Department of Clinical Oncology, The University of Hong Kong, Pokfulam, Hong Kong, China.
PLoS One. 2012;7(9):e44636. doi: 10.1371/journal.pone.0044636. Epub 2012 Sep 5.
Deletion of the short arm of chromosome 3 is one of the most frequent genetic alterations in many solid tumors including nasopharyngeal carcinoma (NPC), suggesting the existence of one or more tumor suppressor genes (TSGs) within the frequently deleted region. A putative TSG RBMS3 (RNA binding motif, single stranded interacting protein 3), located at 3p24-p23, has been identified in our previous study. Here, we reported that downregulation of RBMS3 was detected in 3/3 NPC cell lines and 13/15 (86.7%) primary NPC tissues. Functional studies using both overexpression and suppression systems demonstrated that RBMS3 has a strong tumor suppressive role in NPC. The tumor suppressive mechanism of RBMS3 was associated with its role in cell cycle arrest at the G1/S checkpoint by upregulating p53 and p21, downregulating cyclin E and CDK2, and the subsequent inhibition of Rb-ser780. Further analysis demonstrated that RBMS3 had a pro-apoptotic role in a mitochondrial-dependent manner via activation of caspase-9 and PARP. Finally, RBMS3 inhibited microvessel formation, which may be mediated by down-regulation of MMP2 and β-catenin and inactivation of its downstream targets, including cyclin-D1, c-Myc, MMP7, and MMP9. Taken together, our findings define a function for RBMS3 as an important tumor suppressor gene in NPC.
染色体 3 短臂缺失是许多实体瘤（包括鼻咽癌，NPC）中最常见的遗传改变之一，提示在频繁缺失的区域内存在一个或多个肿瘤抑制基因（TSG）。我们之前的研究在 3p24-p23 位置鉴定了一个假定的 TSG RBMS3（RNA 结合基序，单链相互作用蛋白 3）。在这里，我们报道在 3/3 NPC 细胞系和 13/15（86.7%）原发性 NPC 组织中检测到 RBMS3 的下调。使用过表达和抑制系统的功能研究表明，RBMS3 在 NPC 中具有很强的肿瘤抑制作用。RBMS3 的肿瘤抑制机制与其通过上调 p53 和 p21、下调细胞周期蛋白 E 和 CDK2 以及随后抑制 Rb-ser780 在 G1/S 检查点使细胞周期停滞的作用有关。进一步的分析表明，RBMS3 通过激活 caspase-9 和 PARP 以依赖于线粒体的方式发挥促凋亡作用。最后，RBMS3 抑制微血管形成，这可能是通过下调 MMP2 和 β-catenin 以及失活其下游靶点，包括 cyclin-D1、c-Myc、MMP7 和 MMP9 来介导的。总之，我们的研究结果定义了 RBMS3 在 NPC 中作为一个重要的肿瘤抑制基因的功能。
