Array-CGH analysis of the gastric cancer cell lines suggested that TXNIP loci were intact, suggesting that allelic loss might not be the major mechanism responsible for the downregulation of TXNIP in these cells. Furthermore, our data suggested that promoter hypermethylation of TXNIP may not be an important epigenetic mechanism that regulate the silencing of this gene. Chromatin immunoprecipitation (ChIP) assay revealed that SAHA induced hyperacetylation of histone H3 and H4 at the 5' flanking region of TXNIP gene, suggesting SAHA could promote TXNIP gene transcription via modification of histones located at the promoter region. Our data revealed that the loss or reduced expression of TXNIP in gastric cancer cells is associated with epigenetic histone acetylation mechanism. / Gastric cancer is a common cancer especially in Asian countries and is associated with high morbidity and mortality. Epigenetic inactivation of tumor suppressor is a common mechanism involved in carcinogenesis of a variety of human cancers and recent evidence suggested that targeting epigenetic modifications may be an approach to combat cancer. Our group and others have demonstrated frequent promoter methylation of cancer related genes in gastric cancer. In this study, we aim to identify cancer associated genes regulated by another important epigenetic mechanism, namely histone acetylation. / In addition, we demonstrated that over-expression of TXNIP significantly reduced cell migration ability and inhibited cell invasiveness in gastric cancer cells. Furthermore, absence or reduced expression of TXNIP in gastric cancer was associated with diffuse-type gastric cancer, advanced stage disease and predicted a poor disease specific survival. The findings supported that TXNIP is a functional tumor suppressor gene and may be a potential biomarker in gastric cancer. / We analyzed 25 paired gastric cancer and non-cancer gastric mucosa and found that expression of TXNIP mRNA level was reduced in 84% of gastric cancer and was significantly downregulated as compared to the paired non-cancer gastric tissues (p=0.002). Expression of TXNIP protein by western blot was down-regulated in 3 out of 5 cases. Furthermore, by immunohistochemical staining of TXNIP in tissue array containing 150 cases of gastric cancer also showed frequent down-regulation of TXNIP expression and ∼26% with complete lack of TXNIP expression. / We first showed that suberoylanilide hydroxamic acid (SAHA), a well known histone deacetylase inhibitor, has anti-proliferative effect in a panel of gastric cancer cell lines (MKN1, MKN7, MKN28, MKN45, SNU1, SNU16, AGS, N87 and KatoIII cells). We compared gene expression profiles of SAHA treated vs control AGS cells to identify a set of genes that were differentially upregulated by SAHA treatment. Based on our microarray analysis in nine gastric cancer cell lines (MKN1, MKN7, MKN28, MKN45, SNU1, SNU16, AGS, N87 and KatoIII) and normal gastric tissues, a set of commonly downregulated genes in gastric cancer cells was elucidated. Analysis of these data sets with subsequent confirmation using real-time PCR analysis, genes that were downregulated in gastric cancer cells but upregulated upon SAHA treatment were identified. Among these selected genes, Thioredoxin Interacting Protein (also known as VDUP-1/TBP2/TXNIP ) was down-regulated in all cancer cell lines tested, and its protein expression was significantly induced by SAHA treatment in a numbers of gastric cancer cell lines including AGS, MKN1, MKN45, N87 and KatoIII. Thus, we focused on the TXNIP in the subsequent studies. / Tang, Angie. / Adviser: To Ka Fai. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 180-202). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_344487 |
| Date | January 2010 |
| Contributors | Tang, Angie, Chinese University of Hong Kong Graduate School. Division of Anatomical & Cellular Pathology. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xviii, 205 leaves : ill.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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