The P2Y2 Nucleotide Receptor Mediates the Proliferation and Migration of Human Hepatocellular Carcinoma Cells Induced by ATP
The P2Y2 Nucleotide Receptor Mediates the Proliferation and Migration of Human Hepatocellular Carcinoma Cells Induced by ATP
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DOI：
10.1074/jbc.m113.540047
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发表时间：
2014-07-11
影响因子：
4.8
通讯作者：
Tuo, Biguang
中科院分区：
文献类型：
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作者：
Xie, Rui;Xu, Jingyu;Tuo, Biguang
三磷酸腺苷（ATP）是肿瘤微环境中含量丰富的生化成分，也是P2Y(2)核苷酸受体（P2Y(2)R）的生理性配体。在本研究中，我们探究了ATP对人肝癌（HCC）细胞生物学行为的影响，以及P2Y(2)R在ATP作用中的角色，旨在寻找针对肝癌的新治疗靶点。实验在原代分离的人肝癌细胞、正常肝细胞、人肝癌细胞系及裸鼠中开展。我们发现，与正常人肝细胞及正常肝细胞系LO2相比，原代人肝癌细胞以及人肝癌细胞系HepG2和BEL - 7404中P2Y(2)R的信使核糖核酸（mRNA）和蛋白质表达水平均显著升高。ATP可诱导肝癌细胞内钙离子浓度升高，促进肝癌细胞的增殖与迁移以及裸鼠体内肝癌的生长。P2Y受体拮抗剂苏拉明、P2Y(2)R特异性短发夹核糖核酸（shRNA）、钙库操纵性钙通道抑制剂2 - 氨基乙氧基二苯硼酸盐（2 - APB）和1 -（β - 3 -（4 - 甲氧基苯基）丙氧基 - 4 - 甲氧基苯乙基） - 1H - 咪唑盐酸盐（SKF96365），以及基质相互作用分子1（STIM1）特异性shRNA，均可抑制ATP对肝癌细胞的作用。综上所述，P2Y(2)R通过钙库操纵性钙通道介导的钙离子信号传导，介导了ATP对肝癌细胞生物学行为的作用，靶向P2Y(2)R可能是一种有前景的人肝癌治疗策略。
ATP is an abundant biochemical component of the tumor microenvironment and a physiologic ligand for the P2Y(2) nucleotide receptor (P2Y(2)R). In this study, we investigated the effect of ATP on the cellular behavior of human hepatocellular carcinoma (HCC) cells and the role of P2Y(2)R in ATP action and aimed to find a new therapeutic target against HCC. The experiments were performed in native isolated human HCC cells, normal hepatocytes, human HCC cell lines, and nude mice. We found that the mRNA and protein expression levels of P2Y(2)R in native human HCC cells and the human HCC cell lines HepG2 and BEL-7404 were enhanced markedly compared with human normal hepatocytes and the normal hepatocyte line LO2, respectively. ATP induced intracellular Ca2+ increases in HCC cells and promoted the proliferation and migration of HCC cells and the growth of HCC in nude mice. The P2Y receptor antagonist suramin, P2Y(2)R-specific shRNA, the store-operated calcium channel inhibitors 2-aminoethoxydiphenyl borate (2-APB) and 1-(beta-3-(4-methoxyphenyl) propoxyl-4-methoxyphenethyl) 1H-imidazolehydrochloride (SKF96365), and stromal interaction molecule (STIM1)-specific shRNA inhibited the action of ATP on HCC cells. In conclusion, P2Y(2)R mediated the action of ATP on the cellular behavior of HCC cells through store-operated calcium channel-mediated Ca2+ signaling, and targeting P2Y(2)R may be a promising therapeutic strategy against human HCC.