RBM22在前列腺癌中的抑瘤作用,作为双因子调节关键致癌基因的选择性剪接和转录。

J. Jiménez-Vacas, Antonio J Montero-Hidalgo, E. Gómez-Gómez, P. Sáez-Martínez, A. C. Fuentes-Fayos, A. Closa, T. González-Serrano, Ana Martínez-López, R. Sánchez-Sánchez, P. López-Casas, André Sarmento-Cabral, D. Olmos, E. Eyras, Justo P. Castaño, M. Gahete, R. Luque
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引用次数: 0

摘要

前列腺癌(PCa)是男性癌症相关死亡的主要原因之一。因此,迫切需要鉴定新的治疗分子靶点来改善患者的预后。我们的研究小组最近报道了控制选择性剪接的细胞机制的一些元素可能作为治疗晚期前列腺癌的潜在新工具。然而,作为关键剪接体成分的RBM22在PCa中的存在及其功能作用尚不清楚。因此,RBM22水平首先在三个人类队列和两个临床前小鼠模型(TRAMP/Pbsn-Myc)中进行了研究。结果通过另外两个队列进行了计算机验证。然后,在体外(LNCaP、22Rv1和PC-3细胞系)和体内(异种移植)的PCa模型中测试RBM22过表达对功能的影响(增殖、迁移、肿瘤球/菌落形成)。在RBM22过表达细胞和异种移植肿瘤中进行了高通量方法(即RNA-seq, nCounter PanCancer Pathways Panel)。我们发现,在PCa样本中,RBM22水平(mRNA和蛋白)下调,并且与关键的临床侵袭性特征呈负相关。与此一致,在转基因模型(TRAMP/Pbsn-Myc)中观察到RBM22从非肿瘤到低分化PCa样本逐渐减少。值得注意的是,RBM22过表达降低了体外和体内的侵袭性特征。这些作用与许多基因的剪接失调和细胞周期上游关键调控因子(即CDK1/CCND1/EPAS1)的下调有关。总之,我们的数据表明,RBM22在PCa中起着关键的病理生理作用,并提示靶向RBM22表达/活性的负调节因子可能代表一种新的治疗策略来治疗这种疾病。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Tumor suppressor role of RBM22 in prostate cancer acting as a dual-factor regulating alternative splicing and transcription of key oncogenic genes.
Prostate cancer (PCa) is one the leading causes of cancer-related deaths among men. Consequently, the identification of novel molecular targets for treatment is urgently needed to improve patients' outcomes. Our group recently reported that some elements of the cellular machinery controlling alternative-splicing might be useful as potential novel therapeutic tools against advanced PCa. However, the presence and functional role of RBM22, a key spliceosome component, in PCa remains unknown. Therefore, RBM22 levels were firstly interrogated in three human cohorts and two preclinical mouse models (TRAMP/Pbsn-Myc). Results were validated in in silico using two additional cohorts. Then, functional effects in response to RBM22 overexpression (proliferation, migration, tumorspheres/colonies formation) were tested in PCa models in vitro (LNCaP, 22Rv1, and PC-3 cell-lines) and in vivo (xenograft). High throughput methods (i.e., RNA-seq, nCounter PanCancer Pathways Panel) were performed in RBM22 overexpressing cells and xenograft tumors. We found that RBM22 levels were down-regulated (mRNA and protein) in PCa samples, and were inversely associated with key clinical aggressiveness features. Consistently, a gradual reduction of RBM22 from non-tumor to poorly differentiated PCa samples was observed in transgenic models (TRAMP/Pbsn-Myc). Notably, RBM22 overexpression decreased aggressiveness features in vitro, and in vivo. These actions were associated with the splicing dysregulation of numerous genes and to the downregulation of critical upstream regulators of cell-cycle (i.e., CDK1/CCND1/EPAS1). Altogether, our data demonstrate that RBM22 plays a critical pathophysiological role in PCa and invites to suggest that targeting negative regulators of RBM22 expression/activity could represent a novel therapeutic strategy to tackle this disease.
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