| Project/Area Number |
19K07473
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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 49030:Experimental pathology-related
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| Research Institution | Tohoku University (2021)
University of Tsukuba (2019-2020) |
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Principal Investigator |
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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 |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | THG-1 / 扁平上皮がん / CD44 / リン酸化 / TSC22D4 / SALL4 / beta-Catenin / 細胞老化 / 分子標的治療 / TSC-22 / TSC22D4/THG-1 / がん遺伝子 |
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| Outline of Research at the Start |
扁平上皮がんは重層扁平上皮細胞を主な起源とし、食道、皮膚、肺などに発生する予後不良のがんである。申請者は、THG-1/TSC-22D4と呼ばれる分子が新規がん遺伝子候補であることを見出している。本研究では、がん遺伝子THG-1の分子、生理機能、及び臨床病理学的意義を明らかにし、新規分子腫瘍マーカー、及び分子標的治療の開発を目指す。
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| Outline of Final Research Achievements |
Our groups have been shown that THG-1 (TSC22D4), a TSC22 family member, is expressed normal squamous epithelium, and overexpressed in SCCs. THG-1 is phosphorylated by receptor tyrosine kinase pathways, which is important for the tumorigenic potential of THG-1. CD44 is involved in cancer metastasis and resistance to chemotherapy and radiation. CD44 has a standard isoform (CD44s) and variant isoforms (CD44v), produced by mRNA splicing. In this study, we found that the CD44v expression was decreased in THG-1 knockdown SCC cells and the xenograft tumors. Furthermore, the splicing of CD44v were elevated by EGF treatment in THG-1 expressed SCC cells. Moreover, overexpression of THG-1 with oncogenic RAS in non-tumorigenic human keratinocyte promotes the CD44v expression and tumor formation. These results indicated that THG-1 potentiates the CD44v splicing under the receptor tyrosine kinase pathways and involved in the malignant progression of SCC.
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| Academic Significance and Societal Importance of the Research Achievements |
扁平上皮がんは、肺、食道、子宮頸部などに発生する予後不良のがんで、未だ有効な分子標的治療薬は少ない。本研究では扁平上皮がんに高発現するTHG-1/TCS22D4が、がん幹細胞マーカーであるCD44のスプライシングを制御する新たな分子メカニズムを明らかにした。本研究成果は、機能が未知であったTHG-1/TCS22D4の新規分子機構を明らかにするとともに、本経路を標的にした新たな治療法の開発が期待される。
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