The epigenetic silencing of LIMS2 in gastric cancer and its inhibitory effect on cell migration.
Recent finding has shown that LIMS2 (also known as PINCH2) functions as a natural regulator of the LIMS1-ILK-parvin complex formation and is associated with cell spreading and migration via integrins at focal adhesions. Here, we report for the first time the epigenetic silencing of LIMS2 in gastric tumors. Downregulation of LIMS2 was detected in 91% (10 of 11) of gastric cancer cell lines by real-time quantitative RT-PCR and 80% (8 of 10) of the LIMS2-downregulated cell lines were associated with CpG island hypermethylation at a 5'-upstream region of LIMS2. Furthermore, LIMS2 was restored in its non-expressing cell lines after treatment with 5-Aza-dC and/or trichostatin A. Loss of expression of LIMS2 was also detected in 53% (51 of 96) of primary gastric tumors. This decrease in expression level significantly correlated with an increase of the CpG island hypermethylation. In addition, the methylation status in any normal-appearing gastric tissues was gradually increased in an age-dependent manner, suggesting that the positive methylation in normal-appearing gastric mucosa can be due to 'field cancerization effect' as an early event in gastric carcinogenesis. Moreover, the transient transfection of LIMS2-siRNA significantly stimulated cell migration in gastric cancer cells but had no effects on cell growth. These results suggest that the frequent inactivation of LIMS2 by epigenetic alteration in gastric cancer may be important in tumor progression events, such as invasion and metastasis. Thus, LIMS2 may be useful as a molecular biomarker and a therapeutic target by increasing its expression and activity in gastric cancer.
Kim
Seung-Kyoon
SK
Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Eoeun-dong, Yuseong-gu, Daejeon 305-333, Republic of Korea.
Jang
Hae-Ran
HR
Kim
Jeong-Hwan
JH
Noh
Seung-Moo
SM
Song
Kyu-Sang
KS
Kim
Mi-Rang
MR
Kim
Seun-Young
SY
Yeom
Young-Il
YI
Kim
Nam-Soon
NS
Yoo
Hyang-Sook
HS
Kim
Yong Sung
YS
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018899:CpG Islands; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C490235:LIMS2 protein, human; D008565:Membrane Proteins