Lysophosphatidic acid, a novel lipid growth factor for human thyroid cells: over-expression of the high-affinity receptor edg4 in differentiated thyroid cancer.
Lysophosphatidic acid (LPA) is a small lipid mediator with pleiotropic biological activities, e.g., the regulation of cellular proliferation and various aspects of cellular physiology. Signal transduction is achieved by binding to 2 high-affinity receptors, EDG2 and EDG4, and a group of low-affinity receptors, EDG1-7, all belonging to the superfamily of G protein-coupled receptors. We examined the growth-regulatory effects of LPA in primary cultures of 8 goiters and 1 papillary thyroid cancer. We further assessed mRNA expression of high-affinity receptors EDG2 and EDG4 in 14 normal thyroids, 29 papillary thyroid cancers, 7 follicular thyroid cancers and 13 goiters by quantitative RT-PCR. We also identified mRNA expression of phospholipase A(2) and LPA acyltransferase in fresh thyroid tissues derived from various sources. At concentrations of 10, 50 and 150 microM, LPA induced a 2-fold rise of proliferation (p < 0.001) and acted as strongly as thyrotropin. The combination of LPA and TSH produced significant synergistic effects compared with each substance alone (p < 0.05). Normal thyroid, goiter and papillary or follicular thyroid cancer expressed 2 high-affinity cognate LPA receptors, EDG2 and EDG4. EDG4 receptor mRNA expression was increased 3-fold in differentiated thyroid cancer (p < 0.01), both papillary (p < 0.01) and follicular (p < 0.05), compared to normal thyroid or goiter. Overall expression of EDG2 receptor was unchanged in malignancy; however, increased EDG2 expression in individual samples correlated with lymphonodular metastasis (p = 0.01). Thus, lipid mediators are a novel class of factors involved in the control of proliferation in the human thyroid. Altered mRNA expression of the high-affinity LPA receptor EDG4 suggests a role in the pathogenesis of differentiated thyroid cancer.
Schulte
K M
KM
Clinic for General Surgery and Trauma Surgery, Medizinische Einrichtungen, Heinrich-Heine-Universität, Moorenstr. 5, 40225 Dusseldorf, Germany. SchulteKM@med.uni-duesseldorf.de
Beyer
A
A
Köhrer
K
K
Oberhäuser
S
S
Röher
H D
HD
D000217:Acyltransferases / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002888:Chromosomes, Human, Pair 19; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006042:Goiter / Q000378:metabolism; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010741:Phospholipases A / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
D006133:Growth Substances; D008246:Lysophospholipids; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D000217:Acyltransferases; C018764:2-acylglycerophosphate acyltransferase; D010741:Phospholipases A