Investigation of the roles of bone marrow-derived fibroblasts/myofibroblasts and their molecular mechanism in the carcinogenesis of mouse models of pancreatic cancer
Project/Area Number |
17K09460
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Gastroenterology
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Research Institution | Kyoto University |
Principal Investigator |
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Project Period (FY) |
2017-04-01 – 2021-03-31
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Project Status |
Completed (Fiscal Year 2020)
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Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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Keywords | 膵癌発症マウス / ヒト及びマウス膵癌培養細胞株 / ヒト膵癌オルガノイド / COX-1, -2遺伝子 / CAGE法 / 膵癌幹細胞 / 上皮間葉転換(EMT) / SNAIL2(別称SLUG) / 膵癌自然発症マウス(KPC) / ヒト及びマウス膵癌培養細胞 / CAGE法遺伝子解析 / 上皮間葉転換関連転写因子(EMT-TFs) / SNAIL2(=SLUG)遺伝子 / 膵癌自然発症マウス / ヒト膵癌培養細胞株 / COX-1遺伝子 / COX-2遺伝子 / ヒト膵癌培養細胞 / 膵癌発症複合遺伝子変異マウス / 癌 / 内科 |
Outline of Final Research Achievements |
We changed the research subjects to the following new ones: A) Characterization of our newly established two murine pancreatic cancer cell lines: a) from pancreatic intraepithelial neoplasia (PanIN), b) from intraductal papillary-mucinous neoplasm (IPMN). B) Investigation of molecular mechanism of epithelial-mesenchymal transition (EMT) in human pancreatic cancer by using pancreatic cancer cell lines (PCLs) and patient-derived pancreatic cancer organoids (PDOs). We obtained following results: A) The transcriptome of PanIN cells exhibited properties of stemness, while that of IPMN cells was enriched for PI3K/Akt signal-related genes. Various transcriptional factor networks in PanIN and IPMN cells reflect the distinct molecular profiles of these cell types. B) Among EMT-related transcriptional factors, SNAIL2 is most highly expressed in PCLs as well as PDOs. Suppression of SNAIL2 decreased tumorigenicity, and microarray analysis revealed the mechanism was mainly mediated by IGFBP2.
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Academic Significance and Societal Importance of the Research Achievements |
膵癌の5年相対生存率は男女平均で約8.5%であり、全癌腫中で最低の数値である。従って、膵癌の発癌機構を解明し新たな治療戦略を見出すことは現在の癌診療政策における喫緊の課題であると言える。 今回の研究成果は、PanINとIPMNで異なる転写因子ネットワークが機能しており、前者で幹細胞関連因子が高発現し、後者ではPI3K/Aktシグナルが亢進していることを示した。加えて、ヒト膵癌においてEMT関連因子であるSNAIL2の発現を抑制することにより、癌幹細胞分画が縮小し抗癌剤への抵抗性が減弱すること、従ってSNAIL2およびその主たる下流遺伝子であるIGFBP2が新規の治療標的となることが期待される。
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Report
(5 results)
Research Products
(8 results)
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[Journal Article] Arid1a is essential for intestinal stem cells through Sox9 regulation.2019
Author(s)
Hiramatsu Y, Fukuda A, Ogawa S, Goto N, Ikuta K, Tsuda M, Matsumoto Y, Kimura Y, Yoshioka T, Takada Y, Maruno T, Hanyu Y, Tsuruyama T, Wang Z, Akiyama H, Takaishi S, Miyoshi H, Taketo MM, Chiba T, Seno H.
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Journal Title
Proc Natl Acad Sci U S A.
Volume: 116 (5)
Issue: 5
Pages: 1704-1713
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] E-cadherin regulates proliferation of colorectal cancer stem cells through NANOG.2018
Author(s)
Tamura S, Isobe T, Ariyama H, Nakano M, Kikushige Y, Takaishi S, Kusaba H, Takenaka K, Ueki T, Nakamura M, Akashi K, Baba E.
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Journal Title
Oncology Reports
Volume: 40 (2)
Pages: 693-703
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Nardilysin inhibits pancreatitis and suppresses pancreatic ductal adenocarcinoma initiation in mice.2018
Author(s)
Ikuta K, Fukuda A, Ogawa S, Masuo K, Goto N, Hiramatsu Y, Tsuda M, Kimura Y, Matsumoto Y, Kimura Y, Maruno T, Kanda K, Nishi K, Takaori K, Uemoto S, Takaishi S, Chiba T, Nishi E, Seno H.
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Journal Title
Gut
Volume: 印刷中
Issue: 5
Pages: 882-892
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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