Increased genetic susceptibility to intestinal‐type gastric cancer is associated with increased activity of the <i>RUNX</i>3 distal promoter

Lim, Byungho; Ju, Hyoungseok; Kim, Minjin; Kang, Changwon

doi:10.1002/cncr.26161

Cited by 26 publications

(28 citation statements)

References 36 publications

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“…Of note is the possible regulation of promoter usage by CpG island methylation because an alternative upstream promoter is not located within the CpG island. Importantly, RUNX3 isoforms transcribed from the distal or proximal promoter exert different activities on NFκB‐pathway in a gastric cancer cell line . Up to now no data are published describing RUNX3 in relation to prognosis or chemotherapy sensitivity in EOC.…”

Section: Discussionmentioning

confidence: 99%

RUNX3 and CAMK2N1 hypermethylation as prognostic marker for epithelial ovarian cancer

et al. 2015

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Treatment of epithelial ovarian cancer consists of surgery plus platinum-taxane based chemotherapy. Neither prognostic nor predictive serum or tissue markers except BRCA1/2 mutations are available thus precluding individualized treatment. Aim of this study is the identification and validation of DNA-methylation markers with prognostic value. Genome-wide array analyses were used to determine methylation patterns in groups of serous EOC with different outcome (PFS < vs. > 3 years, each n 5 6) but comparable clinical parameters. Two hundred and twenty differentially methylated regions in tumor tissue of patients with short vs. long PFS (106 hypo-and 114 hypermethylated regions) were identified. Thirty-five of 37 selected CpG islands were validated by MSP using the same samples as for microarray analyses. Six of these regions were analyzed by targeted nextgeneration bisulfite-sequencing confirming array and MSP results. Validation experiments with an enlarged patient group of Type II EOC samples (PFS <3 years n 5 30; >3 years n 5 18) revealed the CpG island of RUNX3 as significantly more often methylated in patients with short PFS (10/30 vs. 0/18; p < 0.01). Marker combinations with significantly different methylation frequencies in patient groups reached an increased sensitivity with equal specificity (RUNX31CAMK2N1; sens 40%; spec 100%; p < 0.01). RUNX3/CAMK2N1 methylation-positive patients of the array-independent subset (n 5 36) showed a significantly lower PFS (p < 0.01) but no other difference in clinical parameters compared to methylation-negative patients. Genomewide methylation analyses reliably identified markers of potentially prognostic value. Hypermethylation of RUNX3/CAMK2N1 is associated with poor clinical outcome in Type II EOC, also after macroscopic complete resection.

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Section: Discussionmentioning

confidence: 99%

RUNX3 and CAMK2N1 hypermethylation as prognostic marker for epithelial ovarian cancer

et al. 2015

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“…WT and mutant 3′UTR regions of MAP2K1 and TEAD4 were PCR‐amplified, and each amplicon was cloned into the psiCHEK‐2 vector (Promega, Madison, WI, USA). Then, the luciferase assay was performed according to a previously described method . Briefly, GC cells (1 × 10 5 ) plated on a 24‐well tissue culture plate were transfected with 0.5 μg of vector containing the 3′UTR region using Lipofectamine 2000 (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

“…Then, the luciferase assay was performed according to a previously described method. 22 Briefly, GC cells (1 × 10 5 ) plated on a 24-well tissue culture plate were transfected with 0.5 μg of vector containing the 3′UTR region using Lipofectamine 2000 (Invitrogen). After 24 hours, luciferase activity was measured using a Dual Luciferase Reporter Assay System (Promega) and a Victor plate reader (Perkin Elmer, Waltham, MA, USA).…”

Section: Luciferase Assaymentioning

confidence: 99%

Epigenetic silencing of miR‐1271 enhances MEK1 and TEAD4 expression in gastric cancer

et al. 2018

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Epigenetic dysregulation is a major driver of tumorigenesis. To identify tumor‐suppressive microRNAs repressed by DNA methylation in gastric cancer (GC), we analyzed the genome‐wide DNA methylation and microRNA expression profiles of EpCAM+/CD44+ GC cells. Among the set of microRNAs screened, miR‐1271 was identified as a microRNA repressed by DNA methylation in GC. Forced miR‐1271 expression substantially suppressed the growth, migration, and invasion of GC cells. To identify candidate target genes and signaling pathways regulated by miR‐1271, we performed RNA sequencing. Among the genes down‐regulated by miR‐1271, MAP2K1 (MEK1) was significantly repressed by miR‐1271, and the associated ERK/MAPK signaling pathway was also inhibited. TEAD4 was also repressed by miR‐1271, and the associated YAP1 signatures within genes regulated by miR‐1271 were significantly enriched. These findings uncovered MEK1 and TEAD4 as novel miR‐1271 targets and suggest that the epigenetic silencing of miR‐1271 is crucial for GC development.

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“…Among these are cytokine genes involved in the adaptive immune system [98,99,100] and pattern recognition factors initiating the innate immune system [101,102]. Furthermore, variation of genes encoding for proteases [103], xenobiotic metabolism enzymes [104], cell cycle regulators [105,106], mucins [107], HLA molecules [108], transcription factors [109], DNA repair enzymes [105,110,111], and micro-RNAs [112] has been reported to bear an increased risk for gastric cancer. Besides a ‘single gene' approach, also pathway-related pattern searches can be performed to allow a broader assessment of the pathobiological background [113].…”

Section: Host-related Factorsmentioning

confidence: 99%

Helicobacter pylori and Gastric Cancer

Bornschein

Malfertheiner

2014

Dig Dis

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Infection with Helicobacter pylori is established as the major risk factor for gastric cancer development. Damage of the mucosal barrier due to H. pylori-induced inflammation enhances the carcinogenic effect of other risk factors such as salt intake or tobacco smoking. The genetic disposition of both the bacterial strain and the host can increase the potential towards gastric cancer formation. Genetic variance of the bacterial proteins CagA and VacA is associated with a higher gastric cancer risk, as are polymorphisms and epigenetic changes in host gene coding for interleukins (IL1β, IL8), transcription factors (CDX2, RUNX3) and DNA repair enzymes. Application of high-throughput assays for genome-wide assessment of either genetic structural variance or gene expression patterns may lead to a better understanding of the pathobiological background of these processes, including the underlying signaling pathways. Understanding of the stepwise alterations that take place in the transition from chronic atrophic gastritis, via metaplastic changes, to invasive neoplasia is vital to define the ‘point of no return' before which eradication of H. pylori has the potential to prevent gastric cancer. Currently, eradication as preventive strategy is only recommended for high-incidence regions in Asia; large population studies with an adequate follow-up are required to demonstrate the effectiveness of such an approach in Western populations.

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Increased genetic susceptibility to intestinal‐type gastric cancer is associated with increased activity of the RUNX3 distal promoter

Cited by 26 publications

References 36 publications

RUNX3 and CAMK2N1 hypermethylation as prognostic marker for epithelial ovarian cancer

RUNX3 and CAMK2N1 hypermethylation as prognostic marker for epithelial ovarian cancer

Epigenetic silencing of miR‐1271 enhances MEK1 and TEAD4 expression in gastric cancer

Helicobacter pylori and Gastric Cancer

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