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RUNX3

runt-related transcription factor 3;RUNX3;runt-related transcription factor 3

CBF-alpha-3|PEA2 alpha C|PEA2-alpha C|PEBP2 alpha C|PEBP2-alpha C|SL3-3 enhancer factor 1 alpha C subunit|SL3/AKV core-binding factor alpha C subunit|acute myeloid leukemia 2 protein|acute myeloid leukemia gene 2|core-binding factor subunit alpha-3|core-b

1p36

protein-coding

Here we presented that the expression of RUNX3 was significantly decreased in 75 cases of clear cell renal cell carcinoma (CCRCC) tissues (p<0.05). Enforced RUNX3 expression mediated 786-O cells to exhibit inhibition of growth, G1 cell-cycle arrest and metastasis in vitro, and to lost tumorigenicity in nude mouse model in vivo. RUNX3-induced growth suppression was found partially to regulate various proteins, including inhibition of cyclinD1, cyclinE, cdk2, cdk4 and p-Rb, but increase of p27(Kip1), Rb and TIMP-1. Therefore, RUNX3 had the function of inhibiting the proliferative and metastatic abilities of CCRCC cells by regulating cyclins and TIMP1.

BACKGROUND: RUNX3 is a major growth regulator of gastric epithelial cells that is involved in gastric tumorigenesis in both humans and mice. In this study, we investigated the involvement of RUNX3 in tumor progression, and in the prognosis of human gastric cancer. METHODS: We analyzed the extent of RUNX3 protein expression by immunohistochemistry in 95 primary gastric adenocarcinomas, and correlated expression levels with clinicopathological parameters. We examined the effects of pFlag/RUNX3 on cell growth, apoptosis, and caspase-3 expression in AGS and SNU1 gastric cancer cell lines by colony-forming assay, terminal deoxynucleotidyl transferase (TdT)-mediate deoxyuridine triphosphatase (dUTP) nick-end labeling (TUNEL) assay, and Western blot analysis, respectively. The pFlag/RUNX3 effects on AGS invasion and migration potentials were also evaluated. RESULTS: RUNX3 expression was lost in 37 (39%) cases of gastric cancer. The expression of RUNX3 in diffuse- and mixed-type cancers was less frequent than expression in intestinal-type cancer (P < 0.001 and P = 0.001, respectively). In addition, the loss of RUNX3 expression was associated with lymph node metastasis (P = 0.02), and correlated with poor gastric cancer survival (P = 0.018). The growth of gastric cancer cells was suppressed after pFlag/RUNX3 transfection. The re-expression of RUNX3 resulted in the upregulation of caspase-3 and promoted apoptosis. Furthermore, Re-expression of RUNX3 induced significant inhibitions of AGS cell invasion and migration in vitro. CONCLUSIONS: This work shows that loss of RUNX3 expression is highly associated with lymph node metastasis and poor prognosis of gastric cancer. The re-expression of RUNX3 may induce apoptosis and inhibit the growth as well as invasion/migration of cancer cells. These results indicate that the targeting of the RUNX3 pathway could represent a potential modality for treating gastric cancer.

Recent studies have suggested that loss of RUNX3 expression is involved with gastric tumor metastasis. However, the precise mechanism of RUNX3-mediated suppression of tumor metastasis remains elusive. We aimed to clarify the effect of RUNX3 on tumor metastasis in gastric cancer cell lines and tumors. Immunohistochemistry revealed that RUNX3 was significantly decreased in metastatic gastric cancer. Gelatin zymography and Western blot showed that instead of regulating matrix metalloproteinase 9 (MMP9) expression, RUNX3 expression inhibited MMP9 enzyme activity, and this was consistent with the upregulation of tissue inhibitor of metalloproteinases 1 (TIMP1) by RUNX3. TIMP1 siRNA treatment impaired RUNX3-mediated suppression of gastric cancer cell invasion. Reporter assays demonstrated regulation of TIMP-1 by RUNX3. Two RUNX3 binding sites were identified in the TIMP-1 promoter and direct interaction of RUNX3 with the TIMP-1 promoter was confirmed in vitro and in vivo. These findings provide evidence for RUNX3-mediated suppression of gastric cancer invasion and metastasis and define a novel molecular mechanism that for the metastasis-inhibiting activity of RUNX3. These data may be applied in the development of RUNX3 for gastric cancer metastasis diagnostics and therapeutics.

OBJECTIVE: To explore the relationships between hypermethylation of human runt-related transcription factor 3 (Runx3) gene promoter and laryngeal squamous cell cancer. METHOD: Promoter hypermethylation and mRNA expression were detected by methylation-specific PCR and RT-PCR. RESULT: The expression of Runx3 gene mRNA detected in laryngeal carcinoma (1.62 +/- 1.01) was lower than that in adjacent tissues samples (5.66 +/- 2.07) (t = 10.72, P < 0.01). No methylation of Runx3 promoter was found in adjacent tissues samples. But hypermethylation was found in 95.0% (38/40) of the laryngeal carcinoma specimens. The rate of methylation of Runx3 promoter in laryngeal carcinoma was higher than that in adjacent tissues (P < 0.01). The Runx3 mRNA were down-regulated in lymphnode metastasis or poorly differentiated groups, but the Runx3 promoter methylation were detected in those groups markedly. CONCLUSION: Hypermethylation of Runx3 promoter is one of the inactivation re-seasons in laryngeal squamous cell carcinoma, and the decreasing of Runx3 mRNA expression may be related to lymph node metastasis and development of laryngeal squamous cell carcinoma.

Here we presented that the expression of RUNX3 was significantly decreased in 75 cases of clear cell renal cell carcinoma (CCRCC) tissues (p<0.05). Enforced RUNX3 expression mediated 786-O cells to exhibit inhibition of growth, G1 cell-cycle arrest and metastasis in vitro, and to lost tumorigenicity in nude mouse model in vivo. RUNX3-induced growth suppression was found partially to regulate various proteins, including inhibition of cyclinD1, cyclinE, cdk2, cdk4 and p-Rb, but increase of p27(Kip1), Rb and TIMP-1. Therefore, RUNX3 had the function of inhibiting the proliferative and metastatic abilities of CCRCC cells by regulating cyclins and TIMP1.