2007 Fiscal Year Final Research Report Summary
Analysis of the effects of tumor hypoxia on dynamics of cancer stem cells
| Project/Area Number |
18590280
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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 |
General medical chemistry
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| Research Institution | Chiba Cancer Center (Research Institute) |
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Principal Investigator |
KEIZO Takenaga Chiba Cancer Center (Research Institute), Division of Chemotherapy, Researcher (80260256)
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| Co-Investigator(Kenkyū-buntansha) |
KOSHIKAWA Nobuko Chiba Cancer Center Research Institute, Division of Pathology, Researcher (90260249)
OHIRA Miki Chiba Cancer Center Research Institute, Division of Biochemistry, Researcher (20311384)
TAKENOBU Hisanori Chiba Cancer Center Research Institute, Division of Pathology, Researcher (60392247)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Cancer / Tissue・Cell / Hypoxia / Cancer stem cell |
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| Research Abstract |
Purpose: In this study, we examined the effects of tumor hypoxia on differentiation state, expression of cancer stem cell-related genes and malignancy of human tumor cells. Results: We cultured human lung adenocarcinoma A549 cells and squamous carcinoma QG56 cells under normoxic or hypoxic (1% O_2) conditions. A549 cells primarily expressed the SP-C gene encoding type II alveolar cell marker surfactant protein C while QG56 cells mainly expressed the AQP5 gene encoding type I alveolar cell marker aquaporin 5 and the CC10 gene encoding Clara cell 10 kDa protein. Upon hypoxic exposure, the expression of these differentiation marker genes was greatly reduced. In contrast, hypoxia markedly enhanced the expression of stem cell marker genes such as CD133, OCT4, and Musashi-1 in both cells. A HIF (hypoxia-inducible factor) inhibitor suppressed all of these changes. Next, we established hypoxia-resistant A549HR cells from A549 cells and found that they exhibit higher cell motility, invasive ability, anchorage-independent growth and tumorgenicity than A549 cells. They expressed a lower level of SP-C gene, while they expressed a higher level of pan-stem cell marker CD133 gene and contained a larger number of Hoechst33342-dim cells than A549 cells. Conclusion: Our data provide evidence that hypoxia induces dedifferentiation and enhances the expression of stemness genes in lung carcinoma cells through HIF signaling pathway. Furthermore, our data indicate that tumor cells selected for hypoxia resistance shows dedifferentiated and cancer stem cell-like phenotypes more than the parent cells.
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