| Project/Area Number |
17K15937
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Gastroenterology
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| Research Institution | Gifu University |
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Principal Investigator |
SAKAI HIROYASU 岐阜大学, 医学部附属病院, 助教 (40738259)
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 非アルコール性脂肪肝炎 / NASH / 肝細胞癌 / レチノイド / 核内受容体 / RXRα / 肝化学発癌 / レチノイド核内受容体 / RXRα受容体 / 感発癌 / メタボリック症候群 / マウスモデル / 肝発癌 / 肝癌 / レチノイド受容体 |
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| Outline of Final Research Achievements |
The role of phosphorylated-RXRa (p-RXRa) on the development of liver tumorigenesis was investigated by using RXRa genetically modified mice. The transgenic mice were more susceptible to the treatment of diethylnitrosamine (DEN), and developed more liver tumors compared to the control mice. In addition, liver tumors observed in the transgenic mice had more PCNA positive cells, indicating that those tumors had high proliferative capacity. Besides, increased mRNA and protein expressions of cyclin D1 were observed in transgenic liver tumors, and the protein expressions of either p-Rb or PCNA, both of which are the downstream targets of cyclin D1, were also increased in those liver tumors. Interestingly, the transgenic liver tumors had more b-catenin protein expression, which regulates the expression of cyclin D1. Thus, these results indicate that the p-RXRa is associated with the development of DEN-induced liver tumorigenesis by promoting b-catenin/cyclin D1 signaling pathway.
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| Academic Significance and Societal Importance of the Research Achievements |
肝癌は本邦において癌死亡率の上位を占める悪性疾患であり、早期診断・治療のみならず、積極的な介入による発癌予防を含めた包括的な対策が求められている。特に、近年では肥満や脂肪肝を背景としたNASH肝癌が増加しており、その詳細な病態解明と有効な肝癌治療法（薬）の開発、及び、臨床への応用は緊急の課題となっている。
現時点でNASH肝発癌モデルの確立には至っていないが、本研究を通して、リン酸化RXRα受容体がin vivoの病態（DEN肝発癌・耐糖能異常）に関与することが明らかになった。今回、in vivoでのエビデンスが示せたことは、「ヒト創薬への応用」を目指す上での大きな一歩となる成果であった。
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