2006 Fiscal Year Final Research Report Summary
Methylation analysis of calcium channel-related genes in gastric cancer
| Project/Area Number |
17590296
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human pathology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
AKIYAMA Yoshimitsu Tokyo Medical and Dental University, Department of Molecular Oncology, Lecturer, 大学院医歯学総合研究科, 講師 (80262187)
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| Project Period (FY) |
2005 – 2006
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| Keywords | calcium channel / gastric cancer / methylation / 3p21 / CpG / prognostic marker |
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| Research Abstract |
The calcium channel voltage-dependent α2δ subunit consists of four genes, CACNA2D1 to CACNA2D4, of which CACNA2D2 and CACNA2D3 are located on 3p21.3 and 3p21.1, respectively. Here we examined the relationship between α2δ subunit gene alterations and gastric carcinogenesis. The expression and methylation status of the α2δ subunit genes were analyzed by RT-PCR and methylation-specific PCR in gastric cancer (GC) cell lines and primary GCs. The effects of CACNA2D3 over-expression were examined by a cell proliferation assay, predicted target gene alterations and measurement of intracellular Ca^<2+> levels. Aberrant methylation of CACNA2D1 and CACNA2D3 mostly corresponded to their expression status in GC cell lines. CACNA2D1 and CACNA2D3 methylation was detected in 10 (14.2%) and 19 (27.1%) of the 70 GC cases, respectively, but no CACNA2D2 methylation was seen in 32 cases. CACNA2D3 methylation was more frequently found in diffuse type than in intestinal type (13/33, 39.4% vs. 6/37, 16.2%;P=0.029) GCs. Among the 45 patients with advanced GCs, those with cancers showing CACNA2D3 methylation had a significantly shorter survival time than those without this methylation (P=0.007). Exogenous CACNA2D3 expression inhibited cell growth, up-regulated p21 and p27 expression, and elevated intracellular Ca^<2+> level. CACNA2D3 siRNA treatment decreased the levels of both p21 and p27 in the CACNA2D3-positive cell lines, indicating that CACNA2D3 may have tumor suppressive functions. Loss of CACNA2D3 and CACNA2D1 expression through aberrant methylation may contribute to gastric carcinogenesis, and CACNA2D3 methylation is a useful prognostic marker for advanced GC patients.
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Research Products
(8 results)
