep. 2014; 9(4):1259-65 [PubMed] Related Publications
The present study investigated the effects of 5-azacytidine (5-azaC) on the expression level of the human runt-related transcription factor 3 (RUNX3) gene and the biological behavior of esophageal carcinoma Eca109 cells. The effect of the demethylation reagent 5-azaC on the viability of Eca109 cells was detected by the MTT assay, which demonstrated that 5-azaC inhibited the viability of Eca109 cells in a time- and dose-dependent manner. Although demethylation of other genes may occur following treatment with 5-azaC, we focused on the RUNX3 gene. When treated with 5-azaC at hypoxic levels, the expression of RUNX3 increased and the methylation degree of the RUNX3 gene was decreased significantly in Eca109 cells. 5-azaC at 50 µM demonstrated the highest RUNX3-induction activity, inducing RUNX3 mRNA and protein expression, and decreasing the degree of methylation of the RUNX3 gene. Methylation specific PCR indicated that 5-azaC induced RUNX3 expression through demethylation. The abilities of migration and invasion of Eca109 cells were inhibited by 5-azaC. The growth of Eca109 cells treated with 5-azaC in vivo was detected by a tumorigenesis experiment. 5-azaC inhibited the growth of Eca109 xenografts in nude mice. Taken together, our findings demonstrated that the RUNX3 gene is hypermethylated in Eca109 cells and that 5-azaC induces the expression of the RUNX3 gene by demethylation, which inhibits the proliferation, migration and invasion of Eca109 cells.

Chen F, Wang M, Bai J, et al.
Role of RUNX3 in suppressing metastasis and angiogenesis of human prostate cancer.
PLoS One. 2014; 9(1):e86917 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
RUNX3 (runt-related transcription factor-3) has been reported to suppress tumor tumorigenesis and metastasis in different human cancers. In this study, we used tissue microarray (TMA) to determine the significance of RUNX3 in prostate cancer progession. Our results showed ectopic expression of RUNX3 in prostate cancer tissues when compared with tumor adjacent normal prostate tissues, and reduced RUNX3 staining was significantly correlated with TNM stage. Moreover, we demonstrated that RUNX3 overexpression inhibited prostate cancer cell migration and invasion resulting from the elevated upregulation of tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), which subsequently inhibited metalloproteinase-2 (MMP-2) expression and activity in vitro. Knock down of RUNX3 expression broke up the balance of TIMP-2/MMP-2, whereas silence of TIMP-2 resulted in the inhibition of MMP-2 expression in prostate cells. We also showed that restoration of RUNX3 decreased vascular endothelial growth factor (VEGF) secretion and suppressed endothelial cell growth and tube formation. Strikingly, RUNX3 was demonstrated to inhibit tumor metastasis and angiogenesis in vivo. Altogether, our results support the tumor suppressive role of RUNX3 in human prostate cancer, and provide insights into development of targeted therapy for this disease.

Berg M, Hagland HR, Søreide K
Comparison of CpG island methylator phenotype (CIMP) frequency in colon cancer using different probe- and gene-specific scoring alternatives on recommended multi-gene panels.
PLoS One. 2014; 9(1):e86657 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: In colorectal cancer a distinct subgroup of tumours demonstrate the CpG island methylator phenotype (CIMP). However, a consensus of how to score CIMP is not reached, and variation in definition may influence the reported CIMP prevalence in tumours. Thus, we sought to compare currently suggested definitions and cut-offs for methylation markers and how they influence CIMP classification in colon cancer.
METHODS: Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), with subsequent fragment analysis, was used to investigate methylation of tumour samples. In total, 31 CpG sites, located in 8 different genes (RUNX3, MLH1, NEUROG1, CDKN2A, IGF2, CRABP1, SOCS1 and CACNA1G) were investigated in 64 distinct colon cancers and 2 colon cancer cell lines. The Ogino gene panel includes all 8 genes, in addition to the Weisenberger panel of which only 5 of the 8 genes included were investigated. In total, 18 alternative combinations of scoring of CIMP positivity on probe-, gene-, and panel-level were analysed and compared.
RESULTS: For 47 samples (71%), the CIMP status was constant and independent of criteria used for scoring; 34 samples were constantly scored as CIMP negative, and 13 (20%) consistently scored as CIMP positive. Only four of 31 probes (13%) investigated showed no difference in the numbers of positive samples using the different cut-offs. Within the panels a trend was observed that increasing the gene-level stringency resulted in a larger difference in CIMP positive samples than increasing the probe-level stringency. A significant difference between positive samples using 'the most stringent' as compared to 'the least stringent' criteria (20% vs 46%, respectively; p<0.005) was demonstrated.
CONCLUSIONS: A statistical significant variation in the frequency of CIMP depending on the cut-offs and genes included in a panel was found, with twice as many positives samples by least compared to most stringent definition used.

Liu Z, Chen L, Zhang X, et al.
RUNX3 regulates vimentin expression via miR-30a during epithelial-mesenchymal transition in gastric cancer cells.
J Cell Mol Med. 2014; 18(4):610-23 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Runt-related transcription factor 3 (RUNX3) is a putative tumour suppressor via regulating the expression of a series of target genes. Clinical studies demonstrated that loss of RUNX3 expression is associated with gastric cancer progression and poor prognosis, but the underlying mechanism is not entirely clear. Accumulating evidence shows that the epithelial-mesenchymal transition (EMT) plays an important role in cancer relapse and metastasis. Therefore, we addressed whether RUNX3 has a role in the EMT in gastric cancer. Knockdown of RUNX3 promoted cell invasion and increased the protein expression of the mesenchymal marker vimentin in human gastric cancer cells. Overexpression of RUNX3 suppressed cell invasion and decreased the protein expression of vimentin in the cells and inhibited gastric cancer cells colonization in nude mice. Furthermore, overexpression of RUNX3 increased the expression of microRNA-30a (miR-30a), and miR-30a directly targeted the 3' untranslated region of vimentin and decreased its protein level. miR-30a inhibitor abrogated RUNX3-mediated inhibition of cell invasion and downregulation of vimentin. Thus, RUNX3 suppressed gastric cancer cell invasion and vimentin expression by activating miR-30a. In gastric cancer patients, levels of RUNX3 were positively correlated with miR-30a and negatively associated with the levels of vimentin. Collectively, our data suggest a novel molecular mechanism for the tumour suppressor activity of RUNX3. Effective therapy targeting the RUNX3 pathway may help control gastric cancer cell invasion and metastasis by inhibiting the EMT.

Ju X, Ishikawa TO, Naka K, et al.
Context-dependent activation of Wnt signaling by tumor suppressor RUNX3 in gastric cancer cells.
Cancer Sci. 2014; 105(4):418-24 [PubMed] Related Publications
RUNX3 is a tumor suppressor for a variety of cancers. RUNX3 suppresses the canonical Wnt signaling pathway by binding to the TCF4/β-catenin complex, resulting in the inhibition of binding of the complex to the Wnt target gene promoter. Here, we confirmed that RUNX3 suppressed Wnt signaling activity in several gastric cancer cell lines; however, we found that RUNX3 increased the Wnt signaling activity in KatoIII and SNU668 gastric cancer cells. Notably, RUNX3 expression increased the ratio of the Wnt signaling-high population in the KatoIII cells. although the maximum Wnt activation level of individual cells was similar to that in the control. As found previously, RUNX3 also binds to TCF4 and β-catenin in KatoIII cells, suggesting that these molecules form a ternary complex. Moreover, the ChIP analyses revealed that TCF4, β-catenin and RUNX3 bind the promoter region of the Wnt target genes, Axin2 and c-Myc, and the occupancy of TCF4 and β-catenin in these promoter regions is increased by the RUNX3 expression. These results suggest that RUNX3 stabilizes the TCF4/β-catenin complex on the Wnt target gene promoter in KatoIII cells, leading to activation of Wnt signaling. Although RUNX3 increased the Wnt signaling activity, its expression resulted in suppression of tumorigenesis of KatoIII cells, indicating that RUNX3 plays a tumor-suppressing role in KatoIII cells through a Wnt-independent mechanism. These results indicate that RUNX3 can either suppress or activate the Wnt signaling pathway through its binding to the TCF4/β-catenin complex by cell context-dependent mechanisms.

Moon JW, Lee SK, Lee JO, et al.
Demethylation of RUNX3 by vincristine in colorectal adenocarcinoma cells.
Anticancer Res. 2014; 34(1):133-40 [PubMed] Related Publications
BACKGROUND: Methylation-mediated inactivation of tumor-suppressor genes is a critical event during the pathogenesis of many malignancies. Vincristine is a conventional anticancer drug used to treat various types of cancers. However, few studies describe the epigenetic-based effects of vincristine. In this study, changes in the methylation of runt-related transcription factor-3 (RUNX3) were investigated in CCD18Co normal colon cells and DLD-1 colorectal adenocarcinoma cells.
MATERIALS AND METHODS: CCD18Co and DLD-1 cells were treated with vincristine, and the methylation status was assessed using quantitative methylation-specific polymerase chain reaction (QMSP). Eleven normal colon tissues and 105 colorectal cancer tissues were investigated by methylation and mRNA expression of RUNX3 using QMSP and real-time reverse transcription polymerase chain reaction (real time-PCR).
RESULTS: RUNX3 was demethylated after vincristine treatment in DLD-1 cells. The expression of RUNX3 mRNA was down-regulated in DLD-1 cells because of DNA hypermethylation, but was restored after vincristine treatment. In addition, hypermethylation of RUNX3 was detected in 70 out of 105 colorectal carcinomas (66.7%). RUNX3 hypermethylation was greater in colon cancer tissues than in rectal cancer tissues. The expression of RUNX3 mRNA was reduced in 68 out of 105 colorectal cancer tissues (64.8%).
CONCLUSION: These results demonstrate that vincristine demethylates RUNX3 in colorectal adenocarcinoma cells, and restores its expression.

Jiang S, Willox B, Zhou H, et al.
Epstein-Barr virus nuclear antigen 3C binds to BATF/IRF4 or SPI1/IRF4 composite sites and recruits Sin3A to repress CDKN2A.
Proc Natl Acad Sci U S A. 2014; 111(1):421-6 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Epstein-Barr virus nuclear antigen 3C (EBNA3C) repression of CDKN2A p14(ARF) and p16(INK4A) is essential for immortal human B-lymphoblastoid cell line (LCL) growth. EBNA3C ChIP-sequencing identified >13,000 EBNA3C sites in LCL DNA. Most EBNA3C sites were associated with active transcription; 64% were strong H3K4me1- and H3K27ac-marked enhancers and 16% were active promoters marked by H3K4me3 and H3K9ac. Using ENCODE LCL transcription factor ChIP-sequencing data, EBNA3C sites coincided (±250 bp) with RUNX3 (64%), BATF (55%), ATF2 (51%), IRF4 (41%), MEF2A (35%), PAX5 (34%), SPI1 (29%), BCL11a (28%), SP1 (26%), TCF12 (23%), NF-κB (23%), POU2F2 (23%), and RBPJ (16%). EBNA3C sites separated into five distinct clusters: (i) Sin3A, (ii) EBNA2/RBPJ, (iii) SPI1, and (iv) strong or (v) weak BATF/IRF4. EBNA3C signals were positively affected by RUNX3, BATF/IRF4 (AICE) and SPI1/IRF4 (EICE) cooccupancy. Gene set enrichment analyses correlated EBNA3C/Sin3A promoter sites with transcription down-regulation (P < 1.6 × 10(-4)). EBNA3C signals were strongest at BATF/IRF4 and SPI1/IRF4 composite sites. EBNA3C bound strongly to the p14(ARF) promoter through SPI1/IRF4/BATF/RUNX3, establishing RBPJ-, Sin3A-, and REST-mediated repression. EBNA3C immune precipitated with Sin3A and conditional EBNA3C inactivation significantly decreased Sin3A binding at the p14(ARF) promoter (P < 0.05). These data support a model in which EBNA3C binds strongly to BATF/IRF4/SPI1/RUNX3 sites to enhance transcription and recruits RBPJ/Sin3A- and REST/NRSF-repressive complexes to repress p14(ARF) and p16(INK4A) expression.

Stewart DJ
Wnt signaling pathway in non-small cell lung cancer.
J Natl Cancer Inst. 2014; 106(1):djt356 [PubMed] Related Publications
Wnt/β-catenin alterations are prominent in human malignancies. In non-small cell lung cancer (NSCLC), β-catenin and APC mutations are uncommon, but Wnt signaling is important in NSCLC cell lines, and Wnt inhibition reduces proliferation. Overexpression of Wnt-1, -2, -3, and -5a and of Wnt-pathway components Frizzled-8, Dishevelled, Porcupine, and TCF-4 is common in resected NSCLC and is associated with poor prognosis. Conversely, noncanonical Wnt-7a suppresses NSCLC development and is often downregulated. Although β-catenin is often expressed in NSCLCs, it was paradoxically associated with improved prognosis in some series, possibly because of E-cadherin interactions. Downregulation of Wnt inhibitors (eg, by hypermethylation) is common in NSCLC tumor cell lines and resected samples; may be associated with high stage, dedifferentiation, and poor prognosis; and has been reported for AXIN, sFRPs 1-5, WIF-1, Dkk-1, Dkk-3, HDPR1, RUNX3, APC, CDX2, DACT2, TMEM88, Chibby, NKD1, EMX2, ING4, and miR-487b. AXIN is also destabilized by tankyrases, and GSK3β may be inactivated through phosphorylation by EGFR. Preclinically, restoration of Wnt inhibitor function is associated with reduced Wnt signaling, decreased cell proliferation, and increased apoptosis. Wnt signaling may also augment resistance to cisplatin, docetaxel, and radiotherapy, and Wnt inhibitors may restore sensitivity. Overall, available data indicate that Wnt signaling substantially impacts NSCLC tumorigenesis, prognosis, and resistance to therapy, with loss of Wnt signaling inhibitors by promoter hypermethylation or other mechanisms appearing to be particularly important. Wnt pathway antagonists warrant exploration clinically in NSCLC. Agents blocking selected specific β-catenin interactions and approaches to increase expression of downregulated Wnt inhibitors may be of particular interest.

Lee YS, Lee JW, Jang JW, et al.
Runx3 inactivation is a crucial early event in the development of lung adenocarcinoma.
Cancer Cell. 2013; 24(5):603-16 [PubMed] Related Publications
Targeted inactivation of Runx3 in mouse lung induced mucinous and nonmucinous adenomas and markedly shortened latency of adenocarcinoma formation induced by oncogenic K-Ras. RUNX3 was frequently inactivated in K-RAS mutated human lung adenocarcinomas. A functional genetic screen of a fly mutant library and molecular analysis in cultured cell lines revealed that Runx3 forms a complex with BRD2 in a K-Ras-dependent manner in the early phase of the cell cycle; this complex induces expression of p14(ARF)/p19(Arf) and p21(WAF/CIP). When K-Ras was constitutively activated, the Runx3-BRD2 complex was stably maintained and expression of both p14(ARF) and p21(WAF/CIP) was prolonged. These results provide a missing link between oncogenic K-Ras and the p14(ARF)-p53 pathway, and may explain how cells defend against oncogenic K-Ras.

Wang S, Liu H, Akhtar J, et al.
Alteration of runt-related transcription factor 3 gene expression and biologic behavior of esophageal carcinoma TE-1 cells after 5-azacytidine intervention.
Asian Pac J Cancer Prev. 2013; 14(9):5427-33 [PubMed] Related Publications
5-Azacytidine (5-azaC) was originally identified as an anticancer drug (NSC102876) which can cause hypomethylation of tumor suppressor genes. To assess its effects on runt-related transcription factor 3 (RUNX3), expression levels and the promoter methylation status of the RUNX3 gene were assessed. We also investigated alteration of biologic behavior of esophageal carcinoma TE-1 cells. MTT assays showed 5-azaC inhibited the proliferation of TE-1 cells in a time and dose-dependent way. Although other genes could be demethylated after 5-azaC intervention, we focused on RUNX3 gene in this study. The expression level of RUNX3 mRNA increased significantly in TE-1 cells after treatment with 5-azaC at hypotoxic levels. RT-PCR showed 5-azaC at 50 μM had the highest RUNX3-induction activity. Methylation-specific PCR indicated that 5-azaC induced RUNX3 expression through demethylation. Migration and invasion of TE-1 cells were inhibited by 5-azaC, along with growth of Eca109 xenografts in nude mice. In conclusion, we demonstrate that the RUNX3 gene can be reactivated by the demethylation reagent 5-azaC, which inhibits the proliferation, migration and invasion of esophageal carcinoma TE-1 cells.

Fu HY, Wu DS, Zhou HR, Shen JZ
CpG island methylator phenotype and its relationship with prognosis in adult acute leukemia patients.
Hematology. 2014; 19(6):329-37 [PubMed] Related Publications
OBJECTIVE: To investigated the relationship between CpG island methylator phenotype (CIMP) and prognosis in adults with acute leukemia.
METHODS: Bone marrow samples from 53 acute myeloid leukemia and 50 acute lymphoblastic leukemia patients were collected. The methylation status of 18 tumor suppressor genes was determined using methylation-specific polymerase chain reaction.
RESULTS: Greater than 30% of acute leukemia patients had methylated p15, p16, CDH1, CDH13, RUNX3, sFRP1, ID4, and DLC-1 genes; methylation of ≥4 were defined as CIMP positive. Age, type of leukemia, white blood cell count, and CIMP status were significantly associated with recurrence-free survival (RFS) and overall survival (OS) (P < 0.05). CIMP status was an independent prognostic factor for OS (hazard ratio: 2.07, 95% confidence interval: 1.03-4.15, P = 0.040). CIMP-negative patients had significantly improved RFS and OS (P < 0.05). p16 and DLC1 methylation was significantly associated with RFS and OS (P < 0.05).
CONCLUSIONS: CIMP may serve as an independent risk factor for evaluating the prognosis of patients with acute leukemia.

Kang KA, Piao MJ, Kim KC, et al.
Compound K, a metabolite of ginseng saponin, inhibits colorectal cancer cell growth and induces apoptosis through inhibition of histone deacetylase activity.
Int J Oncol. 2013; 43(6):1907-14 [PubMed] Related Publications
In this study, we investigated the molecular mechanisms underlying the anti-proliferative effects of Compound K, with specific reference to histone modification. Exposure of HT-29 human colon cancer cells to Compound K resulted in time-dependent inhibition of histone deacetylase (HDAC) activity, mRNA and protein expression. Compound K treatment induced unmethylation of the RUNX3 promoter region such as TSA treatment and an accumulation of acetylated histones H3 and H4 within the total cellular chromatin, resulting in an enhanced ability of these histones to bind to the promoter sequences of the tumor suppressor gene Runt-related transcription factor 3 (RUNX3). Treatment of cells with Compound K increased the mRNA and protein expression of RUNX3, as well as p21, a downstream target of RUNX3. These alterations were consistent with cell cycle arrest at the G0/G1 phases and induction of apoptosis. Our results provide new insights into the mechanisms of Compound K action in human colorectal cancer cells and suggest that HDAC inhibition presents a novel approach to prevent or treat colorectal cancer.

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