Rowther Farjana B, Wei Weinbin, Dawson Timothy P, Ashton Katherine, Singh Anushree, Madiesse-Timchou Mylene P, Thomas D G T, Darling John L, Warr Tracy
Brain Tumour Research Centre, University of Wolverhampton, Wolverhampton, UK.
School of Cancer Sciences, University of Birmingham, Birmingham, UK.
Mol Carcinog. 2016 Mar;55(3):268-79. doi: 10.1002/mc.22276. Epub 2015 Jan 25.
Cyclic nucleotides (cAMP & cGMP) are critical intracellular second messengers involved in the transduction of a diverse array of stimuli and their catabolism is mediated by phosphodiesterases (PDEs). We previously detected focal genomic amplification of PDE1C in >90 glioblastoma multiforme (GBM) cells suggesting a potential as a novel therapeutic target in these cells. In this report, we show that genomic gain of PDE1C was associated with increased expression in low passage GBM-derived cell cultures. We demonstrate that PDE1C is essential in driving cell proliferation, migration and invasion in GBM cultures since silencing of this gene significantly mitigates these functions. We also define the mechanistic basis of this functional effect through whole genome expression analysis by identifying down-stream gene effectors of PDE1C which are involved in cell cycle and cell adhesion regulation. In addition, we also demonstrate that Vinpocetine, a general PDE1 inhibitor, can also attenuate proliferation with no effect on invasion/migration. Up-regulation of at least one of this gene set (IL8, CXCL2, FOSB, NFE2L3, SUB1, SORBS2, WNT5A, and MMP1) in TCGA GBM cohorts is associated with worse outcome and PDE1C silencing down-regulated their expression, thus also indicating potential to influence patient survival. Therefore we conclude that proliferation, migration, and invasion of GBM cells could also be regulated downstream of PDE1C.
环核苷酸（cAMP和cGMP）是关键的细胞内第二信使，参与多种刺激的转导，其分解代谢由磷酸二酯酶（PDEs）介导。我们之前在超过90%的多形性胶质母细胞瘤（GBM）细胞中检测到PDE1C的局灶性基因组扩增，提示其在这些细胞中可能作为一个新的治疗靶点。在本报告中，我们表明PDE1C的基因组增加与低传代GBM来源的细胞培养物中表达增加相关。我们证明PDE1C在驱动GBM培养物中的细胞增殖、迁移和侵袭中至关重要，因为该基因的沉默显著减轻了这些功能。我们还通过全基因组表达分析确定了PDE1C的下游基因效应物，这些效应物参与细胞周期和细胞粘附调节，从而定义了这种功能效应的机制基础。此外，我们还证明长春西汀，一种通用的PDE1抑制剂，也可以减弱增殖，而对侵袭/迁移没有影响。TCGA GBM队列中该基因集（IL8、CXCL2、FOSB、NFE2L3、SUB1、SORBS2、WNT5A和MMP1）中至少一种的上调与更差的预后相关，PDE1C沉默下调了它们的表达，因此也表明其对患者生存有潜在影响。因此我们得出结论，GBM细胞的增殖、迁移和侵袭也可能在PDE1C的下游受到调节。
