Fundamental research on novel therapies for pancreatic cancer targeting glucose metabolism and transcription factor KLF4/FOXM1

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K16323
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Kyuno Takuro 札幌医科大学, 医学部, 研究員 (20722458)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 膵癌 / EMT / タイト結合 / FOXM1 / snail / claudin-1 / 低濃度グルコース培養

Outline of Final Research Achievements

Pancreatic cancer undergoes an epithelial-mesenchymal transition (EMT) process that alters cell morphology during invasion and metastasis, and regulation of EMT may improve prognosis. In pancreatic cancer, the EMT-inducing factor snail promotes EMT by decreasing the intercellular binding factor claudin-1. On the other hand, the transcription factor FOXM1 is involved in malignant transformation in all cancers, and analysis of the relationship between FOXM1 and EMT could lead to elucidation of the mechanism of EMT in pancreatic cancer and development of therapeutic strategies.
In the present study, suppression of FOXM1 in pancreatic cancer cells resulted in downregulation of snail and enhanced expression of claudin-1. When pancreatic cancer cells were cultured with low glucose concentration, FOXM1 expression was decreased, suggesting that EMT of pancreatic cancer is suppressed by the regulation of intracellular glucose metabolism.

Free Research Field

消化器癌

Academic Significance and Societal Importance of the Research Achievements

膵癌は化学療法・放射線治療などの集学的治療の発展により、個々の症例では手術可能となる症例が増えている。しかし、日本では5年生存率が7.7%と依然として予後が極めて悪い難治性癌であり、新たなメカニズムを介した治療法の開発が急務である。
本研究では、細胞内代謝、特に糖代謝の観点から膵癌の転写因子を抑制すると、膵癌の悪性化の指標である上皮間葉移行(EMT)を制御できた。この結果より、実臨床において糖代謝のコントロールによって膵癌の発癌予防や浸潤・転移などの悪性化の抑制につながる可能性が示唆された。