Abstract LB-100: HNF4G overexpression promotes PDAC progression and confers metformin sensitivity in patients with SMAD4-loss of function

Abstract

Abstract BACKGROUND: Genome-wide association studies (GWAS) have identified several genetic regions associated with risk of pancreatic ductal adenocarcinoma (PDAC) while the underlying mechanisms remain largely unknown. This study investigated the functions of genes in these genetic regions and their roles as potential biomarkers or therapeutic targets for PDAC. METHODS: We reanalyzed our previous GWAS data based on referring the 108 risk loci reported in published PDAC GWAS to seek for all susceptibility genes in the Chinese population and found 44 potential risk genes. A siRNA library was used to silence these genes in PDAC cell lines and the malignant phenotypes were examined by using a high content screen method followed by a series of functional assays. RESULTS: Among the 44 genes, HNF4G was the top one who’s silencing significantly repressed PDAC cell migration and invasion. Functional assays showed that HNF4G regulates cell-cell junction pathway, which may be the underlying mechanism for its action. HNF4G was upregulated by SMAD4 loss of function and frequently overexpressed in PDACs. PDAC cell metastasis promoted by the overexpression of HNF4G could be suppressed by metformin, and this effect was seen only in PDAC cells with SMAD4 loss of function, resulting in heterogeneous vulnerability of PDAC to the drug. CONCLUSION: HNF4G overexpression might result in metformin sensitivity in PDAC with SMAD4 loss of function and thus represent as a potential therapeutic target. Citation Format: Chengcheng Wang, Chen Wu, Dongxin Lin, Yupei Zhao. HNF4G overexpression promotes PDAC progression and confers metformin sensitivity in patients with SMAD4-loss of function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-100.