Lysophosphatidic acid promotes cell invasion by up-regulating the urokinase-type plasminogen activator receptor in human gastric cancer cells.
There is a strong correlation between the overexpression of urokinase-type plasminogen activator receptor (uPAR) and gastric cancer invasion. This study examined the effect of phospholipid lysophosphatidic acid (LPA) on uPAR expression in human gastric cancer AGS cells and the underlying signal transduction pathways. Treating human gastric AGS cells with LPA induced the expression of uPAR mRNA and promoter activity in both a time- and dose-dependent manner. Small interfering RNA targeting for LPA receptors, dominant negative Rho-family GTPase (RhoA, Rac1, and Cdc42) and an expression vector encoding a mutated c-jun (TAM67) partially blocked the LPA-induced uPAR expression. Site-directed mutagenesis and electrophoretic mobility shift studies showed that the transcription factors activation protein-1 (AP-1) and nuclear factor (NF)-kappaB are essential for the LPA-induced uPAR transcription. In addition, AGS cells treated with LPA showed enhanced invasion, which was partially abrogated by the uPAR-neutralizing antibodies and inhibitors of Rho kinase, JNK, and NF-kappaB. This suggests that LPA induces uPAR expression through the LPA receptors, Rho-family GTPase, JNK, AP-1 and NF-kappaB signaling pathways, which in turn stimulates the cell invasiveness of human gastric cancer AGS cells.
Kim
Mi Ha
MH
Chonnam University Research Institute of Medical Sciences, Chonnam National University Medical School, Kwangju 501-190, Korea.
Park
Jung Sun
JS
Chang
Hee Jung
HJ
Baek
Min Kyung
MK
Kim
Hyeong Rok
HR
Shin
Boo Ahn
BA
Ahn
Bong Whan
BW
Jung
Young Do
YD
D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D011509:Proteoglycans / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D013274:Stomach Neoplasms / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation
D004338:Drug Combinations; D007797:Laminin; D008246:Lysophospholipids; D016328:NF-kappa B; C524898:PLAUR protein, human; D011509:Proteoglycans; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D018808:Transcription Factor AP-1; C059485:matrigel; D003094:Collagen; C032881:lysophosphatidic acid