RUNX3 is multifunctional in carcinogenesis of multiple solid tumors

Chuang, Linda Shyue Huey; Ito, Yoshiaki

doi:10.1038/onc.2010.88

Cited by 126 publications

(136 citation statements)

References 104 publications

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“…Inactivation or loss of RUNX3 proteins, caused by promoter hypermethylation, loss of heterozygosity on chromosome 1p, point mutation at RUNX3-R122C and protein mislocalization, can be detected in over 80% of gastric cancers (Li et al, 2002;Ito et al, 2005;Yanada et al, 2005;Gargano et al, 2007). RUNX3 has been regarded as a tumor suppressor that is involved in the TGF-b-mediated signaling pathway by interacting with Smad2/3, Smad4, p300 and FoxO3a to regulate the transcription of target genes (Chuang and Ito, 2010). RUNX3 suppresses gastric tumorigenesis through upregulating p21 WAF1/Cip1 (Chi et al, 2005), Bim (Yano et al, 2006) and Claudin-1 (Chang et al, 2010), and downregulating VEGF (Peng et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

RUNX3-mediated transcriptional inhibition of Akt suppresses tumorigenesis of human gastric cancer cells

et al. 2012

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Activation of Akt signaling pathway has been suggested involving in chemoresistance, metastasis and tumorigenesis of gastric cancer. However, the mechanism of Akt regulation in gastric cancer is not fully understood. RUNX3, which was first identified as a transcription factor, suppresses gastric tumorigenesis through regulating expression of target genes. Here, we found that restoration of RUNX3 significantly downregulates the protein and mRNA expression of Akt1 in gastric cancer cell lines, AGS and SNU-1. Knockdown of RUNX3 upregulates protein and mRNA expression of Akt1 in normal gastric epithelial cell line, GES-1. The negative correlation of RUNX3 and Akt expression and downstream b-catenin/cyclin D1 effectors was further confirmed in AGS and GES-1 cell lines, as well as clinical specimens of gastric cancer. We identified two RUNX3-binding sites in Akt1 promoter and the binding of RUNX3 on Akt1 promoter significantly inhibits Akt1 expression. The RUNX3-mediated inhibition of Akt1 caused b-catenin protein degradation and then cyclin D1 downregulation. Restoration of cyclin D1 reverses cell growth inhibition and G1 phase arrest induced by RUNX3 in gastric cancer cells. Our results show that loss of RUNX3 expression can enhance the Akt1-mediated signaling pathway and promote the tumorigenesis process in human gastric cancer.

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Section: Introductionmentioning

confidence: 99%

RUNX3-mediated transcriptional inhibition of Akt suppresses tumorigenesis of human gastric cancer cells

et al. 2012

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“…pylori infection, the major risk factor for GC, contributes to the inactivation of RUNX3 in gastric epithelial cells in various ways, including promoter hypermethylation with mediation of nitric oxide (NO) produced by macrophages after the induction of H. pylori infection 42 ; inflammation and oxidative stress triggered by H. pylori infection 43 ; CagA-dependent, proteasomemediated degradation 38 ; and CagA inhibition of RUNX3 expression through the v-src sarcoma viral oncogene/ mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Src/MEK/ERK) and p38 mitogenactivated protein kinase (MAPK) pathways in gastric epithelial cells. 44 In all of these, aberrant methylation has been widely investigated.…”

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confidence: 99%

Stepwise cumulation of RUNX3 methylation mediated by Helicobacter pylori infection contributes to gastric carcinoma progression

Liu

et al. 2012

Cancer

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BACKGROUND: Helicobacter pylori has been recognized as a definite carcinogen for gastric cancer (GC); however, the pathogenesis of H. pylori infection remains unclear. Runt-related transcription factor 3 (RUNX3) is a candidate tumor suppressor gene whose deficiency is causally related to GC. However, in H. pylori infection-associated GC, the role of RUNX3 has not been studied. METHODS: The authors used real-time methylation-specific polymerase chain reaction analysis to determine methylation status of the RUNX3 promoter in a spectrum of gastric lesions, including 220 samples of chronic atrophic gastritis, 196 samples of intestinal metaplasia, 134 samples of gastric adenoma, 102 samples of dysplasia, and 202 samples of GC with paired noncancerous mucosa tissues and corresponding blood specimens. The association of abnormal methylation with precancerous gastric lesions was evaluated along with the association between RUNX3 methylation and H. pylori infection, and the concordance of methylation levels was investigated between serum and tissues. RESULTS: The results indicated that increasing RUNX3 promoter methylation was correlated with distinct stages of GC progression. GC tissues had the highest methylation proportion (75.2%) compared with precancerous gastric lesions, including chronic atrophic gastritis (15.9%), intestinal metaplasia (36.7%), gastric adenoma (41.8%), and dysplasia (54.9%). H. pylori infection, a major risk factor for GC, contributed to the inactivation of RUNX3 in gastric epithelial cells through promoter hypermethylation. The levels of RUNX3 methylation in serum were in significant concordance with the methylation levels observed in GC tissues (P ¼ .887). CONCLUSIONS: The current findings supported RUNX3 methylation as a risk factors for the carcinogenesis of chronic atrophic gastritis with H. pylori infection and indicated that circulating RUNX3 methylation is a valuable biomarker for the detection of early GC.

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“…Approximately 45-60% of human gastric cancers display a loss of RUNX3 expression due to hemizygous deletion and promoter hypermethylation (14). By interacting with Smad2/3, Smad4, p300, and FoxO3a to regulate the transcription of target genes, RUNX3 is involved in the TGF-β-mediated signaling pathway (15). RUNX3 suppresses gastric tumorigenesis by upregulating p21 (16), Bim (17), and Claudin-1 (18).…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress induces proliferation of colorectal cancer cells by inhibiting RUNX3 and activating the Akt signaling pathway

Kang

Kim

Bae

et al. 2013

International Journal of Oncology

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Abstract. We recently reported that the tumor suppressor Runt-related transcription factor 3 (RUNX3) is silenced in colorectal cancer cells via oxidative stress-induced hypermethylation of its promoter. The resulting downregulation of RUNX3 expression influences cell proliferation. Activation of the Akt signaling pathway is also associated with cell survival and proliferation; however, the effects of oxidative stress on the relationship between RUNX3 and Akt signaling are largely unknown. Therefore, this study investigated the mechanisms involved in cell proliferation caused by oxidative stress-induced silencing of RUNX3. The levels of RUNX3 mRNA and protein were downregulated in response to treatment of the human colorectal cancer cell line SNU-407 with H 2 O 2 . Treatment of the cells with H 2 O 2 also upregulated Akt mRNA and protein expression, and inhibited the binding of RUNX3 to the Akt promoter. The inverse correlation between the expression levels of RUNX3 and Akt in H 2 O 2 -treated cells was also associated with nuclear translocation of β-catenin and upregulation of cyclin D1 expression, which induced cell proliferation. H 2 O 2 treatment also increased the binding of β-catenin to the cyclin D1 promoter. The results presented here demonstrate that reactive oxygen species silence the tumor suppressor RUNX3, enhance the Akt-mediated signaling pathway, and promote the proliferation of colorectal cancer cells.

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RUNX3 is multifunctional in carcinogenesis of multiple solid tumors

Cited by 126 publications

References 104 publications

RUNX3-mediated transcriptional inhibition of Akt suppresses tumorigenesis of human gastric cancer cells

RUNX3-mediated transcriptional inhibition of Akt suppresses tumorigenesis of human gastric cancer cells

Stepwise cumulation of RUNX3 methylation mediated by Helicobacter pylori infection contributes to gastric carcinoma progression

Oxidative stress induces proliferation of colorectal cancer cells by inhibiting RUNX3 and activating the Akt signaling pathway

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