2011 Fiscal Year Final Research Report
Development of dual targeting therapy for cancer stem cells and niche
| Project/Area Number |
21591213
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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 |
Hematology
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
KIKUCHI Shohei 札幌医科大学, 医学部, 研究員 (80515792)
IYAMA Satoshi 札幌医科大学, 医学部, 助教 (50398319)
TAKIMOTO Rishu 札幌医科大学, 医学部, 講師 (10336399)
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| Project Period (FY) |
2009 – 2011
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| Keywords | 癌 / 内科 / シグナル伝達 / 臨床 / 発現制御 |
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| Research Abstract |
Aberrant reactivation of Hedgehog(Hh) signaling has been described in a wide variety of human cancers including cancer stem cells. However, involvement of Hh signaling system in bone marrow(BM) microenvironment in the development of myeloid neoplasm has remained unclear. In this study, we assessed the expression of Hh related proteins in normal human CD34+cells, CD34+leukemic/dysplastic cells and BM stromal cells. Both Indian hedgehog(Ihh) and its signal transducer, SMO were expressed in CD34+acute myeloid leukemia(AML) and myelodysplastic syndrome(MDS) derived cells, suggesting that Ihh could effect in autocrine manner. Remarkably, the intrinsic Hh signaling inhibitor, human hedgehog-interacting protein(HHIP) expression in AML/MDS-associated stromal cells was drastically lower than that in healthy donor derived stromal cells. Moreover, the HHIP expression level in BM stromal cells highly correlated with supporting activity of SMO+leukemic cells. Demethylating agent 5-aza-dC rescued the HHIP expression via demethylation of HHIP gene and reduced the leukemia-supporting activity of AML/MDS-associated stromal cells. This effect of 5-aza-dC could be negated by HHIP shRNA transfer into stromal cells. Interestingly, HHIP-reduced stromal cells preferentially migrated toward Ihh-releasing leukemic cells. These results indicate that suppression of stromal HHIP expression could be involved in the progression of AML/MDS.
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