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 μM, 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. © 2001 Wiley‐Liss, Inc.