Homeobox B9 induces epithelial-to-mesenchymal transition-associated chemosistance by accelerating TGFb pathway

• Project/Area Number: 18K08604
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Chiba Naokazu 東京医科大学, 医学部, 准教授 (90348665)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: HoxB9 / HOXB9

Outline of Final Research Achievements

TGFb signature, Angiogenic factor, and EMT marker were downregulated by knockdown of HoxB9 in vitro. And the sensitivity of chemotherapy reagents was upregulated by knockdown of HoxB9. Approximately 46% of pancreatic cancer resected specimens showed an increase of HoxB9, which was a significant prognostic factor for recurrence-free survival and overall survival. In addition, a positive correlation was observed between the TGFb signature and HoxB9 in the resected specimen samples. From these results, it was speculated that HoxB9 acquired anticancer drug resistance at the same time as upregulation of metastasis and infiltration with EMT changes via the TGFb pathway.

Academic Significance and Societal Importance of the Research Achievements

癌治療における大きな問題点として、癌細胞の抗癌剤耐性を含めた感受性と効果予測因子の正確性が挙げられる。本研究成果により、HoxB9が癌の個別化治療のバイオマーカーとなり、ある種の抗癌剤に治療抵抗性となった癌治療の予後改善のために最終的に臨床応用が可能となる可能性が示唆された。また、HoxB9はある種の分子標的治療薬の効果予測因子となる可能性がすでに検証されており、抗癌剤耐性メカニズムと同様に、分子標的治療薬の感受性変化のバイオマーカーとしても有用となる可能性がある。