Mechanism of Action and Function of a novel HIF-1 activator in p53-deficient cancers

2020 Fiscal Year Final Research Report

• Project/Area Number: 18KK0241
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Kyoto University
• Principal Investigator: Harada Hiroshi 京都大学, 生命科学研究科, 教授 (80362531)
• Co-Investigator(Kenkyū-buntansha): 小林 稔 京都大学, 生命科学研究科, 特定助教 (40644894) ; 子安 翔 京都大学, 医学研究科, 助教 (80781913)
• Project Period (FY): 2018-10-09 – 2021-03-31
• Keywords: がん / 低酸素 / 浸潤・転移関連遺伝子 / 治療抵抗性 / がん抑制遺伝子 / HIF-1 / p53

Outline of Final Research Achievements

Hypoxia-inducible factor 1 (HIF-1) has the function of inducing resistance of cancer cells to conventional therapies, such as chemotherapy and radiotherapy, and malignant phenotypes of cancer cells. Through the collaborative studies between the applicant and overseas researchers, we preliminarily identified a novel gene that activates HIF-1 only in the case of dysfunction of the tumor suppressor gene, p53. In addition, we have found a possibility that the novel gene induces invasiveness of p53-deficient cancer cells. Based on these preliminary findings, we performed extensive research with the aim of elucidating the mechanism of action of the novel gene, validating the usefulness of the novel factor as a therapeutic target, and establishing a rational method for inhibiting the activity of the novel gene.

Free Research Field

がん細胞生物学、低酸素バイオロジー

Academic Significance and Societal Importance of the Research Achievements

本研究によって、p53変異型がん細胞が腫瘍組織内の低酸素環境下で悪性形質と治療抵抗性を獲得するメカニズムに迫ること、および当該メカニズムを効率よく抑制するストラテジーを見出すことが出来た。これまで、発がん過程の中でp53に変異が入ることを引き金に腫瘍の悪性度が劇的に増加する機序は不明であったが、本研究によりその一端が解明された学術的意義は大きい。また、ここで得られた知見を基に、p53変異型腫瘍に対する新たな治療法の確立に繋がることが期待されることから、その波及効果も大きい。