Dual mode regulation of migration by lysophosphatidic acid in human gastric cancer cells.
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.
Shida
Dai
D
Department of Surgical Oncology, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan. SHIDA-DIS@h.u-tokyo.ac.jp
Kitayama
Joji
J
Yamaguchi
Hironori
H
Hama
Kotaro
K
Aoki
Junken
J
Arai
Hiroyuki
H
Yamashita
Hiroharu
H
Mori
Ken
K
Sako
Akihiro
A
Konishi
Tsuyoshi
T
Watanabe
Toshiaki
T
Sakai
Teruyuki
T
Suzuki
Rika
R
Ohta
Hideo
H
Takuwa
Yoh
Y
Nagawa
Hirokazu
H
D002633:Chemotaxis / Q000187:drug effects*; D020869:Gene Expression Profiling; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics; D013274:Stomach Neoplasms / Q000473:pathology*
D008246:Lysophospholipids; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; C032881:lysophosphatidic acid