PPP2R1A regulated by PAX3/FOXO1 fusion contributes to the acquisition of aggressive behavior in PAX3/FOXO1-positive alveolar rhabdomyosarcoma.
PPP2R1A regulated by PAX3/FOXO1 fusion contributes to the acquisition of aggressive behavior in PAX3/FOXO1-positive alveolar rhabdomyosarcoma.
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DOI：
10.18632/oncotarget.25392
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发表时间：
2018-05-18
期刊：
影响因子：
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通讯作者：
Saito T
中科院分区：
文献类型：
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作者：
Akaike K;Suehara Y;Kohsaka S;Hayashi T;Tanabe Y;Kazuno S;Mukaihara K;Toda-Ishii M;Kurihara T;Kim Y;Okubo T;Hayashi Y;Takamochi K;Takahashi F;Kaneko K;Ladanyi M;Saito T
为了更好地表征PAX 3-FOXO 1融合蛋白在ARMS中获得攻击性行为中的致癌作用，我们采用了在ARMS细胞系中使用PAX 3-FOXO 1敲低系统的蛋白质组学方法。该方法揭示了由107个一致上调和114个一致下调的蛋白质组成的蛋白质列表，这些蛋白质预期由PAX 3-FOXO 1融合蛋白调节。此外，我们根据数据挖掘分析确定了16种上调和17种下调的关键蛋白质。我们还评估了PPP 2 R1 A在ARMS细胞中的功能。PPP 2 R1 A的表达在mRNA和蛋白质水平上都被PAX 3-FOXO 1沉默上调。PPP 2 R1 A的沉默显著增加了所有四种ARMS细胞的细胞生长，表明PPP 2 R1 A在ARMS细胞中仍然具有肿瘤抑制功能;然而，PPP 2 R1 A的天然表达在PAX 3-FOXO 1存在下较低。此外，在ARMS细胞系中，通过FTY 720处理，PP 2A（其部分由PPP 2 R1 A编码）的激活抑制细胞生长。在对39种选定蛋白质上的46个特异性Ser/Thr或Tyr磷酸化位点的人磷酸激酶阵列分析中，FTY-720处理降低了eNOS、AKT 1/2/3、RSK 1/2/3和STAT 3磷酸化。这些发现表明PPP 2 R1 A在ARMS中受PAX 3-FOXO 1负调控。PP 2A的激活-可能与激酶通道结合-可能代表ARMS的治疗靶点。我们相信PAX 3-FOXO 1相关的蛋白表达谱对于发现ARMS新的治疗靶点是有价值的。
To better characterize the oncogenic role of the PAX3-FOXO1 fusion protein in the acquisition of aggressive behavior in ARMS, we employed a proteomic approach using a PAX3-FOXO1 knockdown system in ARMS cell lines. This approach revealed a protein list consisting of 107 consistently upregulated and 114 consistently downregulated proteins that were expected to be regulated by PAX3-FOXO1 fusion protein. Furthermore, we identified 16 upregulated and 17 downregulated critical proteins based on a data-mining analysis. We also evaluated the function of PPP2R1A in ARMS cells. The PPP2R1A expression was upregulated at both the mRNA and protein levels by PAX3-FOXO1 silencing. The silencing of PPP2R1A significantly increased the cell growth of all four ARMS cells, suggesting that PPP2R1A still has a tumor suppressive function in ARMS cells; however, the native expression of PPP2R1A was low in the presence of PAX3-FOXO1. In addition, the activation of PP2A—part of which was encoded by PPP2R1A—by FTY720 treatment in ARMS cell lines inhibited cell growth. On the human phospho-kinase array analysis of 46 specific Ser/Thr or Tyr phosphorylation sites on 39 selected proteins, eNOS, AKT1/2/3, RSK1/2/3 and STAT3 phosphorylation were decreased by FTY-720 treatment. These findings suggest that PPP2R1A is a negatively regulated by PAX3-FOXO1 in ARMS. The activation of PP2A—probably in combination with kinase inhibitors—may represent a therapeutic target in ARMS. We believe that the protein expression profile associated with PAX3-FOXO1 would be valuable for discovering new therapeutic targets in ARMS.