Agarwal Saurabh, Ghosh Rajib, Chen Zaowen, Lakoma Anna, Gunaratne Preethi H, Kim Eugene S, Shohet Jason M
Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer Center, and Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030, USA.
Department of Biology & Biochemistry, University of Houston, Houston, Texas 77204, USA.
Oncotarget. 2016 Apr 26;7(17):24018-26. doi: 10.18632/oncotarget.8116.
Neuroblastoma (NB) is the most common extracranial pediatric solid tumor with high mortality rates. The tyrosine kinase c-Src has been known to play an important role in differentiation of NB cells, but the mechanism of c-Src regulation has not been defined. Here, we characterize PAG1 (Cbp, Csk binding protein), a central inhibitor of c-Src and other Src family kinases, as a novel tumor suppressor in NB. Clinical cohort analysis demonstrate that low expression of PAG1 is a significant prognostic factor for high stage disease, increased relapse, and worse overall survival for children with NB. PAG1 knockdown in NB cells promotes proliferation and anchorage-independent colony formation with increased activation of AKT and ERK downstream of c-Src, while PAG1 overexpression significantly rescues these effects. In vivo, PAG1 overexpression significantly inhibits NB tumorigenicity in an orthotopic xenograft model. Our results establish PAG1 as a potent tumor suppressor in NB by inhibiting c-Src and downstream effector pathways. Thus, reactivation of PAG1 and inhibition of c-Src kinase activity represents an important novel therapeutic approach for high-risk NB.
神经母细胞瘤（NB）是最常见的儿童颅外实体瘤，死亡率很高。已知酪氨酸激酶c-Src在NB细胞分化中起重要作用，但c-Src调控机制尚未明确。在此，我们将PAG1（Cbp，Csk结合蛋白），一种c-Src和其他Src家族激酶的核心抑制剂，鉴定为NB中的一种新型肿瘤抑制因子。临床队列分析表明，PAG1低表达是NB患儿疾病分期高、复发增加及总生存期较差的一个重要预后因素。NB细胞中PAG1敲低促进增殖和不依赖贴壁的集落形成，同时c-Src下游的AKT和ERK激活增加，而PAG1过表达显著逆转这些效应。在体内，PAG1过表达在原位异种移植模型中显著抑制NB致瘤性。我们的结果通过抑制c-Src及其下游效应通路将PAG1确立为NB中一种有效的肿瘤抑制因子。因此，重新激活PAG1并抑制c-Src激酶活性代表了一种针对高危NB的重要新型治疗方法。
