| Project/Area Number |
17K16556
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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 |
Digestive surgery
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| Research Institution | Tottori University |
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Principal Investigator |
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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 |
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | テロメラーゼ逆転写酵素 / TERT / C15orf55 / C7orf43 / 肝細胞癌 / テロメラーゼ / 予後因子 / テロメアを伸長するヒトテロメラーゼ逆転写酵素 / テロメア |
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| Outline of Final Research Achievements |
The promoter mutation in the telomerase reverse transcriptase (hTERT) gene is the most common genetic alteration in hepatocellular carcinoma (HCC), suggesting that hTERT upregulation is a critical event in hepatocarcinogenesis. Thus, regulators for hTERT expression would be a promising target for HCC prevention and treatment. Here, we conducted a functional screening of hTERT regulators to find novel therapeutic targets. A genome-wide short-hairpin RNA library was used for the screening. The activity of the TERT promoter was measured by a luciferase assay. C15orf55 and C7orf43 were identified to regulate TERT expression, possibly via the SP1 axis and Hippo pathway, respectively. The expression of both genes was higher in tumor and its adjacent non-tumor tissues of HCC patients than in normal liver tissues with benign disease. Survival data from the TCGA database showed that high expression of these genes was related to poor long-term outcomes of HCC patients.
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| Academic Significance and Societal Importance of the Research Achievements |
肝細胞癌に対する治療の主流は、異常に活性化した経路を標的として治療する分子標的薬だが、有効な治療薬が少ない現状である。本研究では、癌細胞の不死化に必須の遺伝子であるテロメラーゼ逆転写酵素を活性化する因子に着目し、新たな因子2つを見出した。1つはC15orf55という遺伝子で、SP1という転写因子を活性化（プロモーター領域に導く）ことでテロメラーゼ逆転写酵素の発現を上昇させていた。もう1つはC7orf43という遺伝子で、YAP1という転写因子を活性化（核内に導く）ことで遺伝子発現を活性化していた。いずれの遺伝子も肝細胞癌の患者で大量に発現しており、有望な治療標的と考えられた。
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