Suppressing Head and Neck Tumorigenesis Caused by RTK/RAS/PI3K Gene Abnormalities - Therapeutic Application

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K16852
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56050:Otorhinolaryngology-related
• Research Institution: Tohoku University
• Principal Investigator: kurosawa koreyuki 東北大学, 医学系研究科, 講師 (10770349)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: 舌癌 / マウス発がん実験 / PP6 / KRAS

Outline of Final Research Achievements

We examined the effects of PP6 gene (Ppp6c) deficiency on tongue tumor development in K (K-rasG12D)- and KP (K-rasG12D + Trp53-deficient)-inducible mice. Mice of K and KP genotypes developed squamous cell carcinoma in situ in the tongue approximately 2 weeks after induction of gene recombination, and was euthanized due to 20% loss of body weight. Transcriptome analysis revealed significantly different gene expression between tissues of Ppp6c-deficient tongues and those of Ppp6c wild type, while Trp53 deficiency had a relatively smaller effect. We then evaluated signals downstream of RAS as well as those regulated by PP6 and found that Ppp6c deletion in the presence of K-rasG12D enhanced activation of the ERK-ELK1-FOS, AKT-4EBP1 and AKT-FOXO-CyclinD1 axes. Ppp6c deletion combined with K-rasG12D also enhanced DSB accumulation and activated NF kappa B signaling. Overall, we conclude that Ppp6c deficiency serves as a driver of KRAS(G12D)-initiated tumorigenesis in mouse tongue.

Free Research Field

耳鼻咽喉科学

Academic Significance and Societal Importance of the Research Achievements

現在のところ、がん原性RASによって発生したがんの治療法として、数多くの抗RAS試薬が提案されているが、決定的な治療法はまだ確立されていない。今回、我々は、PP6ホスファターゼが変異型RASによりドライブされるERK、AKT、NFkBの異常な活性化を抑制することで、腫瘍抑制因子として機能していることを発見した。現在、世界中でホスファターゼの活性化物質のスクリーニングが行われている。将来的には、PP6 活性化因子が、変異型RASによる発がんを抑える新しい治療戦略となりうるのではないかと考える。