Identification of molecular targets associated with activation of GPCR signal pathway in pancreatic cancer

2014 Fiscal Year Final Research Report

• Project/Area Number: 24659167
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Human pathology
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: FURUKAWA Toru 東京女子医科大学, 医学部, 教授 (30282122)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 膵臓がん / シグナル伝達 / GPCR / MAPK / PI3K / 遺伝子発現 / 分子標的 / GNAS

Outline of Final Research Achievements

We examined phenotypes of pancreatic ductal lineage cells with exogenous expression of either wild-type or mutated (R201H) GNAS. We found that exogenous GNAS upregulated intracellular cAMP and varying altered expression of mucin genes. Exogenous GNAS did not promote cell growth but suppressed it in some of the cells. Global gene expression profiling showed drastic alterations of the gene expression profiles by exogenous mutated GNAS and led to identify downstream genes of activated GPCR pathway. We found interactions between the signaling pathways of GPCR, MAPK, and PI3K on expression of mucin genes. We generated transgenic mice lines with Lox-STOP-Lox (LSL)-GNASR201H under CAG promoter. By crossing this mice line with LSL-KrasG12D mice and Ptf1a-cre mice, we showed that mutated GNAS and Kras cooperatively promoted pancreatic tumorigenesis recapitulating IPMN. This mouse model may serve as a platform to find biomarkers and effective drugs for diseases associated with GNAS mutations.

Free Research Field

人体病理学