2021 Fiscal Year Final Research Report

Biological roles of dysregulated Hippo pathway on cancer stem like function during the tumor progression of gastroenterological cancers

Research Project

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Project/Area Number	19K09177
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 55020:Digestive surgery-related
Research Institution	Kumamoto University
Principal Investigator	Hayashi Hiromitsu 熊本大学, 病院, 助教 (80625773)
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)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	消化器癌 / Hippo pathway / 癌幹細胞 / YAP / TAZ
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.
Free Research Field	消化器癌、Hippo pathway、癌幹細胞
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。