PPP2CA基因突变致智力障碍伴癫痫1例并文献复习

蛋白磷酸酶2A(protein phosphatases of the type2A,PP2A)是非常重要的蛋白磷酸酶,几乎存在于所有真核细胞中,该酶由3种亚基组成异三聚体结构,包括一个65 k U的结构亚基A(α/β),一个36 k U的催化亚基C(α/β)形成的核心酶和一个多样化的调节亚基B[1]。亚基的多样性决定了该酶具有多种催化作用,结合的调节亚基不同,去磷酸化底物就不同,其参与多种细胞信号通路,能调节细胞周期、细胞分化、肿瘤抑制等多种生物学过程[2-3]。

Potential Role and Clinical Value of PPP2CA in Hepatocellular Carcinoma

Background and Aims:Protein phosphatase 2A(PP2A)is associated with many cancers.This study aimed to clarify whether PPP2CA,which encodes the alpha isoform of the catalytic subunit of PP2A,plays a role in hepatocellular carcinoma(HCC)and to identify the potential underlying molecular pathways.Methods:Based on bioinformatics,public databases and our in-house RNA-Seq database,we analyzed the clinical value and molecular mechanism of PPP2CA in HCC.Results:Data were analyzed from 2,545 patients with HCC and 1,993 controls without HCC indexed in The Cancer Genome Atlas database,the Gene Expression Omnibus database and our in-house RNA-Seq database.PPP2CA expression was significantly higher in HCC tissue than in non-cancerous tissues(standardized mean difference:0.69,95%confidence interval[CI]:0.50–0.89).PPP2CA expression was able to differentiate HCC from non-HCC,with an area under the summary receiver operator characteristic curve of 0.79(95%CI:0.75–0.83).Immunohistochemistry of tissue sections confirmed that PPP2CA protein was up-regulated in HCC tissues.High PPP2CA expression in HCC patients was associated with shorter overall,progression-free and disease-free survival.Potential molecular pathways through which PPP2CA may be involved in HCC were determined using miRWalk 2.0 as well as analysis of Gene Ontology categories,Kyoto Encyclopedia of Genes and Genomes pathways,and protein-protein interaction networks.Conclusions:PPP2CA is up-regulated in HCC and higher expression correlates with worse prognosis.PPP2CA shows potential as a diagnostic marker for HCC.Future studies should examine whether PPP2CA contributes to HCC through the candidate microRNAs,pathways and hub genes identified in this study.

抑制PP2Acα促进胃癌进展中WTAP高表达

目的:探讨蛋白磷酸酶2A催化亚基Cα(PP2Acα)的抑制是否会影响胃癌细胞的恶性表型,以及维尔姆肿瘤1相关蛋白(Wilms’tumour 1-associating protein,WTAP)在这一进展中的表达。方法:使用癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库分别比较PP2Acα编码基因(PPP2CA)、WTAP基因在胃癌组织与正常胃黏膜组织中的表达量;使用KM-plot网站(http://kmplot.com/analysis/)分析PPP2CA、WTAP与胃癌预后的关系;使用慢病毒介导的短发卡RNA(short hairpin RNA,sh RNA)在胃癌细胞中敲减PPP2CA,从而抑制PP2Acα的表达;随后提取RNA、蛋白分别进行定量逆转录PCR(quantitative reverse transcription PCR,RT-qPCR)、蛋白免疫印迹(Western blot),检测PPP2CA、WTAP的mRNA水平及蛋白的表达;最后在离体与活体层面观察抑制PP2Acα对于胃癌细胞恶性表型的影响。结果:抑制PP2Acα后,胃癌细胞发生上皮间质转化(epithelial-mesenchymal transition,EMT)形态改变,且增殖、迁移与侵袭能力均得到了增强,并伴随着WTAP蛋白及mRNA水平的显著升高。结论:抑制PP2Acɑ促进胃癌细胞的恶性表型,可能是通过上调WTAP的表达水平实现的。