Expression of Adenosine Receptors in Thyroid Carcinoma.
Tetsuo Kondo, Tadao Nakazawa, Tomonori Kawasaki, Kunio Mochizuki, Dong-Feng Niu, Tetsu Yamane, Ryohei Katoh. University of Yamanashi, Chuo, Japan
Background: The adenosine receptors, comprising A1, A2a, A2b and A3, are G protein-coupled receptors with adenosine as endogenous ligand. A1 and A3 receptors inhibit adenylyl cyclase via coupling to Gi, while A2a and A2b receptors stimulate adenylyl cyclase activity via Gs. Recently overexpression of adenosine receptors have been identified in several human cancers.
Design: To explore the putative importance of adenosine receptors in thyroid carcinogenesis, we examined the expression of four isoforms of adenosine receptors in normal thyroids (25 cases), various thyroid tumors (adenomatous goiter, 18 cases; follicular adenomas, 10 cases; follicular carcinomas, 17 cases; papillary carcinomas, 27 cases; undifferentiated carcinomas, 21 cases) and 6 thyroid carcinoma cell lines (KTC-1, TPC-1, WRO, 8505C, UA-1 and UA-2). To further examine the function of ADORA1 in thyroid carcinomas, highly selective ADORA1 antagonist DPCPX was applied for MTT cell growth assay, matrigel invasion assay, and gelatin zymography for matrix metalloproteinase (MMP) -2 and -9 activities.
Results: Using RT-PCR and Western blotting, we found that adenosine receptor A1 (ADORA1) was consistently upregulated in papillary carcinomas and thyroid cancer cell lines compared with normal thyroids. There were no distinct differences in the mRNA expression of adenosine receptor A2a, A2b and A3 subtypes between normal and neoplastic thyroids. In immunohistochemistry, diffuse cytoplasmic immunopositivity of ADORA1 was observed in a majority of follicular carcinomas, papillary carcinomas and undifferentiated carcinomas, while negative or focal immunopositivity in normal thyroids. The pattern of ADORA1 immunostaining in adenomatous goiter and follicular adenomas varied from negative to diffusely positive among cases. Pharmacologic ADORA1 inhibition significantly impaired thyroid tumor cell growth and tumor cell invasion. In addition, DPCPX suppressed secretion of active forms of MMP-2 and -9 that were induced by selective ADORA1 agonist CPA in thyroid carcinoma cells.
Conclusions: In conclusion, we demonstrated enhanced expression of ADORA1 in human thyroid carcinoma tissues, and potential role of ADORA1 for tumor invasion, suggesting the adenosinergic system as a potential pharmacological target in thyroid cancer therapeutics.
Tuesday, March 1, 2011 1:00 PM
Poster Session IV # 41, Tuesday Afternoon