Osteopontin isoform c promotes the survival of cisplatin-treated NSCLC cells involving NFATc2-mediated suppression on calcium-induced ROS levels.
Osteopontin isoform c promotes the survival of cisplatin-treated NSCLC cells involving NFATc2-mediated suppression on calcium-induced ROS levels.
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DOI：
10.1186/s12885-021-08495-z
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发表时间：
2021-06-29
期刊：
影响因子：
3.8
通讯作者：
Ding W
中科院分区：
文献类型：
--
作者：
Huang J;Hu M;Niu H;Wang J;Si Y;Cheng S;Ding W
肿瘤微环境（TME）对转化细胞的恶性进展和对化疗药物的化学反应起着至关重要的作用。骨桥蛋白 (OPN) 是一种分泌性肿瘤蛋白，具有多种剪接异构体，已知所有这些剪接异构体都能调节肿瘤生长，并能够改变细胞-细胞或细胞-TME 通讯，然而，OPN 剪接异构体的确切作用和调节尚不清楚。在本研究中，评估了 OPN 剪接亚型过表达细胞培养物的条件培养基对细胞功能的影响。使用核钙报告基因检测和活化 T 细胞核因子 c2 (NFATc2) 检测的亚细胞分布方法来研究 OPN 剪接亚型作用的分子机制。我们发现，条件培养基中分泌型 OPNc 可以增加用顺铂处理的 NSCLC 细胞的存活率，其中 OPNc 减少细胞凋亡与细胞钙信号的激活和随后的 NFATc2 核转位有关。结果揭示了肿瘤细胞在化学应激 TME 中存活的 OPN 和下游信号机制，这强调了分泌蛋白在选择性剪接亚型中的重要性。我们的研究不仅证明了 OPN 中和对于抗肿瘤作用的重要性，而且还暗示钙/NFATc2/ROS 轴的调节可能是改善 NSCLC 治疗长期结果的新方法。在线版本包含可在 10.1186/s12885-021-08495-z 获取的补充材料。
Tumor microenvironment (TME) critically contributed to the malignant progression of transformed cells and the chemical responses to chemotherapy reagents. Osteopontin (OPN) is a secretory onco-protein with several splicing isoforms, all of which were known to regulate tumor growth and able to alter cell-cell or cell-TME communication, however, the exact role and regulation of the OPN splicing isoforms was not well understood. In this study, the effects of conditioned medium from the culture of OPN splicing isoforms overexpressing cells on cell functions were evaluated. The methods of nuclear calcium reporter assays and subcellular distribution of nuclear factor of activated T cells c2 (NFATc2) assays were used to investigate the molecular mechanism underlining the roles of OPN splicing isoforms. We found that the survival of NSCLC cells treated with cisplatin was increased by secretory OPNc in the condition medium, where reduction of apoptosis by OPNc was associated with the activation of cellular calcium signals and subsequent nuclear translocation of NFATc2. The results revealed a mechanism of OPN and downstream signal for tumor cells to survive in chemo-stressed TME, which emphasized the importance of secretory proteins in alternative splicing isoforms. Our study not only demonstrated the importance of OPN neutralization for anti-tumor effects, but also implied that modulation in calcium/NFATc2/ROS axis could be a novel approach for improving the long-term outcome of NSCLC treatment. The online version contains supplementary material available at 10.1186/s12885-021-08495-z.
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