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1.
Cell Physiol Biochem. 2018;50(2):411-425. doi: 10.1159/000494153. Epub 2018 Oct 11.

Hypermethylation of miR-338-3p and Impact of its Suppression on Cell Metastasis Through N-Cadherin Accumulation at the Cell -Cell Junction and Degradation of MMP in Gastric Cancer.

Author information

1
Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi An, China.
2
Department of Clinical Medicine, Medical College of Yan'an University, Yan'an, China.
3
The ART Center, Northwest Women's and Children's Hospital, Xi An, China.
4
Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi An, China.
5
Program in Plant Biology and Conservation, Biological Sciences, Weinberg College of Arts and Sciences, Northwestern University, Evanston, Illinois, USA.
6
Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi An, China.
7
Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi An, China.

Abstract

BACKGROUND/AIMS:

MicroRNAs (miRNAs) have been well studied in human carcinogenesis and cancer progression. Our previous study showed the down-regulation of miR-338-3p expression in human gastric cancer (GC). However, the reasons of this dysregulation remain largely unclear.

METHODS:

Bisulfite sequence analysis was performed to explore the methylation status of the promoter region of miR-338-3p. Cell wound-healing and transwell assays were performed to examine the capacity of cell migration and cell interaction. A dual-luciferase reporter was used to validate the bioinformatics-predicted target gene of miR-338-3p. Western blotting, RNA interference, and immunofluorescence (IF) were used to evaluate the expression of MMPs and the location of N-cadherin to determine the mechanism underlying miR-338-3p-induced anti-tumor effects.

RESULTS:

miR-338-3p was epigenetically silenced, and this loss of expression was significantly correlated with the Borrmann Stage in GC. Restoring miR-338-3p expression in BGC-823 cells inhibited cell migration and invasion. Moreover, Ras-related protein (Rab-14) and Hedgehog acyltransferase (Hhat) were identified as direct targets of miR-338-3p. Both enforced expression of miR-338-3p and small interfering RNA induced Rab14-mediated accumulation of N-cadherin in the cell -cell junctions or Hhat-associated matrix metalloproteinase (MMP) degradation, which may underline the metastasis defects caused by loss of miR-338-3p in GC.

CONCLUSION:

These data indicate that miR-338-3p functions as a tumor suppressor in GC, and that the hypermethylation status of its CpG island might be a novel potential strategy for treating GC.

KEYWORDS:

Gastric cancer; Hhat-MMP signaling; Metastasis; Rab14-N-cadherin; miR-338-3p

PMID:
30308487
DOI:
10.1159/000494153
[Indexed for MEDLINE]
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2.
Oncotarget. 2017 Sep 20;8(48):84054-84065. doi: 10.18632/oncotarget.21097. eCollection 2017 Oct 13.

The role of TFPI2 hypermethylation in the detection of gastric and colorectal cancer.

Author information

1
Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, China.
2
Department of Medical Oncology, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Zhejiang 312000, China.
3
Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China.

Abstract

Gastrointestinal cancer is a prevalent disease with high morbidity and mortality. Tissue factor pathway inhibitor 2 (TFPI2) gene could protect the extracellular matrix of cancer cells from degradation and tumor invasion. The goal of our study was to estimate the diagnostic value of TFPI2 hypermethylation in gastric cancer (GC) and colorectal cancer (CRC). TFPI2 methylation was measured by quantitative methylation-specific polymerase chain reaction (qMSP) method in 114 GC and 80 CRC tissues and their paired non-tumor tissues. Our results showed that TFPI2 methylation was significantly higher in tumor tissues (GC: 29.940% vs. 12.785%, P < 0.001; CRC: 26.930% vs. 5.420%, P < 0.001). The methylation level of TFPI2 in colorectal tumor tissues was significantly higher than that in colorectal normal tissues (26.930% versus 0.002%, P < 0.00001). In GC, TFPI2 hypermethylation yielded an area under the curve (AUC) of 0.762 (95% CI: 0.696-0.828) with a sensitivity of 68% and a specificity of 83%. In CRC, TFPI2 hypermethylation yielded an AUC of 0.759 (95% CI: 0.685-0.834) with a sensitivity of 61% and a specificity of 84%. Similarly, TCGA data also supported TFPI2 hypermethylation was a promising diagnostic marker for GC and CRC. Moreover, the dual-luciferase reporter assay showed TFPI2 fragment could upregulate gene expression (fold change = 5, P = 0.005). Data mining further indicated that TFPI2 expression in CRC cell lines was significantly increased after 5'-AZA-deoxycytidine treatment (fold change > 1.37). In conclusion, TFPI2 hypermethylation might be a promising diagnostic biomarker for GC and CRC.

KEYWORDS:

DNA methylation; colorectal cancer; gastric cancer; quantitative methylation-specific polymerase chain reaction; tissue factor pathway inhibitor 2

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no conflicts of interest.

3.
Oncotarget. 2017 Jan 31;8(5):8105-8119. doi: 10.18632/oncotarget.14099.

NDRG4 hypermethylation is a potential biomarker for diagnosis and prognosis of gastric cancer in Chinese population.

Author information

1
Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, China.
2
Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China.

Abstract

In order to assess whether N-Myc downstream regulated gene 4 (NDRG4) methylation was associated with the diagnosis and prognosis of gastric cancer, we measured the methylation of NDRG4 promoter and gene body regions among 110 gastric cancer patients using quantitative methods (MethyLight and pyrosequencing). Both NDRG4 promoter and gene body methylation levels were increased in tumor tissues than paired adjacent normal tissues (P < 0.001). NDRG4 gene body methylation was found to be significantly associated with age and tumor differentiation. NDRG4 promoter hypermethylation was proved to be a predictor of poor overall survival. However, opposite result was observed among The Cancer Genome Atlas (TCGA) cohort. The findings from gastric cell lines and public databases have suggested that NDRG4 methylation level was inversely associated with NDRG4 transcription level. Subsequent luciferase reporter gene assay showed that promoter CpG island but not gene body CpG island was able to upregulate gene expression. Collectively, NDRG4 promoter hypermethylation contributed to the risk of gastric cancer and predicted a poor prognosis in Chinese gastric cancer patients. Moreover, the combined methylation levels of NDRG4 promoter and gene body served as diagnostic biomarkers in gastric cancer.

KEYWORDS:

DNA methylation; N-Myc downstream regulated gene 4; diagnosis; gastric cancer; prognosis

PMID:
28042954
PMCID:
PMC5352386
DOI:
10.18632/oncotarget.14099
[Indexed for MEDLINE]
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4.
Biomed Res Int. 2016;2016:5083841. doi: 10.1155/2016/5083841. Epub 2016 Jul 14.

Downregulation of ADAMTS8 by DNA Hypermethylation in Gastric Cancer and Its Clinical Significance.

Author information

1
Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital, China Medical University, No. 4 Chongshandong Road, Shenyang 110032, China.

Abstract

A disintegrin and metallopeptidase with thrombospondin motif type 8 (ADAMTS8), a member of the ADAMTS family, was discovered as a novel angiogenesis inhibitor. We analyzed the expression and methylation of ADAMTS8 in primary gastric tumors and gastric cancer cell lines. We also examined the relationship between ADAMTS8 expression and methylation and clinicopathologic features. The results showed that the significant downregulation of ADAMTS8 mRNA expression was observed in gastric cancer cell lines and tissues, and its expression was related to invasive depth and lymph node metastasis. CpG was hypermethylated in gastric cancer cell lines MKN45, MGC803, and BGC823, as well as primary gastric cancer specimens. ADAMTS8 mRNA expression was significantly lower in methylated primary gastric tumors. A significant association was found between ADAMTS8 methylation status and lymph node metastasis in primary gastric cancer. Moreover, ADAMTS8 expression was upregulated in the gastric cancer cell lines MGC803, BGC823, and MKN45 after treatment with 5-aza-2'-deoxycytidine. Thus, our results demonstrate that expression of ADAMTS8 mRNA is significantly decreased and DNA methylation is frequent in gastric cancer. ADAMTS8 hypermethylation is associated with decreased expression in gastric cancer and may play an important role in the invasion and metastasis of gastric cancer.

PMID:
27493958
PMCID:
PMC4963609
DOI:
10.1155/2016/5083841
[Indexed for MEDLINE]
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5.
Tumour Biol. 2016 Aug;37(8):11249-57. doi: 10.1007/s13277-016-5001-6. Epub 2016 Mar 5.

The value of serum RASSF10 hypermethylation as a diagnostic and prognostic tool for gastric cancer.

Author information

1
Department of General Surgery, Nantong University Affiliated Hospital, 20 Xisi Street, Nantong, 226001, Jiangsu, China.
2
Department of Pathology, Nantong University Affiliated Hospital, Nantong, 226001, Jiangsu, China.
3
Department of Surgical Comprehensive Laboratory, Nantong University Affiliated Hospital, Nantong, 226001, Jiangsu, China.
4
Department of General Surgery, Nantong University Affiliated Hospital, 20 Xisi Street, Nantong, 226001, Jiangsu, China. wzw3639@163.com.
5
Department of General Surgery, Nantong University Affiliated Hospital, 20 Xisi Street, Nantong, 226001, Jiangsu, China. tdfymaoqsh@sina.com.
6
Department of Minimally Invasive Surgery, The Affiliated Hospital of Nantong University, 20 Xisi Street, Nantong, 226001, Jiangsu, China. tdfymaoqsh@sina.com.

Abstract

The tumor-suppressing role of Ras-association domain family 10 (RASSF10) has been described in several types of cancers. Here, we evaluated the potential use of the hypermethylation status of the RASSF10 promoter in serum as a new diagnostic and prognostic tool in gastric cancer (GC). We used bisulfite sequencing polymerase chain reaction to examine RASSF10 methylation levels in serum and/or tumor samples from 82 GC, 45 chronic atrophic gastritis (CAG), and 50 healthy control patients. In the serum of GC patients, the median level of RASSF10 methylation was higher at 47.84 % than those in the serum of CAG and healthy control patients at 11.89 and 11.35 %, respectively. The median level of RASSF10 methylation in GC tumor tissue was similarly high at 62.70 %. Furthermore, RASSF10 methylation levels were highly correlated between paired serum and tumor samples from GC patients. We performed receiver-operating characteristic curve analyses to verify that serum RASSF10 methylation levels could effectively distinguish GC from control patients. Moreover, multivariate analyses showed that high serum RASSF10 methylation levels in GC patients were associated with large tumors, lymph node metastasis, and high carcinoembryonic antigen (CEA) levels. Survival analyses showed that GC patients with high serum RASSF10 methylation levels had shorter overall and disease-free survival after D2 lymphadenectomy than those with low levels. High serum RASSF10 methylation levels were also an independent predictor of tumor recurrence and GC patient survival. In conclusion, serum RASSF10 promoter methylation levels can serve as a valuable indicator for the diagnosis and prognosis of GC in the clinic.

KEYWORDS:

Diagnosis; Gastric cancer; Hypermethylation; Prognosis; RASSF10; Serum

PMID:
26945573
DOI:
10.1007/s13277-016-5001-6
[Indexed for MEDLINE]
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6.
Oncotarget. 2016 Mar 1;7(9):9788-800. doi: 10.18632/oncotarget.7125.

Helicobacter pylori CagA induces tumor suppressor gene hypermethylation by upregulating DNMT1 via AKT-NFκB pathway in gastric cancer development.

Author information

1
Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
2
Affiliated Hospital of Jining Medical University, Jining, People's Republic of China.
3
Department of Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
4
Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China.

Abstract

Methylation of CpG islands in tumor suppressor gene prompter is one of the most characteristic abnormalities in Helicobacter pylori (HP)-associated gastric carcinoma (GC). Here, we investigated the pathogenic and molecular mechanisms underlying hypermethylation of tumor suppressor genes in HP induced GC development. We found that tumor suppressor genes hypermethylation, represented by MGMT, positively correlated with CagA in clinical specimens, gastric tissues from HP infected C57 mice and GC cell lines transfected by CagA or treated by HP infection. CagA enhanced PDK1 and AKT interaction and increased AKT phosphorylation. The P-AKT subsequent activated NFκB, which then bound to DNMT1 promoter and increased its expression. Finally, the upregulated DNMT1 promoted tumor suppressor genes hypermethylation with MGMT as a representative. In conclusion, CagA increased tumor suppressor genes hypermethylation via stimulating DNMT1 expression through the AKT-NFκB pathway.

KEYWORDS:

AKT-NF-kB pathway; DNMT1; H. pylori CagA; gastric cancer development; hypermethylation

PMID:
26848521
PMCID:
PMC4891084
DOI:
10.18632/oncotarget.7125
[Indexed for MEDLINE]
Free PMC Article
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7.
Clin Chim Acta. 2015 Aug 25;448:124-32. doi: 10.1016/j.cca.2015.07.001. Epub 2015 Jul 3.

Hypermethylation in gastric cancer.

Author information

1
Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, People's Republic of China.
2
Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, People's Republic of China.
3
Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, People's Republic of China. Electronic address: phou@mail.xjtu.edu.cn.

Abstract

Although gastric cancer (GC) is highly prevalent in China and is a leading cause of cancer-related death, major advances in early diagnostic and effective therapeutic strategies have not been made. GC patients are usually diagnosed at an advanced stage and the prognosis is still poor. Over the years, many efforts have been done on exploring the pathology of GC. In particular, genome-wide analysis tools have been widely used in the detection of genetic and epigenetic alterations in GC. For example, many tumor suppressor genes have been found to be aberrantly hypermethylated in GCs, and some even in gastric precancerous lesions, suggesting a role of this molecular event in early gastric tumorigenesis. In addition, accumulating evidences have demonstrated that some hypermethylated genes can be used as potential biomarkers for detection and diagnosis of GC in biopsy specimens and non-invasive body fluids. These exciting advances provide unprecedented opportunities for the development of molecular-based novel diagnostic, prognostic, and therapeutic strategies for GC. Here, we reviewed recent findings on the promoter hypermethylation of tumor suppressor genes in GC and aimed to provide better understanding of the contribution of this epigenetic event to gastric tumorigenesis.

KEYWORDS:

Biomarkers; Clinical utility; Epigenetics; Gastric cancer; Gene methylation

PMID:
26148722
DOI:
10.1016/j.cca.2015.07.001
[Indexed for MEDLINE]
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8.
Cancer Biol Ther. 2015;16(8):1241-51. doi: 10.1080/15384047.2015.1056411. Epub 2015 Jul 6.

UHRF1 promotes proliferation of gastric cancer via mediating tumor suppressor gene hypermethylation.

Author information

1
a Department of Medical Affairs ; The 88th Hospital of PLA ; Tai'an , China.

Abstract

Epigenetic changes play significant roles in cancer development. UHRF1, an epigenetic regulator, has been shown to be overexpressed and to coordinate tumor suppressor gene (TSG) silencing in several cancers. In a previous study, we found that UHRF1 promoted gastric cancer (GC) invasion and metastasis. However, the role and underlying mechanism of UHRF1 in GC carcinogenesis remain largely unknown. In the present study, we investigated UHRF1 expression and function in GC proliferation and explored its downstream regulatory mechanism. The results demonstrated that UHRF1 overexpression was an independent and significant predictor of GC prognosis. Downregulation of UHRF1 suppressed GC proliferation and growth in vitro and in vivo, and UHRF1 upregulation showed opposite effects. Furthermore, downregulation of UHRF1 reactivated 7 TSGs, including CDX2, CDKN2A, RUNX3, FOXO4, PPARG, BRCA1 and PML, via promoter demethylation. These results provide insight into the GC proliferation process, and suggest that targeting UHRF1 represents a new therapeutic approach to block GC development.

KEYWORDS:

BRCA, breast cancer; CDH4, cadherin 4; CDKN2A, cyclin-dependent kinase inhibitor 2A; CDX2, caudal type homeobox 2; DNA methylation; DNMT, DNA methyltransferase; FOXO, forkhead box O; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GC, gastric cancer; GO, gene ontology; MSP, methylation-specific PCR; NC, negative control; PBS, phosphate buffered saline; PI, propidium iodide; PLA, Chinese People's Liberation Army; PML, promyelocytic leukemia; PPARG,peroxisome proliferator-activated receptor gamma; RB, retinoblastoma protein; RUNX3, runt-related transcription factor 3; TSG, tumor suppressor gene; UHRF1; UHRF1, ubiquitin-like containing PHD ring finger 1; gastric cancer; mRNA, messenger RNA; proliferation; qRT-PCR, quantitative reverse transcription–polymerase chain reaction; shRNA, short hairpin RNA; tumor suppressor gene

PMID:
26147747
PMCID:
PMC4622020
DOI:
10.1080/15384047.2015.1056411
[Indexed for MEDLINE]
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9.
Medicine (Baltimore). 2014 Oct;93(19):e107. doi: 10.1097/MD.0000000000000107.

Association of genetic variants in and promoter hypermethylation of CDH1 with gastric cancer: a meta-analysis.

Author information

1
Institute of Social Science Survey (HJ), Peking University, Beijing; Department of Social Science (HJ), Shenyang Medical College; Emergency Department (LL); Department of Gastroenterology (CZ), Shengjing Hospital, China Medical University, Shenyang, Liaoning; Division of Gastroenterology (FD, JY, LM), Second Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi; Department of General Surgery (KX), Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Brain Tumor Center (CZ), Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Biostatistics and Epidemiology (PK), University of Oklahoma Health Sciences Center, Oklahoma City, OK; Rush Alzheimer's Disease Center (JYY); and Department of Neurological Sciences (JYY), Rush University Medical Center, Chicago, IL.

Abstract

Gastric cancer (GC) is a common cause of cancer-related death. The etiology and pathogenesis of GC remain unclear, with genetic and epigenetic factors playing an important role. Previous studies investigated the association of GC with many genetic variants in and promoter hypermethylation of E-cadherin gene (CDH1), with conflicting results reported.To clarify this inconsistency, we conducted updated meta-analyses to assess the association of genetic variants in and the promoter hypermethylation of CDH1 with GC, including C-160A (rs16260) and other less-studied genetic variants,Data sources were PubMed, Cochrane Library, Google Scholar, Web of Knowledge, and HuGE, a navigator for human genome epidemiology.Study eligibility criteria and participant details are as follows: studies were conducted on human subjects; outcomes of interest include GC; report of genotype data of individual genetic variants in (or methylation status of) CDH1 in participants with and without GC (or providing odds ratios [OR] and their variances).Study appraisal and synthesis methods included the use of OR as a measure of the association, calculated from random effects models in meta-analyses. We used I for the assessment of between-study heterogeneity, and publication bias was assessed using funnel plot and Egger test.A total of 33 studies from 30 published articles met the eligibility criteria and were included in our analyses. We found no association between C-160A and GC (OR = 0.88; 95% confidence interval [CI], 0.71-1.08; P = 0.215), assuming an additive model (reference allele C). C-160A was associated with cardia (OR = 0.21; 95% CI, 0.11-0.41; P = 2.60 × 10), intestinal (OR = 0.66; 95% CI, 0.49-0.90; P = 0.008), and diffuse GC (OR = 0.57; 95% CI, 0.40-0.82; P = 0.002). The association of C-160A with noncardia GC is of bottom line significance (OR = 0.65; 95% CI, 0.42-1.01; P = 0.054). Multiple other less-studied genetic variants in CDH1 also exhibited association with GC. Gene-based analysis indicated a significant cumulative association of genetic variants in CDH1 with GC (all Ps <10). Sensitivity analysis excluding studies not meeting Hardy-Weinberg equilibrium (HWE) yielded similar results. Analysis by ethnic groups revealed significant association of C-160A with cardia GC in both Asian and whites, significant association with noncardia GC only in Asians, and no significant association with intestinal GC in both ethnic groups. There was significant association of C160-A with diffuse GC in Asians (P = 0.011) but not in whites (P = 0.081). However, after excluding studies that violate HWE, this observed association is no longer significant (P = 0.126). We observed strong association of promoter hypermethylation of CDH1 with GC (OR = 12.23; 95% CI, 8.80-17.00; P = 1.42 × 10), suggesting that epigenetic regulation of CDH1 could play a critical role in the etiology of GC.Limitations of this study are as follows: we could not adjust for confounding factors; some meta-analyses were based on a small number of studies; sensitivity analysis was limited due to unavailability of data; we could not test publication bias for some meta-analyses due to small number of included studies.We found no significant association of the widely studied genetic variant C-160A, but identified some other genetic variants showing significant association with GC. Future studies with large sample sizes that control for confounding risk factors and/or intensively interrogate CpG sites in CDH1 are needed to validate the results found in this study and to explore additional epigenetic loci that affect GC risk.

PMID:
25340495
PMCID:
PMC4616322
DOI:
10.1097/MD.0000000000000107
[Indexed for MEDLINE]
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10.
Int J Oncol. 2014 Dec;45(6):2576-86. doi: 10.3892/ijo.2014.2667. Epub 2014 Sep 23.

Epigenetic silencing of miRNA-9 is correlated with promoter-proximal CpG island hypermethylation in gastric cancer in vitro and in vivo.

Author information

1
Chongqing Cancer Institute, Chongqing 400030, P.R. China.
2
Department of Gastroenterology, Guizhou Provincial People's Hospital, The Affiliated People's Hospital of Guiyang Medical University, Guizhou 550002, P.R. China.
3
Department of Surgery, The First People Hospital, Jiangbei, Chongqing 400020, P.R. China.
4
Department of Gastroenterology, Children's Hospital, Chongqing Medical University, Chongqing 400014, P.R. China.
5
Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, P.R. China.
6
Laboratory of Clinical Diagnostics, Chongqing Medical University, Chongqing 400016, P.R. China.
7
Department of Gastroenterology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, P.R. China.

Abstract

Silencing of protein-coding tumor suppressor genes (TSGs) by CpG island hypermethylation is a common occurrence in gastric cancer (GC). Here, we examine if tumor suppressor microRNAs (miRNAs) are silenced in a similar manner. Real-time quantitative PCR (RTQ-PCR) was employed to investigate the expression level of four candidate miRNAs in GC tissues (n=30) and cell lines. Basing on RTQ-PCR results and bioinformatics approach, miR-9 was chosen for further study on epigenetic regulation. Bisulfite genomic sequencing PCR (BSP) was performed to assess the methylation status of miR-9 in GC tissues. In both GC cell lines and animal models, demethylation was performed either by treatment with 5-aza-2'-deoxycytidine (5-AZA-CdR) or by siRNA targeting DNMT1. We also analyzed the relationship between miRNAs and several clinicopathological features. Candidate miRNAs (miR-9, miR-433, miR-19b, and miR-370) were found strongly downregulated in GC tissues and cell lines. Their expression was increased following 5-AZA-CdR treatment. CpG island methylation of miR-9 was significantly higher in GC tissues compared to normal controls. After two demethylation treatments, miR-9 methylation degree was significantly decreased and miR-9 expression was ob-viously restored in GC cells and animal models. Deregulation of miR-9 was positively correlated with tumor lesion size. Three other miRNAs, miR-19b, miR-433, and miR-370 were assοciated with lymph node metastasis, decreased curvature, and poorly differentiated carcinoma. miR-19b and miR-433 were positively correlated with male gender. Of four candidate miRNAs downregulated in GC, miR-9 is epigenetically regulated by DNA methylation both in vitro and in vivo.

PMID:
25270964
DOI:
10.3892/ijo.2014.2667
[Indexed for MEDLINE]
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11.
J Cell Mol Med. 2014 Aug;18(8):1655-66. doi: 10.1111/jcmm.12352. Epub 2014 Jun 28.

Transmembrane protein 106A is silenced by promoter region hypermethylation and suppresses gastric cancer growth by inducing apoptosis.

Author information

1
Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Science Center, Beijing, China; Peking University Center for Human Disease Genomics, Peking University, Beijing, China.

Abstract

Inactivation of tumour suppressor genes by promoter methylation plays an important role in the initiation and progression of gastric cancer (GC). Transmembrane 106A gene (TMEM106A) encodes a novel protein of previously unknown function. This study analysed the biological functions, epigenetic changes and the clinical significance of TMEM106A in GC. Data from experiments indicate that TMEM106A is a type II membrane protein, which is localized to mitochondria and the plasma membrane. TMEM106A was down-regulated or silenced by promoter region hypermethylation in GC cell lines, but expressed in normal gastric tissues. Overexpression of TMEM106A suppressed cell growth and induced apoptosis in GC cell lines, and retarded the growth of xenografts in nude mice. These effects were associated with the activation of caspase-2, caspase-9, and caspase-3, cleavage of BID and inactivation of poly (ADP-ribose) polymerase (PARP). In primary GC samples, loss or reduction of TMEM106A expression was associated with promoter region hypermethylation. TMEM106A was methylated in 88.6% (93/105) of primary GC and 18.1% (2/11) in cancer adjacent normal tissue samples. Further analysis suggested that TMEM106A methylation in primary GCs was significantly correlated with smoking and tumour metastasis. In conclusion, TMEM106A is frequently methylated in human GC. The expression of TMEM106A is regulated by promoter hypermethylation. TMEM106A is a novel functional tumour suppressor in gastric carcinogenesis.

KEYWORDS:

apoptosis; epigenetic alteration; gastric cancer; transmembrane protein 106A

PMID:
24975047
PMCID:
PMC4190911
DOI:
10.1111/jcmm.12352
[Indexed for MEDLINE]
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12.
World J Gastroenterol. 2013 Sep 7;19(33):5557-64. doi: 10.3748/wjg.v19.i33.5557.

Hypermethylation of TGF-β1 gene promoter in gastric cancer.

Author information

1
Yong-Qi Wang, Yu-Min Li, School of Life Sciences, Lanzhou University, Lanzhou 730000, Gansu Province, China.

Abstract

AIM:

To examine transforming growth factor-β1 (TGF-β1) promoter methylation in gastric cancer and to determine if Helicobacter pylori (H. pylori) or interleukin (IL)-1β could induce TGF-β1 hypermethylation in vitro.

METHODS:

We examined the frequency and extent of TGF-β1 promoter methylation using methylation-specific PCR in the gastric tissues from 47 gastric cancer patients and 39 non-gastric cancer subjects. H. pylori infection was confirmed by a positive result from either a serological test, histological analysis or C¹³ urea breath test. GES-1 and MKN-45 cells co-cultured with H. pylori or treated with IL-1β for 12, 24 and 48 h in vitro tested the effects of H. pylori or IL-1β on TGF-β1.

RESULTS:

Twenty-four/forty-seven (51%) cases of gastric cancer (GC) tissues showed TGF-β1 promoter methylation, 15/47 (31.9%) cases of matched non-cancerous gastric mucosa tissues from the GC patients, and 11/39 (28%) case of the normal gastric mucosa tissues from non-GC subjects showed TGF-β1 promoter methylation (51% vs 28%, P < 0.05). Significantly higher levels of methylation of TGF-β1 were found in the tumor tissues than in non-tumor tissues from GC patients (0.24 ± 0.06 vs 0.17 ± 0.04, P < 0.05) and normal gastric tissues from non-GC subjects (0.24 ± 0.06 vs 0.15 ± 0.03, P < 0.05). TGF-β1 methylation was found in 48.3% of H. pylori-positive gastric mucosal tissues whereas only 23.1% of H. pylori-negative gastric mucosal tissues showed TGF-β1 methylation (48.3% vs 23.1%, P < 0.05). IL-1β appeared to induce a dose-dependent methylation of TGF-β1 and the strongest methylation was observed in GES-1 cells treated with 2.5 ng/mL of IL-1β for 48 h. Further studies showed that pre-treatment of GES-1 cells with 20 ng/mL IL-1RA for 1 h could partially abolish the effect of IL-1β on TGF-β1 methylation. Infection of GES-1 cells by H. pylori was not found to induce significant TGF-β1 promoter methylation.

CONCLUSION:

Our data revealed that TGF-β1 promoter is methylated in GC patients. IL-1β may be an important mediator for H. pylori induced gene methylation during GC development.

KEYWORDS:

Gastric cancer; Helicobacter pylori; Interleukin-1β; Methylation; Transforming growth factor-β1

PMID:
24023501
PMCID:
PMC3761111
DOI:
10.3748/wjg.v19.i33.5557
[Indexed for MEDLINE]
Free PMC Article
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13.
Biochim Biophys Acta. 2012 Feb;1823(2):298-305. doi: 10.1016/j.bbamcr.2011.11.011. Epub 2011 Dec 20.

Role of PCDH10 and its hypermethylation in human gastric cancer.

Author information

1
Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, 3002 Shungang West Road, Futian District, Shenzhen 518036, Guangdong Province, PR China.

Abstract

Epigenetic changes of genomic DNA are involved in the development and progression of many cancers. Aberrant methylation of CpG islands in the promoter regions of certain tumor-suppressor genes (TSG) is frequently observed in cancer cells. Protocadherin 10 (PCDH10), a member of the cadherin superfamily, is a recently identified putative TSG. PCDH10 is frequently silenced in many solid tumors. However, the role of PCDH10 in gastric cancer is largely unknown. In this study, we examined the expression and methylation status of PCDH10 in gastric cancer cells and tissues by real time PCR and methylation-specific PCR (MSP), and then investigated the biological function of PCDH10. We found that the expression of PCDH10 was markedly reduced in gastric cancer cells and tissues. The reduced expression correlated with hypermethylation of this gene in its promoter region, as demonstrated by MSP and bisulfite genomic sequencing (BGS) analysis. In addition, pharmacological demethylation using 5-Aza restored the expression of PCDH10 in gastric cancer cells. Over-expression of PCDH10 in gastric cancer cells suppressed cell proliferation and migration, but did not cause marked apoptosis. Over-expression of PCDH10 also suppressed growth of xenograft tumors in nude mice. Thus, PCDH10 functions as a TSG in gastric cancer, and might be a useful target for cancer therapy.

PMID:
22206871
DOI:
10.1016/j.bbamcr.2011.11.011
[Indexed for MEDLINE]
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14.
Epigenetics. 2011 Oct 1;6(10):1189-97. doi: 10.4161/epi.6.10.16535. Epub 2011 Oct 1.

Aberrant hypermethylation of miR-9 genes in gastric cancer.

Author information

1
Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, China.

Abstract

Carcinogenesis of the stomach involves multiple steps including genetic mutation or epigenetic alteration of tumor suppressor genes or oncogenes. Recently, tumor suppressive miRNAs have been shown to be deregulated by aberrant hypermethylation during gastric cancer progression. In this study, we demonstrate that three independent genetic loci encoding for miR-9 (miR-9-1, miR-9-2 and miR-9-3) are simultaneously modified by DNA methylation in gastric cancer cells. Methylation-mediated silencing of these three miR-9 genes can be reactivated in gastric cancer cells through 5-Aza-dC treatment. Subsequent analysis of the expression levels of miR-9 showed that it was significantly down-regulated in gastric cancers compared with adjacent normal tissues (P value < 0.005). A similar tendency toward a tumor-specific DNA methylation pattern was shown for miR-9-1, miR-9-2 and miR-9-3 in 72 primary human gastric cancer specimens. Ectopic expression of miR-9 inhibited cell proliferation, migration and invasion, suggesting its tumor suppressive potential in gastric cancer progression.

PMID:
21931274
PMCID:
PMC3225840
DOI:
10.4161/epi.6.10.16535
[Indexed for MEDLINE]
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15.
Int J Cancer. 2010 Jun 1;126(11):2542-52. doi: 10.1002/ijc.24958.

Glutamate receptor, ionotropic, kainate 2 silencing by DNA hypermethylation possesses tumor suppressor function in gastric cancer.

Author information

1
Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.

Abstract

Aberrant DNA methylation is considered a major mechanism for silencing tumor suppressor genes in gastric cancer. We used CpG microarray and differential methylation hybridization strategies to identify potential tumor suppressor genes and recovered glutamate receptor, ionotropic, kainate 2 (GRIK2) as a novel epigenetic target in gastric cancer. Additional experiments showed that the promoter region of GRIK2 was hypermethylated in 3 of the 4 tested gastric cancer cell lines, and its expression was restored by treatment of cells with the DNA methylation inhibitor, 5'-aza-dC. In clinical samples, the GRIK2 promoter was differentially hypermethylated in tumor tissues compared with adjacent normal tissues (p < 0.001), and this methylation was inversely correlated with the expression level of GRIK2 mRNA (r = -0.44). Functional studies further showed that GRIK2-expressing gastric cancer cell lines showed decreased colony formation and cell migration. Taken together, these results suggest that GRIK2 may play a tumor-suppressor role in gastric cancer. Future studies are warranted to examine whether DNA hypermethylation of the GRIK2 promoter can be used as a potential tumor marker for gastric cancer.

PMID:
19824040
DOI:
10.1002/ijc.24958
[Indexed for MEDLINE]
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16.
Int J Cancer. 2009 Feb 1;124(3):739-44. doi: 10.1002/ijc.23960.

Promoter hypermethylation correlates with the Hsulf-1 silencing in human breast and gastric cancer.

Author information

1
Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing, China.

Abstract

The HSulf-1 gene is an important factor that modulates the sulfation status of heparan sulfate proteoglycans (HSPGs) in the extracellular matrix, resulting in disturbance of HSPG-related signal transduction pathways. Recently, HSulf-1 has been reported to be down-regulated in several human cancers. In this study, we first cloned and characterized the 5' promoter region of the HSulf-1 gene (around 400 bp) that contained high basal promoter activity. We also found that this functional promoter region was hypermethylated in a number of human cancer cell lines. Furthermore, we found that hypermethylation in this promoter region correlated with the down-regulation of the HSulf-1 expression in human breast and gastric cancer cell lines and tissue samples. These results suggest that the promoter hypermethylation may be one of the mechanisms of the HSulf-1 gene silencing in human breast and gastric cancers. Finally, we demonstrated that the HSulf-1 promoter was more frequently (p<0.05) methylated in cell-free DNA extracted from serum samples of human breast and gastric cancer patients than that of healthy people (76.2%, 55.0% and 19.0%, respectively), indicating that detection of the HSulf-1 promoter methylation in serum samples may have clinical implications in early detection and diagnosis of human breast and gastric cancers.

PMID:
19006069
DOI:
10.1002/ijc.23960
[Indexed for MEDLINE]
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17.
Cancer Lett. 2007 Jun 18;251(1):78-85. Epub 2006 Dec 19.

Downregulation and CpG island hypermethylation of NES1/hK10 gene in the pathogenesis of human gastric cancer.

Author information

1
Department of Gastroenterology, Ruijin Hospital, Jiaotong University School of Medicine, Shanghai 200025, China.

Abstract

The normal epithelial cell-specific-1 (NES1)/Kallikrein 10 gene is proposed to be a novel putative tumor suppressor gene in several malignant diseases. The role of NES1 gene in gastric cancer has not been fully understood. Our study revealed that CpG island hypermethylation plays an important role in the downregulation of NES1 mRNA expression in gastric cancer. In situ hybridization showed that loss or reduction of NES1 mRNA expression is associated with differentiation level during tumor progression suggesting that NES1 inactivation might contribute to the malignant progression of human gastric cancers.

PMID:
17182177
DOI:
10.1016/j.canlet.2006.11.006
[Indexed for MEDLINE]
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