Correlation of epigenetic aberrance with STAT3 signaling pathway in gastric carcinogenesis.
ABSTRACT It has been suggested that STAT3 signaling plays important roles in regulating epigenetic aberrance during tumorigenesis, especially in the expression of certain key epigenetic enzymes such as DNMTs, HDACs, and HMTs. However, there has been no report on the relationship of STAT3 signaling and epigenetic aberrance in gastrocarcinogenesis.
The purpose of this study was to explore the interrelationship of STAT3 signaling pathway and epigenetic aberrance in gastrocarcinogenesis.
Immunohistochemistry was utilized to examine the protein expressions of pSTAT3, DNMT1, HDAC1, and EZH2 in 153 tissue specimens, including 20 of normal gastric epithelium tissue, 21 of intestinal metaplasia (IM), 24 of dysplasia (DYS), 23 of early gastric cancer (EGC) and 65 of advanced gastric cancer (AGC), and then analyze their possible relationship with clinicopathological factors.
We found that the four protein expressions were obviously enhanced following the malignant process of gastric carcinogenesis. Pearson correlation analysis of all the pathological groups showed that expression of pSTAT3 was highly associated with DNMT1, but not with HADC1 and EZH2. However, significant correlations were detected among the expression of DNMT1, HDAC1, and EZH2. Further analysis of each pathological group demonstrated that pSTAT3's expression was dramatically related with DNTM1 in the IM (P = 0.021) and EGC groups (P = 0.013) and correlated with EZH2 in the DYS group (P = 0.020). Furthermore, pSTAT3's expression was associated with T staging (P = 0.015) in the AGC group, whereas DNMT1 was associated with gender (P = 0.021), HDAC1 with Lauren classification (P = 0.007), and EZH2 with T staging (P = 0.003) and lymphatic staging (P = 0.038).
The STAT3 signaling pathway may correlate with epigenetic aberrance during gastrocarcinogenesis.
- SourceAvailable from: Theresa K Kelly
Article: Epigenetics in cancer.[show abstract] [hide abstract]
ABSTRACT: Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer. The initiation and progression of cancer, traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic alterations. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer including DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs, specifically microRNA expression. The reversible nature of epigenetic aberrations has led to the emergence of the promising field of epigenetic therapy, which is already making progress with the recent FDA approval of three epigenetic drugs for cancer treatment. In this review, we discuss the current understanding of alterations in the epigenetic landscape that occur in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, including the cancer stem cell model, and the potential use of this knowledge in designing more effective treatment strategies.Carcinogenesis 09/2009; 31(1):27-36. · 5.64 Impact Factor
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ABSTRACT: To date, several reports on methylation of various genes in gastric cancer (GC) have been published. However, most of these studies focused on cancer tissues or a single gene only and gave no information about the methylation status of specific genes in the premalignant stages or about the concurrent methylation of other genes in specific lesions. We attempted to investigate methylation of multiple genes in a large sample collection of GC (n = 80), gastric adenoma (GA) (n = 79), intestinal metaplasia (IM) (n = 57), and chronic gastritis (CG) (n = 74). We determined the methylation frequency of 12 genes, including APC, COX-2, DAP-kinase, E-cadherin, GSTP1, hMLH1, MGMT, p16, p14, RASSF1A, THBS1, and TIMP3 by methylation-specific PCR. Five different classes of methylation behaviors were found: (1) genes methylated in GC only (GSTP1 and RASSF1A); (2) genes showing low methylation frequency (<12%) in CG, IM, and GA, but significantly higher methylation frequency in GC (COX-2, hMLH1, and p16); (3) a gene with low and similar methylation frequency (8.8-21.3%) in four-step lesions (MGMT); (4) genes with high and similar methylation frequency (53-85%) in four-step lesions (APC and E-cadherin); and (5) genes showing an increasing tendency with or without fluctuation of the methylation frequency along the progression (DAP-kinase, p14, THBS1, and TIMP3). The average number of methylated genes was 2.7, 3.6, 3.4, and 5.2 per 12 tested genes in CG, IM, GA, and GC, respectively. Our results suggest that tumor suppressor genes show a gene type-specific methylation profile and that aberrant CpG island methylation tends to accumulate along the pathway of multistep carcinogenesis.Laboratory Investigation 05/2003; 83(5):635-41. · 3.96 Impact Factor
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ABSTRACT: Chronic infection of the gastric mucosa with Helicobacter pylori has long been recognized as a significant risk factor for gastric cancer, and indeed, this model represents the prototypical inflammation-associated cancer. In this review, we present the latest clinical and experimental evidence showing that gastrin peptides and their receptors [the cholecystokinin (CCK2) receptors] potentiate the progression of gastric cancer and other gastrointestinal malignancies in the presence of inflammation. We highlight the feed-forward mechanisms by which gastrin and CCK2 receptor expression are upregulated during inflammation and in gastrointestinal cancers, summarize gastrin's proinflammatory role by inducing the production of cyclooxgenase-2 (COX-2) and interleukin-8 (IL-8), and relate evidence suggesting that gastrin and their receptors modulate the function of immune cells and fibroblasts following cellular stress, injury, repair, as well as during cancer progression. We discuss trends for future studies directed toward the elucidation of gastrin peptides' role in regulating intercellular molecular signaling mechanisms between local and circulating immune cells, fibroblasts, epithelial cells, and other cell types in the microenvironments of inflammation-related cancers. Elucidation of the molecular and cellular pathways that relate inflammation with cancer may provide additional opportunities to develop complementary therapies that target the inflammatory microenvironment of the cancer.Current opinion in endocrinology, diabetes, and obesity 11/2009; 17(1):33-9.