Piovan Erich, Tosello Valeria, Indraccolo Stefano, Masiero Massimo, Persano Luca, Esposito Giovanni, Zamarchi Rita, Ponzoni Maurilio, Chieco-Bianchi Luigi, Dalla-Favera Riccardo, Amadori Alberto
Oncology Section, Department of Oncology and Surgical Sciences, University of Padova, Italy.
Cancer Res. 2007 Sep 15;67(18):8605-14. doi: 10.1158/0008-5472.CAN-06-4722.
The chemokine receptor CXCR4 plays a central role in organ-specific homing and tumor spreading and is induced by hypoxia. B lymphocytes are exposed to low oxygen tensions during their development, but the influence of hypoxia on their physiology is poorly understood. Here, we show that hypoxia is associated with up-regulation of CXCR4 expression in human normal and malignant B cells, through both transcriptional and posttranslational mechanisms. However, a dichotomic functional response to CXCR4 triggering was observed: both peripheral B cells and lymphomas arising from mature B cells displayed increased responses to CXCR4 triggering under hypoxia, whereas germinal center (GC) B cells as well as GC-derived lymphomas showed CXCR4 receptor desensitization. This phenomenon was associated with differential modulation of key signal-transducing molecules, including mitogen-activated protein kinase phosphatase-1 and regulator of G protein signaling molecule-1. The unresponsiveness of GC-derived lymphomatous B cells to CXCR4 triggering under hypoxia may have implications for the development and pathogenesis of GC-derived lymphoid tumors.
趋化因子受体CXCR4在器官特异性归巢和肿瘤扩散中起核心作用，且由缺氧诱导产生。B淋巴细胞在其发育过程中暴露于低氧张力下，但其生理功能受缺氧的影响却鲜为人知。在此，我们表明，缺氧通过转录和翻译后机制，与人正常和恶性B细胞中CXCR4表达上调相关。然而，观察到对CXCR4触发的二分功能反应：外周B细胞和源自成熟B细胞的淋巴瘤在缺氧条件下对CXCR4触发的反应均增加，而生发中心（GC）B细胞以及源自GC的淋巴瘤则表现出CXCR4受体脱敏。这种现象与关键信号转导分子的差异调节有关，包括丝裂原活化蛋白激酶磷酸酶-1和G蛋白信号调节分子-1。缺氧条件下源自GC的淋巴瘤B细胞对CXCR4触发无反应，这可能对源自GC的淋巴瘤的发生和发病机制有影响。
