Claudin-1 Has Tumor Suppressive Activity and Is a Direct Target of RUNX3 in Gastric Epithelial Cells

Chang, Ti Ling; Ito, Kosei; Ko, Tun Kiat; Liu, Qiang; Salto-Tellez, Manuel; Yeoh, Khay Guan; Fukamachi, Hiroshi; Ito, Yoshiaki

doi:10.1053/j.gastro.2009.08.044

Cited by 82 publications

(77 citation statements)

References 46 publications

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“…We found recently that claudin-1 is a direct and positive target of Runx3 and that Runx3 À/À -derived gastric epithelial cells have reduced levels of claudin-1 and increased tumorigenic potential when compared with the Runx3 þ / þ cells. This is partly because Runx3 cooperates with TGF-b effectors Smads to directly upregulate claudin-1 transcription (Chang et al, 2010). As the expression of claudin-1 inhibits proliferation in gastric cancer cells, these findings present another mechanism underlying RUNX3's tumor suppressive effects and invite speculation on the function of RUNX3 during later stages of cancer.…”

Section: Molecular Mechanisms That Underlie Runx3's Anti-tumor Propermentioning

confidence: 92%

RUNX3 is multifunctional in carcinogenesis of multiple solid tumors

2010

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The study of RUNX3 in tumor pathogenesis is a rapidly expanding area of cancer research. Functional inactivation of RUNX3-through mutation, epigenetic silencing, or cytoplasmic mislocalization-is frequently observed in solid tumors of diverse origins. This alone indicates that RUNX3 inactivation is a major risk factor in tumorigenesis and that it occurs early during progression to malignancy. Conversely, RUNX3 has also been described to have an oncogenic function in a subset of tumors. Although the mechanism of how RUNX3 switches from tumor suppressive to oncogenic activity is unclear, this is of clinical relevance with implications for cancer detection and prognosis. Recent developments have significantly contributed to our understanding of the pleiotropic tumor suppressive properties of RUNX3 that regulate major signaling pathways. This review summarizes the important findings that link RUNX3 to tumor suppression.

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Section: Molecular Mechanisms That Underlie Runx3's Anti-tumor Propermentioning

confidence: 92%

RUNX3 is multifunctional in carcinogenesis of multiple solid tumors

2010

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“…13 These results suggest that claudin-4 might promote tumorigenesis or may suppress tumorigenesis by different molecular mechanisms in association with tissue-specific circumstances. Similarly, claudin-1 has shown a tumorsuppressive activity in gastric cancer, 46 in contrast to its cancer-promoting role in colon cancer. 10 Epigenetic silencing of multiple genes by frequent CpG island hypermethylation in early gastric tumorigenesis and gastric carcinoma has been reported; 29,30 however, the upregulation of gene expression by such an epigenetic mechanism is not well known.…”

Section: Bivalent Histone Modifications Are Associated With Cldn4 Repmentioning

confidence: 99%

Claudin-4 overexpression is associated with epigenetic derepression in gastric carcinoma

Kwon

Kim

Jeong

et al. 2011

Laboratory Investigation

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The tight junction (TJ) protein claudin-4 is aberrantly upregulated in gastric cancer, but its clinical significance and the molecular mechanisms underlying claudin-4 overexpression in gastric cancer remain unclear. Here, we investigated its roles and epigenetic mechanisms regulating CLDN4 expression in gastric cancer. We show that increased membranous expression of claudin-4 in gastric carcinoma is associated with better patient prognosis, whereas cytoplasmic claudin-4 expression did not show a significant association with prognosis. Consistent with the correlation of increased membranous claudin-4 with favorable clinicopathological factors, claudin-4 overexpression inhibited the migration and invasion of gastric cancer cells; in contrast, it did not affect cell growth. Claudin-4 expression also increased the barrier function of TJs. Claudin-4 upregulation was strongly correlated with DNA hypomethylation in both gastric tissues and gastric cancer cells. Moreover, CLDN4 expression was repressed in normal gastric tissues in association with bivalent histone modifications, and loss of repressive histone methylations and gain of active histone modifications were associated with CLDN4 overexpression in gastric cancer cells. Interestingly, CLDN4 repression could be markedly derepressed by combined treatments that simultaneously target both histone modifications and DNA demethylation in CLDN4-hypermethylated cells, whereas concomitant changes in histone methylations and acetylations are required for CLDN4 induction in CLDN4-repressed cells with low DNA methylation. Taken together, this study reveals that membranous claudin-4 expression is associated with gastric cancer progression and that it is an independent positive prognosis marker in gastric carcinoma. Furthermore, our findings suggest that epigenetic derepression may be a possible mechanism underlying CLDN4 overexpression in gastric cancer and that claudin-4 may have potential as a promising target for the treatment of gastric cancer.

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“…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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Claudin-1 Has Tumor Suppressive Activity and Is a Direct Target of RUNX3 in Gastric Epithelial Cells

Cited by 82 publications

References 46 publications

RUNX3 is multifunctional in carcinogenesis of multiple solid tumors

RUNX3 is multifunctional in carcinogenesis of multiple solid tumors

Claudin-4 overexpression is associated with epigenetic derepression in gastric carcinoma

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

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