The epigenetic silencing of LIMS2 in gastric cancer and its inhibitory effect on cell migration

Kim, Seung-Kyoon; Jang, Hae-Ran; Kim, Jeong‐Hwan; Noh, Seung Man; Song, Kyu‐Sang; Kim, Mirang; Kim, Seun-Young; Yeom, Young‐Il; Kim, Nam-Soon; Yoo, Hyang–Sook; Kim, Yong‐Sung

doi:10.1016/j.bbrc.2006.08.128

Cited by 49 publications

(40 citation statements)

References 34 publications

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“…For cell line DNA, RLGS gels were also run in pairs consisting of cell line DNA alone and DNA of the cell line mixed with DNA from normal tissue. Differences between cell line DNA were detected as described (24). Spot intensities were compared with the Master RLGS profile (25), or with our RLGS profile (22), to identify its sequence.…”

Section: Rlgs Analysismentioning

confidence: 99%

Epigenetic inactivation of protein kinase D1 in gastric cancer and its role in gastric cancer cell migration and invasion

et al. 2007

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Protein kinase D (PKD) 1 influences cell migration by mediating both trans-Golgi vesicle fission and integrin recycling to the cell surface. Using restriction landmark genomic scanning methods, we found that the promoter region of PKD1 was aberrantly methylated in gastric cancer cell lines. Silencing of PKD1 expression was detected in 72.7% of gastric cancer cell lines examined, and the silencing was associated with CpG hypermethylation in the promoter region of PKD1. Treatment with 5-aza-2#-deoxycytidine and trichostatin A partially reversed PKD1 methylation and restored gene expression in PKD1-silenced cell lines. Real-time reverse transcription-polymerase chain reaction analysis of 96 paired clinical primary gastric cancer samples revealed that 59% of the analyzed tumors had a >2-fold decrease in PKD1 expression compared with each normal-appearing tissue and that this downregulation of PKD1 expression was significantly correlated with increased methylation. We also observed a gradual increase in the level of promoter methylation of PKD1 in aging, normal-appearing mucosal tissues, suggesting that PKD1 methylation may be one of the earliest events that predispose an individual to gastric cancer. PKD1 expression was required for directional migration of gastric cancer cells. Furthermore, knock down of PKD1 by RNA interference promoted the invasiveness of cell lines that expressed PKD1 at relatively high levels. Based on these results, we propose that PKD1 is frequently silenced by epigenetic regulation, which plays a role in cell migration and metastasis in gastric cancer.

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Section: Rlgs Analysismentioning

confidence: 99%

Epigenetic inactivation of protein kinase D1 in gastric cancer and its role in gastric cancer cell migration and invasion

et al. 2007

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“…For cell line DNA, RLGS gels were also run in pairs consisting of cell line DNA alone and DNA of the cell line mixed with DNA from normal tissue. The differences between the two profiles of tumor and normal DNA or of cell line and normal DNA were detected as described (31). Once a difference in spot intensity was detected between paired normal and tumor samples or between normal and cell line samples, we compared the spots with the previous master RLGS profile (7) or our RLGS profile (20) to identify their sequences.…”

Section: Rlgs Analysismentioning

confidence: 99%

Epigenetic Down-Regulation and Suppressive Role of DCBLD2 in Gastric Cancer Cell Proliferation and Invasion

Kim

Lee

Jang

et al. 2008

Molecular Cancer Research

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The promoter region of Discoidin, CUB and LCCL domain containing 2 (DCBLD2) was found to be aberrantly methylated in gastric cancer cell lines and in primary gastric cancers, as determined by restriction landmark genomic scanning. DCBLD2 expression was inversely correlated with DCBLD2 methylation in gastric cancer cell lines. Treatment with 5-aza-2 ¶-deoxycytidine and trichostatin A partially reversed DCBLD2 methylation and restored gene expression in DCBLD2-silenced cell lines. In an independent series of 82 paired gastric cancers and adjacent normal tissues, DCBLD2 expression was down-regulated in 79% of gastric cancers as compared with normal tissues as measured by real-time reverse transcription-PCR. Pyrosequencing analysis of the DCBLD2 promoter region revealed abnormal hypermethylation in gastric cancers, and this hypermethylation was significantly correlated with down-regulation of DCBLD2 expression. Furthermore, ectopic expression of DCBLD2 in gastric cancer cell lines inhibited colony formation in both anchorage-dependent and anchorage-independent cultures and also inhibited invasion through the collagen matrix. These data suggest that downregulation of DCBLD2, often associated with promoter hypermethylation, is a frequent event that may be related to the development of gastric cancer. (Mol Cancer Res 2008;6(2):222 -30)

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“…Ninety-six pairs of frozen gastric tumors and normal adjacent tissues were accessed from the Stomach Cancer Bank at Chungnam National University Hospital, Daejeon, Korea, as described (17)(18)(19). Specimens were originally obtained from tumors immediately after resection.…”

Section: Methodsmentioning

confidence: 99%

“…Real-time reverse transcription-PCR (RT-PCR) was performed as described (17)(18)(19). Total cellular RNA (5 Ag) was reverse transcribed into cDNA using SuperScript II (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

“…We have used restriction landmark genomic scanning (RLGS) to identify methylation markers in gastric cancer on a whole-genome scale (16). We previously reported aberrant methylation of LIMS2, a regulator of cell migration (17), DCBLD2, a cell growth repressor (18), and Protein kinase D1 (19) in gastric cancer by RLGS and pyrosequencing, a quantitative methylation analysis of multiple CpG sites.…”

Section: Introductionmentioning

confidence: 99%

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LRRC3B, Encoding a Leucine-Rich Repeat-Containing Protein, Is a Putative Tumor Suppressor Gene in Gastric Cancer

Kim

Kim²,

Jang³

et al. 2008

Cancer Research

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Leucine-rich repeat-containing 3B (LRRC3B) is an evolutionarily highly conserved leucine-rich repeat-containing protein, but its biological significance is unknown. Using restriction landmark genomic scanning and pyrosequencing, we found that the promoter region of LRRC3B was aberrantly methylated in gastric cancer. Gastric cancer cell lines displayed epigenetic silencing of LRRC3B, but treatment with the DNA methylation inhibitor 5-aza-2 ¶-deoxycytidine and/or the histone deacetylase inhibitor trichostatin A increased LRRC3B expression in gastric cancer cell lines. Real-time reverse transcription-PCR analysis of 96 paired primary gastric tumors and normal adjacent tissues showed that LRRC3B expression was reduced in 88.5% of gastric tumors compared with normal adjacent tissues. Pyrosequencing analysis of the promoter region revealed that LRRC3B was significantly hypermethylated in gastric tumors. Stable transfection of LRRC3B in SNU-601 cells, a gastric cancer cell line, inhibited anchorage-dependent and anchorage-independent colony formation, and LRRC3B expression suppressed tumorigenesis in nude mice. Microarray analysis of LRRC3B-expressing xenograft tumors showed induction of immune responserelated genes and IFN signaling genes. H&E-stained sections of LRRC3B-expressing xenograft tumors showed lymphocyte infiltration in the region. We suggest that LRRC3B is a putative tumor suppressor gene that is silenced in gastric cancers by epigenetic mechanisms and that LRRC3B silencing in cancer may play an important role in tumor escape from immune surveillance. [Cancer Res 2008;68(17):7147-55]

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The epigenetic silencing of LIMS2 in gastric cancer and its inhibitory effect on cell migration

Cited by 49 publications

References 34 publications

Epigenetic inactivation of protein kinase D1 in gastric cancer and its role in gastric cancer cell migration and invasion

Epigenetic inactivation of protein kinase D1 in gastric cancer and its role in gastric cancer cell migration and invasion

Epigenetic Down-Regulation and Suppressive Role of DCBLD2 in Gastric Cancer Cell Proliferation and Invasion

LRRC3B, Encoding a Leucine-Rich Repeat-Containing Protein, Is a Putative Tumor Suppressor Gene in Gastric Cancer

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