Gastrokine 1 inhibits the carcinogenic potentials of Helicobacter pylori CagA

Yoon, Jung Hwan; Seo, Ho Suk; Choi, Sang-Bang; Chae, Hiun-Suk; Choi, Won Seok; Kim, Olga; Ashktorab, Hassan; Smoot, Duane T.; Nam, Suk Woo; Lee, Jung Young; Park, Won Sang

doi:10.1093/carcin/bgu199

Cited by 38 publications

(37 citation statements)

References 46 publications

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“…19 The primer sequences are shown in Supplementary Table S1. The expression of H. pylori CagA and differentiation-associated proteins was examined by real-time PCR and western blotting analysis, as previously described.…”

Section: Effect Of Caga and Gkn1 On Intestinal Metaplasiamentioning

confidence: 99%

“…19 Thus, to determine whether NKX6.3-induced gastric differentiation is dependent on GKN1, we examined the NKX6.3, CDX2, and SOX2 expression in AGS NKX6.3 and MKN1 NKX6.3 cells after GKN1 silencing with shGKN1 (Supplementary Figure S2a). Notably, GKN1 silencing did not affect the expression levels of NKX6.3, SOX2, and CDX2 at the mRNA level ( Supplementary Figures S2b-d), suggesting that NKX6.3 may regulate gastric differentiation in a GKN1-independent manner.…”

Section: Nkx63 Controls Gastric Differentiation In a Gkn1-independenmentioning

confidence: 99%

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Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation

et al. 2016

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Intestinal metaplasia in gastric mucosa is considered a preneoplastic lesion that progresses to gastric cancer. However, the molecular networks underlying this lesion formation are largely unknown. NKX6.3 is known to be an important regulator in gastric mucosal epithelial differentiation. In this study, we characterized the effects of NKX6.3 that may contribute to gastric intestinal metaplasia. NKX6.3 expression was significantly reduced in gastric mucosae with intestinal metaplasia. The mRNA expression levels of both NKX6.3 and CDX2 predicted the intestinal metaplasia risk, with an area under the receiver operating characteristic curve value of 0.9414 and 0.9971, respectively. Notably, the NKX6.3 expression level was positively and inversely correlated with SOX2 and CDX2, respectively. In stable AGS NKX6.3 and MKN1 NKX6.3 cells, NKX6.3 regulated the expression of CDX2 and SOX2 by directly binding to the promoter regions of both genes. Nuclear NKX6.3 expression was detected only in gastric epithelial cells without intestinal metaplasia. Furthermore, NKX6.3-induced TWSG1 bound to BMP4 and inhibited BMP4-binding activity to BMPR-II. These data suggest that NKX6.3 might function as a master regulator of gastric differentiation by affecting SOX2 and CDX2 expression and the NKX6. Gastric cancer is still one of the malignancies with high incidence and mortality rates worldwide. 1 The stages of the precancerous cascade for gastric adenocarcinoma are a series of histologically recognizable changes in the gastric mucosa that follow a specific sequence: non-atrophic gastritis, multifocal atrophic gastritis, intestinal metaplasia, and dysplasia. 2-4 Of these, intestinal metaplasia is the replacement of gastric epithelium by epithelium displaying an intestinal phenotype with the appearance of goblet, Paneth, and absorptive cells. It is well known that Helicobacter pylori infection, high salt intake, smoking, and alcohol consumption are risk factors for gastric intestinal metaplasia. [5][6][7][8] Interestingly, altered expression of Muc5ac with the aberrant expression of Muc2 and caudal-related homologue 2 (CDX2) was detected in intestinal metaplasia of the stomach, which is characterized by the appearance of goblet cells and is considered to be a preneoplastic stage of gastric carcinogenesis. [9][10][11][12] Patients with gastric intestinal metaplasia showed a six-fold increased risk of gastric cancer than did those without gastric intestinal metaplasia. 13 Although much is known about the morphology and physiology of gastric intestinal metaplasia, the regulatory mechanisms that govern their intestinal differentiation still remain unclear.It was recently reported that NKX6.3, a third member of the NKX6 subfamily of NKX genes, is a novel transcription factor required for gastric epithelial differentiation. 14 In mouse embryos, NKX6.3 expression is restricted to endoderm-derived cells in the gastric antrum, pylorus, and proximal duodenum. 15 As a stratified squamous epithelium extends from the esophagus to the fundus of the m...

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Section: Effect Of Caga and Gkn1 On Intestinal Metaplasiamentioning

confidence: 99%

Section: Nkx63 Controls Gastric Differentiation In a Gkn1-independenmentioning

confidence: 99%

Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation

et al. 2016

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“…However, strains of H pylori carrying the cytotoxin‐associated antigen A (CagA) gene are related to gastric carcinoma . CagA, the most important virulence factor of H pylori , enters into gastric epithelial cells with the help of the T4SS system and influences the expression of tumor suppressor genes in the host, such as GKN1, RUNX3, and P53 . We have found that H pylori CagA promotes malignant transformation of gastric epithelial cells through the dysregulation of mir‐155/KLF4 signaling pathway .…”

Section: Introductionmentioning

confidence: 99%

Helicobacter pylori infection leads to KLF4 inactivation in gastric cancer through a TET1‐mediated DNA methylation mechanism

Zhao

Liu

et al. 2020

Cancer Medicine

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Krüppel‐like factor 4 (KLF4) has a tumor suppressor role in the progression of gastric cancer (GC), and inhibition or loss of KLF4 expression was identified in GC. The aim of this study was to explore the new molecular mechanism of KLF4 inactivation in gastric cancer. Herein, we report that Helicobacter pylori infection or Cag pathogenicity island protein A (CagA) gene transduction resulted in KLF4 expression downregulation and promoted gastric epithelial cell and gastric cancel cell proliferation, migration, and colony formation. Mechanistically, we found that CagA gene transduction led to DNA methylation of the KLF4 promoter, an effect that was relevant to the significant downregulation of TET1 expression. Causally, knockdown of TET1 expression decreased KLF4 expression, whereas overexpression of TET1 had the opposite effect. Clinically, we found that KLF4 expression and the 5‐hmC levels were lower in GC cells with H pylori infection than in GC cells without H pylori infection. Thus, our study not only sheds new light on how H pylori infection promotes the progression of GC but also elucidates a novel mechanism of KLF4 inactivation in GC pathogenesis. During pathogenesis, an alteration in the H pylori/CagA‐TET1‐KLF4 signaling pathway plays a critical role, suggesting that this pathway may be a prospective target for gastric carcinoma intervention and therapy.

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“…For example, gastrokine 1 has the ability to inhibit CagA-induced cell proliferation and EMT by directly binding to CagA; this interaction prevents CagA interaction with SHP2 and E-cadherin [47]. However, H. pylori overcomes this effect via downregulation of gastrokine 1 in GC tissues.…”

Section: Introductionmentioning

confidence: 99%

“…However, H. pylori overcomes this effect via downregulation of gastrokine 1 in GC tissues. This is a CagA-mediated event and the resulting decreased gastrokine 1 levels result in activation of NF-κB and PI3K/Akt [47]. An additional tumor suppressor example can be found with trefoil factor 1 (TFF1), which inhibits β-catenin and NF-κB-p65 nuclear translocation via negative regulation of Akt/GSK-3β.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms of gastric cancer initiation and progression by Helicobacter pylori

Servetas

Bridge²,

Merrell³

2016

Current Opinion in Infectious Diseases

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Purpose of Review Infection with the Gram-negative, microaerophilic pathogen Helicobacter pylori results in gastric cancer (GC) in a subset of infected individuals. As such, H. pylori is the only World Health Organization classified bacterial class I carcinogen. Numerous studies have identified mechanisms by which H. pylori alters host cell signaling pathways to cause disease. The purpose of this review is to highlight recent studies that explore mechanisms associated with induction of GC. Recent Findings Over the last year and a half, new mechanisms contributing to the etiology of H. pylori associated GC development have been discovered. In addition to utilizing the oncogenic CagA toxin to alter host cell signaling pathways, H. pylori also induces host DNA damage and alters DNA methylation to perturb downstream signaling. Furthermore, H. pylori activates numerous host cell pathways and proteins that result in epithelial-to-mesenchymal transition (EMT) and induction of cell survival and proliferation. Summary Mounting evidence suggests that H. pylori promotes gastric carcinogenesis using a multifactorial approach. Intriguingly, many of the targeted pathways and mechanism show commonality with diverse forms of cancer.

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Gastrokine 1 inhibits the carcinogenic potentials of Helicobacter pylori CagA

Cited by 38 publications

References 46 publications

Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation

Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation

Helicobacter pylori infection leads to KLF4 inactivation in gastric cancer through a TET1‐mediated DNA methylation mechanism

Molecular mechanisms of gastric cancer initiation and progression by Helicobacter pylori

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