Biological roles of dysregulated Hippo pathway on cancer stem like function during the tumor progression of gastroenterological cancers
| Project/Area Number |
19K09177
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 55020:Digestive surgery-related
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| Research Institution | Kumamoto University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
山下 洋市 熊本大学, 大学院生命科学研究部(医), 准教授 (00404070)
石本 崇胤 熊本大学, 病院, 特任准教授 (00594889)
中川 茂樹 熊本大学, 病院, 特任助教 (10594872)
今井 克憲 熊本大学, 大学院生命科学研究部(医), 助教 (60555746)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 消化器癌 / Hippo pathway / 癌幹細胞 / YAP / TAZ / Yap / Taz / 抗がん剤抵抗性 / 癌 |
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| Outline of Research at the Start |
YAP/TAZの発現変化が癌幹細胞様性質獲得に寄与し、さらに免疫による癌細胞死から回避している、という仮説に基づいて、その他の消化器癌において同様の研究を進めてきた。また、PDL-1, PDL-2による癌免疫逃避機構とYAP/TAZの発現変化が関与する基礎的実験結果を得ている。本研究では、消化器癌における腫瘍抑制シグナルHippo pathway の構成成分YAP/TAZによる癌幹細胞性の制御機構および免疫回避機構について分子生物学的に紐解き、臨床的特性と対比することにより癌幹細胞および癌免疫をターゲットにした新しい癌治療法の確立を目指す。
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| Outline of Final Research Achievements |
ATP binding cassette subfamily B member 1 (ABCB1) is an ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity. It is responsible for decreased drug accumulation in multidrug-resistant cells and often mediates the development of resistance to anticancer drugs. Thus, ABCB1 plays an important role in the chemoresistance of cancer cells, and is known as a cancer stem cell transcription factor. Hyperglycemia induced ABCB1 expression, and it was also upregulated by YAP/TAZ overexpression in pancreatic cancer cells. Conversely, knockdown of YAP or TAZ attenuated ABCB1 expression compared to controls. Indeed, pancreatic cancer cells cultured with hyperglycemia displayed accelerated chemoresistance response to gemcitabine and oxaliplatin. YAP/TAZ inhibitor successfully overcome the chemoresistance. These findings indicate that hyperglycemia promote chemoresistance by upregulating ABCB1 expression via YAP/TAZ overexpression in pancreatic cancer cells.
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| Academic Significance and Societal Importance of the Research Achievements |
ヒト固形癌では腫瘍抑制シグナル伝達系Hippo pathwayの破綻による転写因子YAP/TAZの発現上昇が高頻度に認められており、近年発がんおよび癌進展におけるHippo pathwayの破綻が注目される。Hippo pathwayの破綻はYAPとTAZの発現上昇を引き起こすが、YAP/TAZの発現上昇はABCB1といった癌幹細胞マーカーの発現を増加させ抗がん剤抵抗性に寄与することを明らかにした。
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Report
(4 results)
Research Products
(6 results)
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[Journal Article] Extracellular Vesicles from Cancer-Associated Fibroblasts Containing Annexin A6 Induces FAK-YAP Activation by Stabilizing β1 Integrin, Enhancing Drug Resistance2020
Author(s)
Uchihara T, Miyake K, Yonemura A, Komohara Y, Itoyama R, Koiwa M, Yasuda T, Arima K, Harada K, Eto K, Hayashi H, Iwatsuki M, Iwagami S, Baba Y, Yoshida N, Yashiro M, Masuda M, Ajani Jaffer A, Tan Patrick, Baba H, Ishimoto T
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Journal Title
Cancer Research
Volume: 80
Issue: 16
Pages: 3222-3235
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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