Targeting epigenetic alterations in a mouse model of E-cadherin/p53-deficient diffuse-type gastric cancer

2015 Fiscal Year Final Research Report

• Project/Area Number: 25830074
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Shimada Shu 東京医科歯科大学, 医歯(薬)学総合研究科, 助教 (20609705)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 胃がん / マウスモデル / E-cadherin / p53 / エピジェネティクス / 分子標的治療

Outline of Final Research Achievements

Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and a poor patient prognosis. We have established an E-cadherin/p53 double conditional knockout (DCKO) mouse line as the first genetically engineered one, which morphologically and molecularly recapitulates human DGC. In this study, we derived mouse DGC (MDGC) cell lines from primary tumors and lymph node metastases of the DCKO mice. We identified that the expression levels of epigenetic regulators and frequently methylated genes were up- and down-regulated in mouse primary DGC, respectively. Treatment with some epigenetic inhibitors could markedly induce differentiation and attenuate sphere formation of the MDGC cell lines in vitro. Moreover, these agents demonstrated enhanced tumor-suppressor activity in vivo. These results suggest that epigenetic alteration may play significant roles in diffuse-type gastric carcinogenesis and support to develop a relevant therapeutic strategy in human DGC.

Free Research Field

分子腫瘍学