Ganglioside GM2, highly expressed in the MIA PaCa-2 pancreatic ductal adenocarcinoma cell line, is correlated with growth, invasion, and advanced stage

Norihiko Sasaki,Kenichi Hirabayashi,Kimimasa Takahashi,Fumio Hasegawa,Yoko Itakura,Masaki Michishita,Naoya Nakamura,Masashi Toyoda,Toshiyuki Ishiwata,Fujiya Gomi

doi:10.1038/s41598-019-55867-4

Abstract

Gangliosides, a group of glycosphingolipids, are known to be cell surface markers and functional factors in several cancers. However, the association between gangliosides and pancreatic ductal adenocarcinoma (PDAC) has not been well elucidated. In this study, we examined the expression and roles of ganglioside GM2 in PDAC. GM2+ cells showed a higher growth rate than GM2− cells in the adherent condition. When GM2– and GM2+ cells were cultured three-dimensionally, almost all cells in the spheres expressed GM2, including cancer stem cell (CSC)-like cells. A glycolipid synthesis inhibitor reduced GM2 expression and TGF-β1 signaling in these CSC-like cells, presumably by inhibiting the interaction between GM2 and TGFβ RII and suppressing invasion. Furthermore, suppression of GM2 expression by MAPK inhibition also reduced TGF-β1 signaling and suppressed invasion. GM2+ cells formed larger subcutaneous tumors at a high incidence in nude mice than did GM2– cells. In PDAC cases, GM2 expression was significantly associated with younger age, larger tumor size, advanced stage and higher histological grade. These findings suggest that GM2 could be used as a novel diagnostic and therapeutic target for PDAC.

Highlights

Gangliosides, a group of glycosphingolipids, are known to be cell surface markers and functional factors in several cancers
PD0325901 treatment attenuated activation of TGF-β1 signaling (Fig. 6c) and further inhibited increases in invasion of TGF-β1-treated sphere cells (Fig. 6d). These results suggest that suppression of GM2 expression by treatment with an MEK inhibitor suppressed the increased invasion associated with activation of TGF-β1 signaling in cancer stem cell (CSC)-like cells
Several gangliosides have previously been identified in CSCs32

Summary

Introduction

Gangliosides, a group of glycosphingolipids, are known to be cell surface markers and functional factors in several cancers. In PDAC cases, GM2 expression was significantly associated with younger age, larger tumor size, advanced stage and higher histological grade. These findings suggest that GM2 could be used as a novel diagnostic and therapeutic target for PDAC. Changes in ganglioside levels affect the expression of raft-associated proteins on the cell surface and lead to reduced membrane fluidity, resulting in cellular dysfunctions, such as impaired signal transduction[11,12,13,14]. We showed expression of GM2 in human PDAC cells and PDAC tissues, and identified that GM2 is correlated with growth, invasion and advanced stage of PDAC. Our results suggest that GM2 could be a novel diagnostic and therapeutic target for some types of pancreatic cancer

Methods

Results

Conclusion