Fibulin 1 is downregulated through promoter hypermethylation in gastric cancer

Cheng, Yingduan; Jin, Hongchuan; Liu, Xin; Siu, Jennifer; Wong, Y P; Ng, Enders K. O.; Yu, Jun; Leung, Wai K.; Sung, Joseph J.Y.; Chan, Francis K.L.

doi:10.1038/sj.bjc.6604760

Cited by 67 publications

(58 citation statements)

References 25 publications

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“…We indeed found many tumor suppressor genes such as ZIC1, SFRP2 (secreted frizzled-related protein 2), FBLN1 (fibulin 1), and UCHL1 (ubiquitin carboxyl-terminal esterase L1) which were markedly upregulated after pharmacological demethylation in these gastric cancer cell lines [9,12,15,16] . In this study, we focused on SLC19A3 (solute carrier family 19, member 3 or THTR2, thiamine transporter-2) which was downregulated in other cancers such as breast cancer [17,18] .…”

Section: Introductionmentioning

confidence: 96%

Promoter Hypermethylation Mediates Downregulation of Thiamine Receptor SLC19A3 in Gastric Cancer

Liu¹,

Lam²,

Wang³

et al. 2009

Tumor Biol

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As an important way to inactivate tumor suppressor genes (TSGs) during cancer development, promoter hypermethylation can be used to define novel TSGs and identify biomarkers for cancer diagnosis. SLC19A3 (solute carrier family 19, member 3) was found to be such a biomarker. SLC19A3 expression was downregulated in gastric cancer cell lines (71%, 5/7) and restored after pharmacological demethylation. Notably, hypermethylation of SLC19A3 promoter was detected in gastric cancer cell lines (57%, 4/7), primary gastric carcinoma tissues (51%, 52/101) and precancerous lesion (intestinal metaplasia) tissues (32%, 8/25). Exogenous SLC19A3 expression caused growth inhibition of gastric cancer cells. In summary, SLC19A3 was epigenetically downregulated in gastric cancer. Methylation of SLC19A3 promoter could be a novel biomarker for early gastric cancer development.

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Section: Introductionmentioning

confidence: 96%

Promoter Hypermethylation Mediates Downregulation of Thiamine Receptor SLC19A3 in Gastric Cancer

Liu¹,

Lam²,

Wang³

et al. 2009

Tumor Biol

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“…Genomic DNA was bisulphite treated with Zymo DNA Modification Kit (Zymo Research, Orange, CA, USA) according to the protocol provided by the manufacturer. MSP was carried out for 40 cycles with annealing temperature at 62 1C, as earlier described (Cheng et al, 2008). For BGS, PCR products amplified with BGS primers was agarose gel purified and subjected to direct DNA sequencing using ABI PRISM BigDye Terminator Cycle Sequencing Kit in ABI 3100 sequencer (Applied Biosystems).…”

Section: Sirna Transfectionmentioning

confidence: 99%

Warburg effect revisited: an epigenetic link between glycolysis and gastric carcinogenesis

et al. 2009

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In cancer cells, glucose is often converted into lactic acid, which is known as the 'Warburg effect'. The reason that cancer cells have a higher rate of aerobic glycolysis, but not oxidative phosphorylation, remains largely unclear. Herein, we proposed an epigenetic mechanism of the Warburg effect. Fructose-1,6-bisphosphatase-1 (FBP1), which functions to antagonize glycolysis was downregulated through NF-kappaB pathway in Ras-transformed NIH3T3 cells. Restoration of FBP1 expression suppressed anchorage-independent growth, indicating the relevance of FBP1 downregulation in carcinogenesis. Indeed, FBP1 was downregulated in gastric carcinomas (Po0.01, n ¼ 22) and gastric cancer cell lines (57%, 4/7). Restoration of FBP1 expression reduced growth and glycolysis in gastric cancer cells. Moreover, FBP1 downregulation was reversed by pharmacological demethylation. Its promoter was hypermethylated in gastric cancer cell lines (57%, 4/7) and gastric carcinomas (33%, 33/ 101). Inhibition of NF-kappaB restored FBP1 expression, partially through demethylation of FBP1 promoter. Notably, Cox regression analysis revealed FBP1 promoter methylation as an independent prognosis predicator for gastric cancer (hazard ratio: 3.60, P ¼ 0.010). In summary, we found that NF-kappaB functions downstream of Ras to promote epigenetic downregulation of FBP1. Promoter methylation of FBP1 can be used as a new biomarker for prognosis prediction of gastric cancer. Such an important epigenetic link between glycolysis and carcinogenesis partly explains the Warburg effect.

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“…Note It has been previously reported both in gastric and prostate cancer models that Fibulin-1 acts as a tumor suppressor gene and is regulated by promoter hypermethylation (Cheng et al, 2008;Wlazlinski et al, 2007). Very recently, also in hepatocellular carcinoma (HCC) model, a downmodulation of fibulin-1 expression caused by its promoter hypermethylation has been proposed as a marker of HCC progression (Kanda et al, 2011).…”

Section: Hypermethylation Of Fibulin-1 Gene In Epithelial Cancersmentioning

confidence: 99%