| Project/Area Number |
15590332
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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 |
Experimental pathology
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
YASUI Kohichiroh Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Research Associate, 医学研究科, 助手 (30323695)
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| Co-Investigator(Kenkyū-buntansha) |
INAZAWA Johji Tokyo Medical and Dental University, Medical Research Institute, Professor, 難治疾患研究所, 教授 (30193551)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | cancer / SKP2 / proliferation / apoptosis / gene amplification / lymph-node metastasis / p27 |
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| Research Abstract |
SKP2, an F-box protein constituting the substrate recognition subunit of the SCF(SKP2) ubiquitin ligase complex, is implicated in ubiquitin-mediated degradation of the cyclin-dependent kinase inhibitor p27(KIP1). Our earlier studies revealed SKP2 as a target gene within the 5p13 amplicon that is often seen in small-cell lung cancers (SCLC) and showed that down-regulation of SKP2 expression by means of an antisense oligonucleotide inhibited the growth of SCLC cells in culture. SKP2-antisense treatment not only suppressed DNA synthesis, as determined by [(3)H]thymidine incorporation, but also induced spontaneous apoptosis characterized by an increase in the sub-G1 population, fragmentation of nuclei, and activation of caspase-3. We examined amplification status and expression levels of SKP2 in non-small-cell lung cancer (NSCLC) and investigated its clinicopathological significance in this type of tumor because amplification of DNA at 5p13 is observed frequently in NSCLCs as well as in SCLCs. SKP2 exhibited amplification in 5 (20%) of 25 cell lines derived from NSCLC, and the transcript was overexpressed in 11 (44%) of the 25 lines. Moreover, expression of SKP2 was up-regulated significantly in 60 primary NSCLC tumors as compared to nontumorous lung tissues (P<0.0001). Elevated expression of SKP2 correlated significantly with positive lymph node metastasis (P=0.007), with stage II or higher of the international TNM classification (P=0.014), with poor or moderate differentiation (P<0.001), and with the presence of squamous cell carcinoma (P=0.037). Reduction of SKP2 expression by transfection of an anti-sense oligonucleotide inhibited invasion and migration of NSCLC cells in culture. Our results suggest that SKP2 may be involved in progression of NSCLC, and that targeting this molecule could represent a promising therapeutic option.
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