Concurrent hypermethylation of multiple tumor-related genes in gastric carcinoma and adjacent normal tissues

Leung, Wai Keung; Yu, Jun; Ng, Enders Kwok Wai; To, Ka Fai; K., Po; Lee, Tin‐Lap; Go, Minnie Y.Y.; Chung, Sai Ho; Sung, Joseph J.Y.

doi:10.1002/1097-0142(20010615)91:12<2294::aid-cncr1261>3.0.co;2-g

Cited by 120 publications

(59 citation statements)

References 23 publications

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“…Inactivation of tumor suppressor genes has been known to contribute to the abnormal proliferation, transformation, and progression in human cancers. Aberrant promoter methylation of cancer-related key genes, such as p16, E-cadherin, TIMP-3, APC, THBS1, and hMLH1, has been observed frequently in gastric carcinoma (Kang et al, 2001;Leung et al, 2001). …”

supporting

confidence: 92%

Promoter Methylation and Silencing of PTEN in Gastric Carcinoma

Kang

Lee

Kim

2002

Laboratory Investigation

222

158

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SUMMARY:The PTEN/MMAC1/TEP1 gene (phosphatase and tensin homolog deleted on chromosome 10/mutated in multiple advanced cancers/TGF-␤ regulated and epithelial cell enriched phosphatase 1), which regulates the signaling pathways of Akt, is a novel tumor suppressor gene implicated in multiple cancers. Because a number of tumor suppressor genes are known to be silenced by aberrant promoter methylation, we examined the methylation status of the 5' CpG islands of PTEN using methylation-specific PCR. The altered expression of PTEN in 310 gastric carcinomas was analyzed by immunohistochemical staining using tissue-array and clinicopathologic profiles related to PTEN expression were characterized. Of 310 consecutive gastric carcinomas, 62 cases (20%) showed expression loss of PTEN. Altered PTEN expression was significantly associated with tumor depth and size, lymphatic invasion, advanced stage, pTNM stage, and patient survival (p Ͻ 0.001). The promoter methylation frequency of PTEN was found to be present in 26 (39%) of 66 cases examined, and 19 (73%) of 26 gastric cancer tissues showing promoter methylation exhibited the loss of PTEN expression. Abnormalities in the expression of PTEN significantly correlated with promoter methylation (p Ͻ 0.001). In conclusion, silencing of the PTEN gene occurs frequently in gastric carcinoma and aberrant promoter methylation is a major mechanism of silencing of the PTEN gene. The abnormalities of the PTEN gene are associated with tumor progression, metastasis, and survival. (Lab Invest 2002, 82:285-291).

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supporting

confidence: 92%

Promoter Methylation and Silencing of PTEN in Gastric Carcinoma

Kang

Lee

Kim

2002

Laboratory Investigation

222

158

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“…Concurrent methylation of multiple tumor-related genes has been detected in 20% of normal tissues adjacent to gastric carcinoma by Leung et al [83]. We have also shown concurrent methylation (CIMP-H) in 15% of IM but not in chronic gastritis or normal gastric mucosa using a panel of six genes/loci including p16, hMLH1 and four CpG islands (MINT1, MINT2, MINT25 and MINT31) [81].…”

Section: Determined the Methylation Frequency Of 12 Genes Including supporting

confidence: 70%

“…Similar to colorectal cancer, the presence of methylation of hMLH1 gene is strongly associated with loss of hMLH1 protein expression and MSI-H phenotype in gastric carcinomas [52,81,83]. In contrast to gastric carcinoma, methylation of hMLH1 genes in gastric precursor lesions appears to be less frequently associated with MSI-H phenotype and loss of hMLH1 protein expression [81].…”

Section: Epigenetic Alterations In Gastric Carci-nomamentioning

confidence: 99%

Epigenetic alterations in gastric carcinogenesis

Choi

2005

Cell Res

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Gastric cancer is believed to result in part from the accumulation of multiple genetic alterations leading to oncogene overexpression and tumor suppressor loss. Epigenetic alterations as a distinct and crucial mechanism to silence a variety of methylated tissue-specific and imprinted genes, have been extensively studied in gastric carcinoma and play important roles in gastric carcinogenesis. This review will briefly discuss the basic aspects of DNA methylation and CpG island methylation, in particular the epigenetic alterations of certain critical genes implicated in gastric carcinogenesis and its relevance of clinical implications.

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“…It is well known that the lack of E-cadherin plays an important role in the development of gastric cancer and EMT. Three mechanisms of gene deletion include mutation (25), methylation (26) and E-box in the promoter region (27,28). Results of a previous study have shown that KLF17 is a negative regulation of E-cadherin by binding the E-Box promoter in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition

Liu¹,

Wang²,

Zhou³

et al. 2014

Oncology Reports

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Abstract. Previously, we reported that hypoxia was able to induce invasion and metastasis in gastric cancer and that hypoxia-inducible factor-1 (HIF-1) is a key factor involved in this tumor type. Krüppel-like factor 8 (KLF8) as a transcriptional repressor has been suggested as a promoter of tumor metastasis in breast cancer and an inducer of the epithelial-mesenchymal transition (EMT). KLF8 is also highly expressed in gastric cancer tissues, contributing to poor prognosis. However, the association between KLF8 and HIF-1 in regulating the progression of human gastric cancer in hypoxia is unclear. In the present study, we found that KLF8 was overexpressed in gastric cancer metastatic tissues and cells. Additionally, KLF8 siRNA significantly inhibited SGC7901 cell invasion and migration compared with SGC7901, SGC7901/Scr-si cells. Hypoxia is thus able to induce KLF8 expression and EMT in SGC7901 cells. However, following the examination of changes in cell morphology and epithelial and mesenchymal markers, it was found that KLF8 siRNA and HIF-1 siRNA strongly reversed EMT in cells undergoing hypoxia. Furthermore, hypoxia-induced KLF8 overexpression was attenuated by HIF-1 siRNA. Experiments using luciferase promoter constructs resulted in a marked increase in the activity of cells exposed to hypoxia and decreased activity in cells co-transfected with HIF-1 siRNA. The chromatin immunoprecipitation assay revealed proximal HRE at -133 is the main HIF-1 binding site in the KLF8 promoter.In conclusion, the results demonstrated that KLF8 is actively enhanced by hypoxia and is a novel HIF-1 target. KLF8 is a novel EMT regulating transcription factor that involved in the progression of gastric cancer. The specific anti-EMT drugs in combination with anti-hypoxia are new promising cancer therapies.

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Concurrent hypermethylation of multiple tumor-related genes in gastric carcinoma and adjacent normal tissues

Cited by 120 publications

References 23 publications

Promoter Methylation and Silencing of PTEN in Gastric Carcinoma

Promoter Methylation and Silencing of PTEN in Gastric Carcinoma

Epigenetic alterations in gastric carcinogenesis

Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition

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