| Project/Area Number |
19K17812
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53050:Dermatology-related
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| Research Institution | Iwate Medical University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | HDAC6 / 乳房外Paget病 / COX2 / 浸潤 / 転移 / PGE2 / 乳房外ペジェット病 / COX / CAF |
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| Outline of Research at the Start |
乳房外Paget病は、外陰部に好発する皮膚悪性腫瘍である。腫瘍細胞の大部分は表皮内に留まり、浸潤・転移例は少ないものの、一旦浸潤・転移の生じた進行期症例には、局所切除に加え、抗がん薬を併用した薬物療法や、放射線療法が試みられている。しかし、多くは治療抵抗性であり予後不良な症例が多い。
本研究では、進行期乳房外Paget病に対する効果的な薬物療法開発のために、HDAC6-COX2関連分子の動態を解析し、Paget細胞の浸潤・転移機構に関する役割を明らかにする。さらに、HDAC6およびCOX2阻害薬が、浸潤・転移の抑制効果を有するかxenograftモデルを用いた基礎実験を行う。
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| Outline of Final Research Achievements |
For the effective treatment in advanced extramammary Paget disease, we analyzed HDAC6-COX2-related molecules and studied their role in invasion and metastasis. Activation of HDAC6-COX2-PGE2 was examined in co-culture systems as well as by immunostaining in human tumors.
HDAC6-COX2 may play an important role in the microenvironment formed by tumor cells and surrounding cancer-related fibroblasts (CAFs). Immunostaining revealed that HDAC6 was overexpressed in extramammary Paget's disease in the advanced stage, and many fibroblasts that appeared to be αSMA-positive CAF were found around it. These HDAC6-positive cells formed agglomerates and showed the dynamics of collective cell invasion. It was suggested that the secretion of PGE in extramammary Paget's disease is involved in the induction of overexpression of HDAC6 and may be involved in the acquisition of infiltration / metastatic ability.
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| Academic Significance and Societal Importance of the Research Achievements |
進行期の乳房外Paget病に対して有効な化学療法は無く、新たな治療薬の開発が切望されている。炎症性の症状を思わせる、乳房外Paget病の患者は、比較的多く、自分の研究テーマであるHDAC6とCOX2が極めて近い位置関係で作用している事が明らかになった。既にCOX2阻害薬は臨床応用されちぇおり、HDAC6阻害薬も臨床試験に入っている。本研究の基礎データは、今後の乳房外Paget病の治療に対して重要な意義を持つと思われる。
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