Jin Hana, Lee Jong-Sil, Kim Dong-Chul, Ko Young-Shin, Lee Gyeong-Won, Kim Hye-Jung
Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Korea.
Department of Pathology, College of Medicine, Institute of Health Sciences, Gyeongsang National University Hospital, Gyeongsang National University, Jinju 52727, Korea.
Cancers (Basel). 2021 Apr 27;13(9):2105. doi: 10.3390/cancers13092105.
Recently, we found that the expressions of adenosine (ADO) receptors A2AR and A2BR and the ectonucleotidase CD73 which is needed for the conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and the extracellular ADO level are increased in TNBC MDA-MB-231 cells and RT-R-MDA-MB-231 cells compared to normal cells or non-TNBC cells. The expression of A2AR, but not A2BR, is significantly upregulated in breast cancer tissues, especially TNBC tissues, compared to normal epithelial tissues. Therefore, we further investigated the role of ADO-activated A2AR and its signaling pathway in the progression of RT-R-TNBC. ADO treatment induced MDA-MB-231 cell proliferation, colony formation, and invasion, which were enhanced in RT-R-MDA-MB-231 cells in an A2AR-dependent manner. A2AR activation by ADO induced AKT phosphorylation and then β-catenin, Snail, and vimentin expression, and these effects were abolished by A2AR-siRNA transfection. In an in vivo animal study, compared to 4T1-injected mice, RT-R-4T1-injected mice exhibited significantly increased tumor growth and lung metastasis, which were decreased by A2AR-knockdown. The upregulation of phospho-AKT, β-catenin, Snail, and vimentin expression in mice injected with RT-R-4T1 cells was also attenuated in mice injected with RT-R-4T1-A2AR-shRNA cells. These results suggest that A2AR is significantly upregulated in BC tissues, especially TNBC tissues, and ADO-mediated A2AR activation is involved in RT-R-TNBC invasion and metastasis through the AKT-β-catenin pathway.
最近，我们发现，与正常细胞或非三阴性乳腺癌（TNBC）细胞相比，TNBC的MDA-MB-231细胞和放疗抵抗性（RT-R）的MDA-MB-231细胞中，腺苷（ADO）受体A2AR和A2BR以及将三磷酸腺苷（ATP）转化为二磷酸腺苷（ADP）所需的胞外核苷酸酶CD73的表达，以及细胞外ADO水平均升高。与正常上皮组织相比，乳腺癌组织尤其是TNBC组织中，A2AR而非A2BR的表达显著上调。因此，我们进一步研究了ADO激活的A2AR及其信号通路在放疗抵抗性TNBC进展中的作用。ADO处理诱导MDA-MB-231细胞增殖、集落形成和侵袭，而在RT-R-MDA-MB-231细胞中这些作用以A2AR依赖的方式增强。ADO激活A2AR诱导AKT磷酸化，进而诱导β-连环蛋白、Snail和波形蛋白表达，而这些作用可被A2AR-siRNA转染消除。在一项体内动物研究中，与注射4T1细胞的小鼠相比，注射RT-R-4T1细胞的小鼠肿瘤生长和肺转移显著增加，而A2AR基因敲低可使其降低。注射RT-R-4T1细胞的小鼠中磷酸化AKT、β-连环蛋白、Snail和波形蛋白表达的上调，在注射RT-R-4T1-A2AR-shRNA细胞的小鼠中也减弱。这些结果表明，A2AR在乳腺癌组织尤其是TNBC组织中显著上调，且ADO介导的A2AR激活通过AKT-β-连环蛋白途径参与放疗抵抗性TNBC的侵袭和转移。
