The development of novel treatment for hepato-biliary-pancreatic cancer with target of cancer stroma
Project/Area Number |
16K10572
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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 |
Digestive surgery
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Research Institution | Osaka University |
Principal Investigator |
Noda Takehiro 大阪大学, 医学系研究科, 助教 (50528594)
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Co-Investigator(Kenkyū-buntansha) |
和田 浩志 地方独立行政法人大阪府立病院機構大阪国際がんセンター(研究所), その他部局等, 消化器外科 副部長 (00572554)
後藤 邦仁 大阪大学, 医学系研究科, 助教 (10362716)
阪本 卓也 大阪大学, 医学部附属病院, 医員 (40645074)
江口 英利 大阪大学, 医学系研究科, 准教授 (90542118)
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Project Period (FY) |
2016-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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Keywords | 胆道癌 / 上皮間葉移行 / 化学療法耐性 / 低酸素 / 予後因子 / 胆管癌 / 間質 / 肝癌 / 膵癌 |
Outline of Final Research Achievements |
The prognosis of biliary tract cancer is unfavorable due to its chemoresistance. Hypoxia triggers epithelial-to-mesenchymal transition, which is related to drug resistance. In this study, we focused on the functional roles of procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), a hypoxia-induced gene, and assessed the clinical significance of PLOD2. The expression of PLOD2 was induced by hypoxia in vitro and was upregulated in GEM-resistant cell lines, which had low expression of epithelial markers and high expression of mesenchymal markers. Downregulation of PLOD2 by siRNA resulted in improved chemoresistance, recovery of E-cadherin, and reduction of N-cadherin. In the resected samples, PLOD2 expression was significantly correlated with lymph node metastasis and stage. Recurrence-free survival and overall survival rates were significantly lower in patients with high expression of PLOD2. PLOD2 expression was an independent prognostic factor for overall survival.
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Academic Significance and Societal Importance of the Research Achievements |
肝胆膵領域癌のうち、胆道癌はその発生頻度および悪性度から難治癌の一つであり、世界的にも研究が進んでいないのが現状である。またその生命予後は、化学療法や周術期管理法が進歩した現在においても決して満足のいくものではない。本研究により胆道癌における化学療法耐性機序の一端が解明され、低酸素誘導遺伝子PLOD2が新規の予後因子が同定された。さらに化学療法耐性機序として、低酸素刺激による上皮間葉移行によるメカニズムが関与していることが示された。遠隔転移を有する胆道癌において化学療法耐性が最重要課題であり、今後は上記メカニズムに対する治療法の開発が進むことが期待される。
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Report
(4 results)
Research Products
(9 results)
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[Journal Article] Hypoxia-Induced PLOD2 is a Key Regulator in Epithelial-Mesenchymal Transition and Chemoresistance in Biliary Tract Cancer2018
Author(s)
Okumura Y, Noda T, Eguchi H, Sakamoto T, Iwagami Y, Yamada D, Asaoka T, Wada H, Kawamoto K, Gotoh K, Kobayashi S, Takeda Y, Tanemura M, Umeshita K, Doki Y, Mori M
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Journal Title
Ann Surg Oncol
Volume: 25
Issue: 12
Pages: 3728-3737
DOI
Related Report
Peer Reviewed / Open Access
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