Treatment Strategies for DUSP6 Inactivated Pancreatic Cancer

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07386
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Tohoku University
• Principal Investigator: Saiki Yuriko 東北大学, 医学系研究科, 准教授 (80311223)
• Co-Investigator(Kenkyū-buntansha): 古川 徹 東北大学, 医学系研究科, 教授 (30282122)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: pancreatic cancer / Dusp6

Outline of Final Research Achievements

Dual-specificity phosphatase 6 (DUSP6) is an ERK-specific phosphatase and acts as a negative feedback regulator of ERK activity. In human pancreas, DUSP6 expression increases in Pan-IN lesions, but decreases in invasive lesions. In this study, we use Dusp6 knockout mice to explore the role of Dusp6 in KrasG12D-driven pancreatic carcinogenesis.
We crossed Pdx1-Cre; KrasLSL-G12D (KC) mice and Dusp6 knockout mice to generate Pdx1-Cre; KrasLSL-G12D; Dusp6 -/- mice. To study the effects of deleting Dusp6 on pancreatic carcinogenesis, we generated aged-matched cohorts of KC mice, which were wild, heterozygous or homozygous for the knockout allele of Dusp6. Histological analysis revealed significantly increased acinar to ductal metaplasia (ADM) and PanIN lesions in mice lacking Dusp6 compared with KrasG12D expression alone. Our data suggest a tumor suppressive role of Dusp6 in pancreatic carcinogenesis.

Free Research Field

腫瘍病理、マウスモデル

Academic Significance and Societal Importance of the Research Achievements

現在までに10種類のdual-specificity phosphatase が知られているが、DUSP6はその中でERK特異的な脱リン酸化酵素として最も早く同定された。はじめに、DUSP6が膵臓がんにおいて腫瘍抑制因子としてはたらく可能性が見いだされ、それにつづいて、卵巣がん，肺がんでもDUSP6の機能喪失性異常が報告されている。しかし、DUSP6の不活化により発癌がうながされることを、個体レベルで証明した報告はない。本研究は、世界に先駆けて生体内でのDUSP6の腫瘍抑制因子としての働きを明らかにした。