Bertoni Ana Paula Santin, de Campos Rafael Paschoal, Tsao Marisa, Braganhol Elizandra, Furlanetto Tania Weber, Wink Márcia Rosângela
Departamento de Ciências Básicas da Saúde and Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Rua Sarmento Leite, 245, Prédio III, Sala 613, Porto Alegre, RS, CEP 90050-170, Brazil.
Departamento de Farmacociências, Universidade Federal de Ciências da Saúde de Porto Alegre, Rua Sarmento Leite, 245, Prédio Principal, Sala 305, Porto Alegre, RS, CEP 90050-170, Brazil.
Cancer Microenviron. 2018 Jun;11(1):61-70. doi: 10.1007/s12307-018-0206-4. Epub 2018 Feb 17.
The incidence of differentiated thyroid cancer has been increasing. Nevertheless, its molecular mechanisms are not well understood. In recent years, extracellular nucleotides and nucleosides have emerged as important modulators of tumor microenvironment. Extracellular ATP is mainly hydrolyzed by NTPDase1/CD39 and NTPDase2/CD39L1, generating AMP, which is hydrolyzed by ecto-5'-nucleotidase (CD73) to adenosine, a possible promoter of tumor growth and metastasis. There are no studies evaluating the expression and functionality of these ectonucleotidases on normal or tumor-derived thyroid cells. Thus, we investigated the ability of thyroid cancer cells to hydrolyze extracellular ATP generating adenosine, and the expression of ecto-enzymes, as compared to normal cells. We found that normal thyroid derived cells presented a higher ability to hydrolyze ATP and higher mRNA levels for ENTDP1-2, when compared to papillary thyroid carcinoma (PTC) derived cells, which had a higher ability to hydrolyze AMP and expressed CD73 mRNA and protein at higher levels. In addition, adenosine induced an increase in proliferation and migration in PTC derived cells, whose effect was blocked by APCP, a non-hydrolysable ADP analogue, which is an inhibitor of CD73. Taken together, these results showed that thyroid follicular cells have a functional purinergic signaling. The higher expression of CD73 in PTC derived cells might favor the accumulation of extracellular adenosine in the tumor microenvironment, which could promote tumor progression. Therefore, as already shown for other tumors, the purinergic signaling should be considered a potential target for thyroid cancer management and treatment.
分化型甲状腺癌的发病率一直在上升。然而，其分子机制尚未完全明确。近年来，细胞外核苷酸和核苷已成为肿瘤微环境的重要调节因子。细胞外ATP主要由NTPDase1/CD39和NTPDase2/CD39L1水解，生成AMP，AMP再由胞外5'-核苷酸酶（CD73）水解为腺苷，腺苷可能是肿瘤生长和转移的促进剂。目前尚无研究评估这些外切核苷酸酶在正常或肿瘤来源的甲状腺细胞上的表达和功能。因此，我们研究了甲状腺癌细胞水解细胞外ATP生成腺苷的能力，以及与正常细胞相比外切酶的表达情况。我们发现，与甲状腺乳头状癌（PTC）来源的细胞相比，正常甲状腺来源的细胞具有更高的ATP水解能力和ENTDP1-2的mRNA水平，而PTC来源的细胞具有更高的AMP水解能力，且CD73 mRNA和蛋白的表达水平更高。此外，腺苷可诱导PTC来源的细胞增殖和迁移增加，其作用被APCP（一种不可水解的ADP类似物，是CD73的抑制剂）阻断。综上所述，这些结果表明甲状腺滤泡细胞具有功能性嘌呤能信号传导。PTC来源的细胞中CD73的高表达可能有利于肿瘤微环境中细胞外腺苷的积累，从而促进肿瘤进展。因此，正如其他肿瘤所显示的那样，嘌呤能信号传导应被视为甲状腺癌管理和治疗的潜在靶点。
