| Project/Area Number |
16K09334
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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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| Research Field |
Gastroenterology
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| Research Institution | Hokkaido University |
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Principal Investigator |
Goki Suda 北海道大学, 大学病院, 特任助教 (20447460)
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| Co-Investigator(Kenkyū-buntansha) |
坂本 直哉 北海道大学, 医学研究院, 教授 (10334418)
森川 賢一 北海道大学, 医学研究院, 助教 (60384377)
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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 |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | HBV / HCC / HBx / truncated HBx / 肝細胞癌 / HBｘ / インテグレーション / CSCｓ / 肝癌幹細胞 / 癌 / ＨＢｘ |
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| Outline of Final Research Achievements |
Recently GWAS about HBV-related HCC revealed that COOH-truncated HBx was integrated in host genome at high frequency. We aimed to analyze the relationship between COOH-truncated HBx expression and CSCs which is related to malignant potential. COOH-truncated HBx(truncated HBx/HepG2) shows significantly resistant to anti-tumor agent, 5-FU. Soft gel agar colony formation assay shows that truncated-HBx/HepG2 cells make significantly more colonies than control. Flow cytometry analysis reveals that truncated HBx/HepG2 cells express high levels of CD44, one of cancer stemness maker. Subsequently we investigated what factor up-regulate CD44 in truncated HBx/HepG2 cells by Human Stem Cell PCR Array (Qiagen).This PCR-array results indicated that LTBP1 is significantly up-regulated in only Truncated-HBx/HepG2 . The expression level of CD44 were significantly down-regulated by siRNA knockdown of LTBP1. In sorted CD44high cells, LTBP1 were significantly up-regulated compared with CD44low cells.
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| Academic Significance and Societal Importance of the Research Achievements |
HBV肝癌におけるC末端欠損HBX蛋白のインテグレーションの影響は十分には明らかなではなかった。今検討では、C末端欠損HBX蛋白のインテグレーションによりCSCｓが高率に誘導される事、その機序としてLTBP-1が関与している事が明らかとなった。CSCｓは抗癌剤耐性や、転移に関与する事が知られており、C末端欠損HBX蛋白のインテグレーションがみられる症例では肝癌悪性化が惹起されている事が想定され注意を要する事が初めて明らかとなった。更に、CSCsをターゲットとして治療を考えるうえでLTBP-1が新たな治療ターゲットとなりうる事を今研究で初めて明らかとなった。
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