Analysis of the mechanism of hypoxia-inducible factor cascade regulation by Fra-1 in esophageal squamous cell carcinoma.

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K16324
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Chiba University
• Principal Investigator: Toyozumi Takeshi 千葉大学, 医学部附属病院, 助教 (80645606)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 食道扁平上皮癌 / Fra-1 / HIF-1α / 低酸素

Outline of Final Research Achievements

We confirmed suppression of HIF-1α expression in a Fra-1 knockdown model using an esophageal squamous cell carcinoma (ESCC) cell line, and observed high expression of HIF-1α in a hypoxic environment. In a HIF-1α knockdown model, we confirmed suppression of changes in cell function and enhancement of 5FU sensitivity. We confirmed a positive correlation between high HIF-1α expression and tumor growth using a mouse subcutaneous implantation model.
We revealed that Wnt/β-catenin pathway-related proteins are downstream regulatory proteins of HIF-1α, and revealed direct binding between β-catenin and HIF-1α in ESCC cell lines.
Furthermore, the results of immunostaining using preoperatively untreated esophageal cancer resection specimens showed that high HIF-1α expression is a factor that worsens the prognosis of esophageal squamous cell carcinoma.

Free Research Field

消化器外科

Academic Significance and Societal Importance of the Research Achievements

食道扁平上皮癌におけるFra-1発現とHIF-1α発現の関連やHIF-1αの下流カスケードを明らかにした研究報告は少なく、食道扁平上皮癌の低酸素環境における分子病態学的変化についてはいまだに不明点が多い。本研究成果はFra-1の下流カスケードとしてのHIF-1α、さらにHIF-1αの下流カスケードとしてのWnt/β-catenin経路関連タンパクの存在を明らかにし、食道扁平上皮癌の低酸素環境解析における新たな研究シーズならびに治療ターゲットを提供した。