雄激素受体相互作用因子在前列腺癌中的表达及其临床意义

Significance of androgen receptor and its interactors in prostate cancer

目的探讨雄激素受体(AR)及其相互作用因子在前列腺癌(PCa)中的表达、变异及其对肿瘤预后的影响。方法基于STRING数据库分析AR及其相互作用因子的相互作用和GO富集;通过UALCAN分析AR及其相互作用因子在PCa中的表达;通过cBioPortal分析AR及其相互作用因子在PCa中表达变异及其与预后的关系。结果AR及其相互作用因子相互作用网络节点为10,边数为21,平均节点度为4.2,平均局部聚类系数为0.89,其中NCOA2和EP300在AR相互作用网络中节点度最高。UALCAN分析显示RAN、TNK2、PXN和NRIP1在癌组织中上调(P<0.05);相反NCOR1在癌组织中下调(P<0.05);NCOR2、NCOA2、EP300、SOX9和RAN表达水平改变不显著。cBioPortal分析表明近30%的PCa组织中存在AR及其相互作用因子的表达变异,包括基因扩增、基因突变、深度缺失以及多重变异4个类型。AR变异率为18%,主要包括基因扩增和突变;NCOA2变异率为9%,主要变异类型为基因扩增。神经内分泌前列腺癌中的变异类型主要为基因扩增(8.7%),而去势抵抗前列腺癌主要表现为基因突变(11.43%)。AR及其相互作用因子变异的PCa总生存率显著下降,变异组(n=95)中位生存期为70个月(95%CI,60~105),而未变异组(n=45)中位生存期为141个月[95%CI,115.13~NA(无),P<0.001]。GO富集分析显示pre-mRNA内含子结合以及组蛋白脱乙酰酶复合物具有最高的富集指数。结论AR及其相互作用因子有可能作为一个有效指标被用来评估PCa进展及预后,研究其表达及变异可为揭示肿瘤进展的分子机制提供新的依据。

Objective To analyze the expressions of androgen receptor(AR)and its interactors in prostate cancer(PCa)and their effects on tumor prognosis.Methods The AR interaction network and GO enrichment were analyzed based on STRING database.The expressions of AR and its interactors in PCa were analyzed with UALCAN.The alterations of AR and its interactors in PCa and their association with prognosis were analyzed with cBioPortal.Results The number of nodes in AR-network was 10,the number of edges was 21,the average node degree was 4.2,and the average local clustering coefficient was 0.89.NCOA2 and EP300 had the highest node degree in AR-network.UALCAN analysis showed RAN,TNK2,PXN and NRIP1 were significantly up-regulated in PCa(P<0.05),while NCOR1 was significantly down-regulated(P<0.05),and NCOR2,NCOA2,EP300,SOX9 and RAN remained unchanged.cBioPortal analysis showed that alterations of AR and its interactors occurred in nearly 30%of PCa samples,including gene amplification,gene mutation,deep deletion and multiple variation.The alteration rate of AR was 18%,including gene amplification and mutation.The alteration rate of NCOA2 was 9%,and the main variation type was gene amplification.The main type of variation in neuroendocrine PCa was gene amplification(8.7%),while in castration resistant prostate cancer(CRPC),it was gene mutation(11.43%).The overall survival rate of PCa patients with alterations of AR and its interactors decreased significantly.The median survival of the altered group(n=95)was 70 months(95%CI:60~105 m),while that of non-altered group(n=45)was 141 months[95%CI:115.13~NA(not available),P<0.001].GO enrichment analysis showed that pre-mRNA intron binding and histone deacetylase complex had the highest enrichment index.Conclusion The expression and alteration of AR and its interactors might be a useful marker to evaluate the progression and prognosis of PCa,and will provide new insights for the mechanism study of tumor progression.