Helicobacter pylori Causes Epigenetic Dysregulation of FOXD3 to Promote Gastric Carcinogenesis

Cheng, Alfred S.L.; Li, May S.; Kang, Wei; Cheng, Victoria Y.Y.; Chou, Jian–Liang; Lau, Sing; Go, Minnie Y.Y.; Lee, Ching C.; Ling, T. K. W.; Ng, Enders K. O.; Yu, Jun; Huang, Tim H-M.; To, Ka Fai; Chan, Michael W.Y.; Sung, Joseph J.Y.; Chan, Francis K.L.

doi:10.1053/j.gastro.2012.10.002

Cited by 128 publications

(130 citation statements)

References 67 publications

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“…Despite progress in diagnosis and treatment, the 5-year survival rate of patients with lung cancer is only 9-20% (23). FOXD3 has been suggested to be a tumor suppressor in various types of cancer (8)(9)(10). However, the underlying mechanism of FOXD3 activity in lung cancer remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…The abnormal expression of FOXD3 has been reported to participate in tumor onset and progression in non-small cell lung cancer tumor cells (8). Other studies have indicated tumor suppressive activities for FOXD3, including the inhibition of cell growth and invasion in various types of cancer, including gastric cancer and melanoma (9,10). A number of genes associated with tumorigenesis have been reported to be targets of FOXD3.…”

Section: Introductionmentioning

confidence: 99%

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Screening of FOXD3 targets in lung cancer via bioinformatics analysis

Jiang

Liu

2017

Oncol Lett

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Abstract. The purpose of the present study was to explore the targets of forkhead box D3 (FOXD3) in lung cancer, and thus contribute to the diagnosis and therapy of the disease. The gene expression profile of GSE64513 was downloaded from the Gene Expression Omnibus database. The dataset contained 3 FOXD3 knockout A549 lung cancer cell samples and 3 normal A549 cell samples. The differentially expressed genes (DEGs) between the FOXD3-knockout and normal A549 cells were identified using the limma package in R. The alternative splicing genes (ASGs) in FOXD3-knockout samples were identified by Replicate Multivariate Analysis of Transcript Splicing software. The Database for Annotation, Visualization and Integrated Discovery was used to identify the enriched functions and pathways of DEGs and ASGs. A protein-protein interaction (PPI) network was constructed based on results from the Search Tool for the Retrieval of Interacting Genes database and visualized using Cytoscape software. A total of 1,853 DEGs and 2,249 ASGs were identified in FOXD3-knockout A549 cells compared with normal A549 cells. The DEGs were enriched in 338 Gene Ontology (GO) terms and 21 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and the ASGs were enriched in 470 GO terms and 22 KEGG pathways. A total of 199 overlaps between the DEGs and the ASGs were identified; a PPI network constructed based on the overlapping genes contained 97 nodes and 115 pairs. FOXD3 may serve an important role in regulating the growth, migration and proliferation of tumor cells in lung cancer. The present study indicates that a number of genes, including AURKA and NOS3, may be targets of FOXD3, mediating its effect in lung cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Screening of FOXD3 targets in lung cancer via bioinformatics analysis

Jiang

Liu

2017

Oncol Lett

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“…In addition to immune system, H. pylori is known to perturb the expression of host genes by different mechanisms. For examples, H. pylori can cause promoter hypermethylation and silencing of FOXD3, leading to decreased levels of cell death modulators CYFIP2 and RARB to favor the proliferation of gastric cancer cells [3]. Moreover, H. pylori can epigenetically down-regulate the transcription of miR-490-3p, thereby resume the expression of its direct target SMARCD1 which is a member of the SWItch/SucroseNonFermentable (SWI/ SNF) chromatin remodeling family with oncogenic functional roles [4].…”

mentioning

confidence: 99%

“…Moreover, H. pylori can epigenetically down-regulate the transcription of miR-490-3p, thereby resume the expression of its direct target SMARCD1 which is a member of the SWItch/SucroseNonFermentable (SWI/ SNF) chromatin remodeling family with oncogenic functional roles [4]. The H. Pylori deregulated host genes are of clinical significance as demonstrated by their respective correlations with various clinicpathological features of gastric cancer patients [3,4].Based on the deteriorating effects of H. pylori, different first-and second-line therapies have been developed for elimination of H. pylori in patients. Common regimens include proton-pump inhibitors, ranitidine bismuth citrate and bismuth, which are often applied in combination to increase the therapeutic response [5].…”

mentioning

confidence: 99%

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confidence: 99%

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Rectifying the Epigenetic Field Defect in Gastric Carcinogenesis

2015

J Cancer Sci

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Gastric cancer is undoubtedly a fatal malignancy worldwide with high incidence and dismal prognosis. Its formation and development can be driven by genetic defects, dietary factors, alcohol consumption, viral infection, etc. Despite the multifactorial nature, more than 80% of gastric cancers are closely related to Helicobacter pylori (H. pylori) infection [1]. It is believed that H. pylori triggers chronic gastritis that results in gastric atrophy, intestinal metaplasia and dysplasia, and then finally to adenocarcinoma. Such microbial infection is associated with strong host response such as cytokine stimulation and neutrophil activation which play an important driver role in gastric carcinogenesis. The stimulated cytokines include pro-inflammatory interleukin-1β (IL-1β), IL-2, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α), of which the IL-8 action in stimulating neutrophils is significantly enhanced upon infection by CagA-positive H. pylori [2]. In addition to immune system, H. pylori is known to perturb the expression of host genes by different mechanisms. For examples, H. pylori can cause promoter hypermethylation and silencing of FOXD3, leading to decreased levels of cell death modulators CYFIP2 and RARB to favor the proliferation of gastric cancer cells [3]. Moreover, H. pylori can epigenetically down-regulate the transcription of miR-490-3p, thereby resume the expression of its direct target SMARCD1 which is a member of the SWItch/SucroseNonFermentable (SWI/ SNF) chromatin remodeling family with oncogenic functional roles [4]. The H. Pylori deregulated host genes are of clinical significance as demonstrated by their respective correlations with various clinicpathological features of gastric cancer patients [3,4].Based on the deteriorating effects of H. pylori, different first-and second-line therapies have been developed for elimination of H. pylori in patients. Common regimens include proton-pump inhibitors, ranitidine bismuth citrate and bismuth, which are often applied in combination to increase the therapeutic response [5]. In patients free of precancerous lesions, removal of H. pylori can significantly reduce the risk of stomach cancer formation. Nevertheless, the efficacy of H. pylori eradication in treating gastric cancer remains obscure, if not unsatisfactory [6]. Such outcome is apparently due to the irreversible H. pylori-triggered damages to gastric mucosa, implicating the carcinogenic effect of this organism is mainly exerted at early stage of infection. To find an alternative approach for gastric cancer therapy, extensive research had previously been performed to characterize the molecular deregulations induced by H. pylori infection, among which epigenetic alternation has emerged as a potential therapeutic target owning to its reversible nature by exogenous agents. Importantly, pathogenic epigenetic changes are not confined to H. pylori-associated gastric cancers, but are also found in other non-microbial subtypes, suggesting that such abnormalities exist in the majority of stomach cance...

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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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Helicobacter pylori Causes Epigenetic Dysregulation of FOXD3 to Promote Gastric Carcinogenesis

Cited by 128 publications

References 67 publications

Screening of FOXD3 targets in lung cancer via bioinformatics analysis

Screening of FOXD3 targets in lung cancer via bioinformatics analysis

Rectifying the Epigenetic Field Defect in Gastric Carcinogenesis

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

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