Lysophosphatidic acid (LPA) is an extracellular biological lipid which interacts with G protein-coupled LPA receptors (LPA(1) to LPA(6)). LPA signaling via LPA receptors mediates several cellular responses. In the present study, to assess the roles of LPA(4), LPA(6) and LPA(6) in cellular functions of pancreatic cancer cells, we generated LEA receptor knockdown cells from PANC-1 cells (PANC-sh4, PANC-sh5 and PANC-sh6 cells, respectively). In cell motility assay, PANC-sh4 and PANC-sh5 cells enhanced the cell motile activities, compared with control cells. In contrast, the cell motile activity of PANC-sh6 cells was suppressed. The invasive activities of PANC-sh4 and PANC-sh5 cells were markedly stimulated, while PANC-sh6 cells showed the low invasive activity. In colony assay, PANC-sh4 and PANC-sh5 cells formed the large sized colonies, but not PANC-sh6 cells. When endothelial cells were incubated with supernatants from PANC-sh4 and PANC-sh5 cells, the cell motility and tube formation of endothelial cells were significantly induced, but not PANC-sh6 cells. These results suggest that the diverse roles of LPA(4), LPA(6) and LPA(6) are involved in the activation of tumor progression in pancreatic cancer cells. (C) 2015 Elsevier Inc. All rights reserved.