Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Barrett, Caitlyn W.; Wei, Ning; Chen, Xi; Smith, J. Joshua; Washington, Mary Kay; Hill, Kristina E.; Coburn, Lori A.; Peek, Richard M.; Chaturvedi, Rupesh; Wilson, Keith T.; Burk, Raymond F.; Williams, Christopher S.

doi:10.1158/0008-5472.can-12-3150

Cited by 159 publications

(148 citation statements)

References 46 publications

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“…Of note, the matched tumor/normal pairs from the same patients allow an unbiased and efficient analysis of the H3K4me3 width. As observed in cell lines, broad H3K4me3 in normal lung tissues is associated with tumor suppressors (Fig 7a) and shortening of broad H3K4me3 is frequently observed at established tumor suppressors, such as GPX3 35 and PLK2 36–38 (Fig 7b). In total, we identified 209, 108, and 248 genes with shortened, lengthened, and stable broad H3K4me3 in lung tumors relative to normal lung tissues (Fig 7c).…”

Section: Resultssupporting

confidence: 54%

Broad H3K4me3 is associated with increased transcription elongation and enhancer activity at tumor-suppressor genes

et al. 2015

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Tumor suppressors are mostly defined by inactivating mutations in tumors, yet little is known about their epigenetic features in normal cells. Through integrative analysis of 1,134 genome-wide epigenetic profiles, mutations from >8,200 tumor-normal pairs, and our experimental data from clinical samples, we discovered broad H3K4me3 (wider than 4 kb) as the first epigenetic signature for tumor suppressors in normal cells. Broad H3K4me3 is associated with increased transcription elongation and enhancer activity together leading to exceptionally high gene expression, and is distinct from other broad epigenetic features, such as super-enhancers. Broad H3K4me3 conserved across normal cells may represent pan-cancer tumor suppressors, such as P53 and PTEN, whereas cell-type-specific broad H3K4me3 may indicate cell-identity genes and cell-type-specific tumor suppressors. Furthermore, widespread shortening of broad H3K4me3 in cancers is associated with repression of tumor suppressors. Together, the broad H3K4me3 epigenetic signature provides mutation-independent information for the discovery and characterization of novel tumor suppressors.

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Section: Resultssupporting

confidence: 54%

Broad H3K4me3 is associated with increased transcription elongation and enhancer activity at tumor-suppressor genes

et al. 2015

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“…Interestingly, a recent study has shown GPX3 hypermethylation and underexpression in human colon cancer. This study demonstrated that GPX3-deficient mouse model exhibited increased inflammation and tumor number, suggesting that loss of GPX3 is involved in inflammatory colonic tumorigenesis 45. Of major importance, the fact that neutral bile salts are still capable of activating NF-κB pathway and up-regulating pro-inflammatory cytokines and chemokines in esophageal epithelium, strongly suggests that strategies focusing on reducing acids only in GERD patients may not be sufficient to prevent the development of BE and/or progression to EAC.…”

Section: Discussionmentioning

confidence: 64%

Glutathione Peroxidase 7 Suppresses Bile Salt-Induced Expression of Pro-Inflammatory Cytokines in Barrett's Carcinogenesis

Peng¹,

Hu²,

Soutto³

et al. 2014

J. Cancer

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Esophageal adenocarcinoma (EAC) is the most frequent malignancy in the esophagus in the US and its incidence has been rising rapidly in the past few decades. Chronic gastroesophageal reflux disease (GERD), where the esophageal epithelium is abnormally exposed to acid and bile salts, is a pro-inflammatory condition that is the main risk factor for the development of Barrett's esophagus (BE) and its progression to EAC. Glutathione peroxidase 7 (GPX7) is frequently silenced through DNA hypermethylation during Barrett's tumorigenesis. In this study, we investigated the role of GPX7 in regulating the bile salts-induced inflammatory signaling in Barrett's carcinogenesis. Using quantitative real-time PCR (qRT-PCR), we demonstrated a significant induction in the expression levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8) and chemokines (CXCL-1 and CXCL-2) in esophageal cells after exposure to acidic (pH4) or neutral (pH7) bile salts. Western blot analysis showed that exposure to acidic and neutral bile salts increased p-NF-κB-p65 (S536) protein levels independent of ROS. Reconstitution of GPX7 expression in EAC cells abolished the increase of p-p65 (S536) protein levels and mRNA expression of cytokines and chemokines upon treatment with acidic and neutral bile salts. Examination of human primary EAC tissues by qRT-PCR demonstrated significant overexpression of cytokines (TNF-α, IL-1β and IL-8) in EAC samples, as compared to normal samples, with significant inverse correlation with GPX7 expression level. Taken together, the loss of GPX7 expression promotes bile salt-induced activation of pro-inflammatory cytokines and chemokines; important contributors to GERD-associated Barrett's carcinogenesis.

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“…Interestingly, the list was enriched for genes related to oxidoreductase activity (five genes: AOX1, PTGS1, ACOX2, COX7A1, and the tumor suppressor GPX3; ref. 22). Because the downregulation is seen in both cancer cell lines and primary tumors, we deduce that the changes are caused by a permanent reprograming of metabolism in cancer cells rather than response to tumor microenvironment, or cell culture conditions.…”

Section: Potential Pan-cancer Biomarkersmentioning

confidence: 81%

Transcriptome Analysis of Recurrently Deregulated Genes across Multiple Cancers Identifies New Pan-Cancer Biomarkers

Kaczkowski¹,

Tanaka

Kawaji

et al. 2016

Cancer Research

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Genes that are commonly deregulated in cancer are clinically attractive as candidate pan-diagnostic markers and therapeutic targets. To globally identify such targets, we compared Cap Analysis of Gene Expression profiles from 225 different cancer cell lines and 339 corresponding primary cell samples to identify transcripts that are deregulated recurrently in a broad range of cancer types. Comparing RNA-seq data from 4,055 tumors and 563 normal tissues profiled in the The Cancer Genome Atlas and FANTOM5 datasets, we identified a core transcript set with theranostic potential. Our analyses also revealed enhancer RNAs, which are upregulated in cancer, defining promoters that overlap with repetitive elements (especially SINE/Alu and LTR/ERV1 elements) that are often upregulated in cancer. Lastly, we documented for the first time upregulation of multiple copies of the REP522 interspersed repeat in cancer. Overall, our genomewide expression profiling approach identified a comprehensive set of candidate biomarkers with pan-cancer potential, and extended the perspective and pathogenic significance of repetitive elements that are frequently activated during cancer progression.Cancer Res; 76(2); 216-26. Ó2015 AACR.

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Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Cited by 159 publications

References 46 publications

Broad H3K4me3 is associated with increased transcription elongation and enhancer activity at tumor-suppressor genes

Broad H3K4me3 is associated with increased transcription elongation and enhancer activity at tumor-suppressor genes

Glutathione Peroxidase 7 Suppresses Bile Salt-Induced Expression of Pro-Inflammatory Cytokines in Barrett's Carcinogenesis

Transcriptome Analysis of Recurrently Deregulated Genes across Multiple Cancers Identifies New Pan-Cancer Biomarkers

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