Gene deregulation in gastric cancer

Stöck, Michael; Otto, Florian

doi:10.1016/j.gene.2005.06.026

Cited by 114 publications

(99 citation statements)

References 198 publications

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“…In GC, the cyclin E gene is amplified in 15-20% of gastric cancers, whereas cyclin B2 or cyclin C is also up-regulated (36). Amplification or mutation of the cyclin D1 gene has not been reported in GC, although elevated cyclin D1 expression has been observed in ≈50% of GC cases (37).…”

Section: Discussionmentioning

confidence: 99%

Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer

Hayakawa

Hirata

Nakagawa

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Mitogen-activated protein kinase (MAPK) pathways regulate multiple cellular functions and are highly active in many types of human cancers. Apoptosis signal-regulating kinase 1 (ASK1) is an upstream MAPK involved in apoptosis, inflammation, and carcinogenesis. This study investigated the role of ASK1 in the development of gastric cancer. In human gastric cancer specimens, we observed increased ASK1 expression, compared to nontumor epithelium. Using a chemically induced murine gastric tumorigenesis model, we observed increased tumor ASK1 expression, and ASK1 knockout mice had both fewer and smaller tumors than wild-type (WT) mice. ASK1 siRNA inhibited cell proliferation through the accumulation of cells in G1 phase of the cell cycle, and reduced cyclin D1 expression in gastric cancer cells, whereas these effects were uncommon in other cancer cells. ASK1 overexpression induced the transcription of cyclin D1, through AP-1 activation, and ASK1 levels were regulated by cyclin D1, via the Rb-E2F pathway. Exogenous ASK1 induced cyclin D1 expression, followed by elevated expression of endogenous ASK1. These results indicate an autoregulatory mechanism of ASK1 in the development of gastric cancer. Targeting this positive feedback loop, ASK1 may present a potential therapeutic target for the treatment of advanced gastric cancer. JNK | c-JunG astric cancer (GC) is a common cancer worldwide, associated with a high mortality despite its declining incidence in recent decades. Smoking, salted or smoked foods, and Helicobacter pylori appear to be major environmental inducers of GC (1-3). Although the role of H. pylori in causing mucosal effects has been investigated, which molecular signal(s) initiate the program of irreversible transformation remain unclear, and thus molecular targeting therapies for GC have not been well established.Mitogen-activated protein kinase (MAPK) pathways are important for the development of gastric tumorigenesis (4). Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed MAPK kinase kinase (MAP3K), activated by various stress stimuli, including reactive oxygen species (ROS), TNF-α, and LPS (5-7). ASK1 activates the JNK and p38 signaling pathways and is required for both oxidative stress and cytokine-induced apoptosis (5). Furthermore, ASK1 affects multiple cellular functions, including survival, differentiation, and the innate immune response (5,7,8) and has been reported to be involved in the pathogenesis of various human diseases, including neurodegenerative (9), cardiovascular (10), and inflammatory diseases (11,12). Additionally, ASK1 has been shown to participate in both colon (12) and skin (13) tumorigenesis through the regulation of inflammation and apoptosis. However, no reported study has demonstrated a role for ASK1 in gastric tumorigenesis.In this study, we examined the role of ASK1 in gastric tumorigenesis using both human GC samples and ASK1-deficient (ASK1 −/− ) mice. We demonstrated that ASK1 is important for gastric tumorigenesis through the regulation of cyclin D1 e...

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Section: Discussionmentioning

confidence: 99%

Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer

Hayakawa

Hirata

Nakagawa

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Like other cancers, the development of gastric cancer is a multistep process with accumulation of genetic and epigenetic changes [9,10]. Although a number of miRNAs that are associated with gastric cancer have been identified to date, the role of many of them in tumorigenesis and the underlying mechanism remain to be determined.…”

Section: Introductionmentioning

confidence: 99%

MiR-375 frequently downregulated in gastric cancer inhibits cell proliferation by targeting JAK2

et al. 2010

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“…Besides environmental factors (Chyou et al, 1990;Nomura et al, 1990;Parsonnet et al, 1991;Tsugane and Sasazuki, 2007;Suzuki et al, 2009;Polk and Peek, 2010), genetic alterations of oncogenes, tumor-suppressor genes, cell cycle regulators, cell adhesion molecules and DNA repair genes have been identified to contribute to development or progression of gastric cancer (Wu et al, 1997;Zheng et al, 2004;Stock and Otto, 2005). The gene instability in gastric cancer including gene amplification, loss of heterozygosity (Sano et al, 1991) or microsatellite instability (Fang et al, 2003) may cause the inactivation of some tumor-suppressor genes, such as p53, and deregulation of some signaling molecules so as to enhance some signaling pathways, such as Wnt or Ras-dependent mitogen-activated protein kinase (MAPK) pathway, which may promote the tumorigenesis (Kim et al, 1991;Clements et al, 2002;Stock and Otto, 2005). In another way, the gene silencing in gastric cancer frequently results from promoter hypermethylation caused by overexpression of DNA methyltransferase 1 and involves many genes expression such as hMLH1, E-cadherin, transforming growth factor (TGF)-b receptor type I and RUNX3 that loss of them may exacerbate the gastric cancer progression (Etoh et al, 2004;Stock and Otto, 2005;Sato and Meltzer, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…The gene instability in gastric cancer including gene amplification, loss of heterozygosity (Sano et al, 1991) or microsatellite instability (Fang et al, 2003) may cause the inactivation of some tumor-suppressor genes, such as p53, and deregulation of some signaling molecules so as to enhance some signaling pathways, such as Wnt or Ras-dependent mitogen-activated protein kinase (MAPK) pathway, which may promote the tumorigenesis (Kim et al, 1991;Clements et al, 2002;Stock and Otto, 2005). In another way, the gene silencing in gastric cancer frequently results from promoter hypermethylation caused by overexpression of DNA methyltransferase 1 and involves many genes expression such as hMLH1, E-cadherin, transforming growth factor (TGF)-b receptor type I and RUNX3 that loss of them may exacerbate the gastric cancer progression (Etoh et al, 2004;Stock and Otto, 2005;Sato and Meltzer, 2006). The more comprehensive investigations of molecular mechanisms related to gastric carcinogenesis will provide more evidences for developing novel diagnostic and therapeutic strategies against gastric cancer.…”

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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Gene deregulation in gastric cancer

Cited by 114 publications

References 198 publications

Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer

Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer

MiR-375 frequently downregulated in gastric cancer inhibits cell proliferation by targeting JAK2

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

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