Novel therapeutic strategy for sarcomas by targeting PPRX1 positive cancer stem-like cells

• Project/Area Number: 18K15212
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Okayama University
• Principal Investigator: Yamada Daisuke 岡山大学, 医歯薬学総合研究科, 助教 (50733680)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 骨肉腫 / PRRX1 / 転移 / PKAシグナル / 薬剤抵抗性 / がん遺伝子 / がん幹細胞 / 肉腫 / 薬剤耐性

Outline of Final Research Achievements

We performed PRRX1 immunostaining on 35 human osteosarcoma specimens to assess the correlation between PRRX1 level and overall survival. In patients with osteosarcoma, the expression level of PRRX1 positively correlated with poor prognosis or the ratio of lung metastasis. Additionally, we found PRRX1 expression on in 143B cells, a human osteosarcoma line with a high metastatic capacity. Downregulation of PRRX1 not only suppressed proliferation and invasion but also increased the sensitivity to cisplatin and doxorubicin. When 143B cells were subcutaneously transplanted into nude mice, PRRX1 knockdown decreased tumor sizes and rates of lung metastasis. Interestingly, forskolin, a chemical compound identified by Connectivity Map analysis using RNA expression signatures during PRRX1 knockdown, decreased tumor proliferation and cell migration to the same degree as PRRX1 knockdown. These results demonstrate that PRRX1 promotes tumor malignancy in human osteosarcoma.

Academic Significance and Societal Importance of the Research Achievements

発生過程において、PRRX1は四肢に存在する肢芽間葉系細胞に発現していることが報告されているが、骨肉腫における機能に関しては解析がなされていなかった。本研究により、ヒト骨肉腫においてPRRX1が悪性化促進因子として機能することが明らかとなり、さらにPKAシグナルがPRRX1を介した骨肉腫の悪性化に関与している可能性が示唆された。以上の結果より、PRRX1の高発現による腫瘍の悪性化メカニズムの解明につながる知見が得られただけでなく、PRRX1が骨肉腫治療の有望な治療標的になることが明らかとなった。

Research Products

• [Journal Article] PRRX1 promotes malignant properties in human osteosarcoma (2021)
  • Author(s): Joko Ryoji、Yamada Daisuke、Nakamura Masahiro、Yoshida Aki、Takihira Shota、Takao Tomoka、Lu Ming、Sato Kohei、Ito Tatsuo、Kunisada Toshiyuki、Nakata Eiji、Ozaki Toshifumi、Takarada Takeshi
  • Journal Title: Translational Oncology Volume: 14 Issue: 1 Pages: 100960-100960
  • DOI: 10.1016/j.tranon.2020.100960
  • NAID: 120007004820
  • Peer Reviewed / Open Access