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 biol ogical activities, e.g., the regulation of cellular proliferation and vario us aspects of cellular physiology. Signal transduction is achieved by bindi ng 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 r eceptors. We examined the growth-regulatory effects of LPA in primary cultu res of 8 goiters and I papillary thyroid cancer. We further assessed mRNA e xpression of high-affinity receptors EDG2 and EDG4 in 14 normal thyroids, 2 9 papillary thyroid cancers, 7 follicular thyroid cancers and 13 goiters by quantitative RT-PCR. We also identified mRNA expression of phospholipase A , and LPA acyltransferase in fresh thyroid tissues derived from various sou rces. At concentrations of 10, 50 and 150 muM, LPA induced a 2-fold rise of proliferation (p < 0.001)and acted as strongly as thyrotropin. The combina tion of LPA and TSH produced significant synergistic effects compared with each substance alone (p < 0.05). Normal thyroid, goiter and papillary or fo llicular thyroid cancer expressed 2 high-affinity cognate LPA receptors, ED G2 and EDG4. EDG4 receptor mRNA expression was increased 3-fold in differen tiated thyroid cancer (p < 0.01), both papillary (p < 0.01) and follicular (p < 0.05), compared to normal thyroid or goiter. Overall expression of EDG 2 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 different iated thyroid cancer. <(c)> 2001 Wiley-Liss, Inc.