Combinatorial epigenetic deregulation by <i>Helicobacter pylori</i>
 and Epstein-Barr virus infections in gastric tumourigenesis

Wu, William Ka Kei; Yu, Jun; Chan, Matthew T. V.; To, Ka Fai; Cheng, Alfred S.L.

doi:10.1002/path.4731

Cited by 17 publications

(12 citation statements)

References 36 publications

(43 reference statements)

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“…Several studies also revealed that PCDH10 (protocadherin 10) is calcium dependent cell adhesion molecule which suppresses tumor in gastric epithelial hypermethylated in H. pylori associated GC and EBV-infected individual [287–289]. SWI/SNF remodelling complex which is commonly observed in GC is found associated with both pathogens, EBV and H. pylori [290]. A recent study suggested that host protein SHP 1 interacts with H. pylori CagA protein and dephosphorylates CagA, thus preventing oncogenic activity of CagA.…”

Section: Ebv and H Pylori Factors Contributing To The Developmentmentioning

confidence: 99%

Status of Epstein-Barr Virus Coinfection withHelicobacter pyloriin Gastric Cancer

Singh

Jha

2017

Journal of Oncology

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Epstein-Barr virus is a ubiquitous human herpesvirus whose primary infection causes mononucleosis, Burkett's lymphoma, nasopharyngeal carcinoma, autoimmune diseases, and gastric cancer (GC). The persistent infection causes malignancies in lymph and epithelial cells. Helicobacter pylori causes gastritis in human with chronic inflammation. This chronic inflammation is thought to be the cause of genomic instability. About 45%-word population have a probability of having both pathogens, namely, H. pylori and EBV. Approximately 180 per hundred thousand population is developing GC along with many gastric abnormalities. This makes GC the third leading cause of cancer-related death worldwide. Although lots of research are carried out individually for EBV and H. pylori, still there are very few reports available on coinfection of both pathogens. Recent studies suggested that EBV and H. pylori coinfection increases the occurrence of GC as well as the early age of GC detection comparing to individual infection. The aim of this review is to present status on coinfection of both pathogens and their association with GC.

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Section: Ebv and H Pylori Factors Contributing To The Developmentmentioning

confidence: 99%

Status of Epstein-Barr Virus Coinfection withHelicobacter pyloriin Gastric Cancer

Singh

Jha

2017

Journal of Oncology

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“…Promoter hypermethylation in specific tumor suppressor genes has been associated with H. pylori infection in the multistep carcinogenetic process by several groups [27, 28]. Global DNA hypomethylation also increases throughout the process that leads to the deterioration of normal gastric mucosa to invasive cancer [29–31].…”

Section: Introductionmentioning

confidence: 99%

Early detection of gastric cancer using global, genome-wide and IRF4, ELMO1, CLIP4 and MSC DNA methylation in endoscopic biopsies

et al. 2017

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Clinically useful molecular tools to triage gastric cancer patients are not currently available. We aimed to develop a molecular tool to predict gastric cancer risk in endoscopy-driven biopsies obtained from high-risk gastric cancer clinics in low resource settings.We discovered and validated a DNA methylation biomarker panel in endoscopic samples obtained from 362 patients seen between 2004 and 2009 in three high-risk gastric cancer clinics in Lima, Perú, and validated it in 306 samples from the Cancer Genome Atlas project (“TCGA”). Global, epigenome wide and gene-specific DNA methylation analyses were used in a Phase I Biomarker Development Trial to identify a continuous biomarker panel that combines a Global DNA Methylation Index (GDMI) and promoter DNA methylation levels of IRF4, ELMO1, CLIP4 and MSC.We observed an inverse association between the GDMI and histological progression to gastric cancer, when comparing gastritis patients without metaplasia (mean = 5.74, 95% CI, 4.97−6.50), gastritis patients with metaplasia (mean = 4.81, 95% CI, 3.77−5.84), and gastric cancer cases (mean = 3.38, 95% CI, 2.82−3.94), respectively (p < 0.0001). Promoter methylation of IRF4 (p < 0.0001), ELMO1 (p < 0.0001), CLIP4 (p < 0.0001), and MSC (p < 0.0001), is also associated with increasing severity from gastritis with no metaplasia to gastritis with metaplasia and gastric cancer.Our findings suggest that IRF4, ELMO1, CLIP4 and MSC promoter methylation coupled with a GDMI>4 are useful molecular tools for gastric cancer risk stratification in endoscopic biopsies.

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“…It has been reported that KLF4 expression was reduced in a series of GC tissue and GC cell lines could be due to promoter methylation, 17 but H pylori infection increased the promoter methylation of tumor suppressor genes. [26][27][28] To explore whether CagA increases the KLF4 promoter methylation levels to reduce KLF4 expression, we analyzed the CpG island methylation level of the KLF4 promoter region from the transcription start site to the first exon ( Figure 4A). The genomic DNA of GES-1 cells was transiently transfected with CagA for 48 hours, while western blotting showed that KLF4 protein expression decreased ( Figure 4B).…”

Section: Caga Transfection Increases Klf4 Promoter Methylationmentioning

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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Combinatorial epigenetic deregulation by Helicobacter pylori and Epstein-Barr virus infections in gastric tumourigenesis

Cited by 17 publications

References 36 publications

Status of Epstein-Barr Virus Coinfection withHelicobacter pyloriin Gastric Cancer

Status of Epstein-Barr Virus Coinfection withHelicobacter pyloriin Gastric Cancer

Early detection of gastric cancer using global, genome-wide and IRF4, ELMO1, CLIP4 and MSC DNA methylation in endoscopic biopsies

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

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