Ephrin Receptor A4 Expression Enhances Migration, Invasion and Neurotropism in Pancreatic Ductal Adenocarcinoma Cells
Satoru Furuhashi, Yoshifumi Morita, Shinya Ida, Ryuta Muraki, Ryo Kitajima, Makoto Takeda, Hirotoshi Kikuchi, Yoshihiro Hiramatsu, Mitsutoshi Setou, Hiroya Takeuchi
Abstract
BACKGROUND/AIM: We sought to identify the mechanisms of perineural invasion in pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: We utilized in vitro cancer cell-nerve co-culture models comprising human PDAC cell lines (MIA Paca2 and PANC-1) and a dorsal root ganglion (DRG) isolated from neonatal mice. We compared gene expression profiles between cell lines with/without DRG conditioned medium (DRG-CM) using RNA-sequencing (RNA-seq). RESULTS: Migration, invasion, and neurotropism were significantly enhanced in MIA Paca2 but not in PANC-1 cells co-cultured with DRGs. Among 285 genes which showed significant differences in expression levels between cell lines in RNA-seq, we focused on Ephrin receptor A4 (EPHA4), which was upregulated in MIA Paca2 cells treated with DRG-CM. The abilities of migration, invasion, and neurotropism enhanced by DRG co-culture were abolished when EPHA4 was knocked down by siRNA in MIA Paca2 cells. CONCLUSION: EPHA4 can be a potential target gene to regulate perineural invasion in PDAC cells.