Shida Dai, Kitayama Joji, Yamaguchi Hironori, Hama Kotaro, Aoki Junken, Arai Hiroyuki, Yamashita Hiroharu, Mori Ken, Sako Akihiro, Konishi Tsuyoshi, Watanabe Toshiaki, Sakai Teruyuki, Suzuki Rika, Ohta Hideo, Takuwa Yoh, Nagawa Hirokazu
Department of Surgical Oncology, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.
Exp Cell Res. 2004 Dec 10;301(2):168-78. doi: 10.1016/j.yexcr.2004.08.008.
Lysophosphatidic acid (LPA), which interacts with at least three G protein-coupled receptors (GPCRs), LPA1/Edg-2, LPA2/Edg-4, and LPA3/Edg-7, is a lipid mediator with diverse effects on various cells. Here, we investigated the expression profiles of LPA receptors and patterns of LPA-induced migration in gastric cancer cells. Northern blot analysis revealed that various gastric cancer cells expressed variable levels of LPA1, LPA2, and LPA3 without a consistent pattern. Using a Boyden chamber assay, LPA markedly increased cell migration of LPA1-expressing cells, the effects of which were almost totally abrogated by Ki16425, an LPA antagonist against LPA1 and LPA3. In contrast, LPA by itself did not significantly induce migration in MKN28 and MKN74 cells, which exclusively expressed LPA2. However, when hepatocyte growth factor (HGF) was placed with LPA in the lower chamber, LPA induced migration of these cells in a dose-dependent manner. Immunoprecipitation analysis revealed that LPA induced transient tyrosine phosphorylation of c-Met in LPA2-expressing cells, which suggests that the transactivation of c-Met by LPA causes a cooperative migratory response with HGF to these cells. Our results indicate that LPA regulates the migration of gastric cancer cells in a receptor-specific manner and suggest that the expression pattern of LPA receptors may affect the metastatic behavior of gastric cancer.
溶血磷脂酸（LPA）是一种对多种细胞具有多种作用的脂质介质，它与至少三种G蛋白偶联受体（GPCR），即LPA1/Edg-2、LPA2/Edg-4和LPA3/Edg-7相互作用。在此，我们研究了LPA受体在胃癌细胞中的表达谱以及LPA诱导的迁移模式。Northern印迹分析显示，各种胃癌细胞表达的LPA1、LPA2和LPA3水平各不相同，没有一致的模式。使用Boyden小室试验，LPA显著增加了表达LPA1的细胞的迁移，其作用几乎完全被Ki16425（一种针对LPA1和LPA3的LPA拮抗剂）消除。相比之下，LPA本身并未显著诱导仅表达LPA2的MKN28和MKN74细胞的迁移。然而，当在下室中将肝细胞生长因子（HGF）与LPA一起放置时，LPA以剂量依赖性方式诱导这些细胞的迁移。免疫沉淀分析显示，LPA在表达LPA2的细胞中诱导c-Met的瞬时酪氨酸磷酸化，这表明LPA对c-Met的反式激活导致与HGF对这些细胞的协同迁移反应。我们的结果表明，LPA以受体特异性方式调节胃癌细胞的迁移，并表明LPA受体的表达模式可能影响胃癌的转移行为。
