Segovia Cristina, Martínez-Fernández Mónica, Dueñas Marta, Rubio Carolina, López-Calderón Fernando F, Costa Clotilde, Saiz-Ladera Cristina, Fernández-Grajera María, Duarte José, Muñoz Huberto García, de la Rosa Federico, Villacampa Felipe, Castellano Daniel, Paramio Jesús M
Unidad de Oncología Molecular, CIEMAT (ed70A), Madrid, Spain.
Grupo de Oncología celular y Molecular, Hospital Universitario 12 de Octubre, Madrid, Spain.
Oncotarget. 2017 Feb 7;8(6):10531-10542. doi: 10.18632/oncotarget.14453.
The high rates of tumor recurrence and progression represent a major clinical problem in non-muscle invasive bladder cancer. Previous data showed that EZH2-dependent signaling mediates these processes, whereas the frequent alterations of PIK3CA gene (copy gains and mutations) are predictive of reduced recurrence. Here we show, using clinical samples and bladder cancer cell lines, a functional interaction between EZH2- and PIK3CA-dependent signaling pathways. PIK3CA alterations mediated, on the one hand, the increased expression of two miRNAs, miR-101 and miR-138, which posttranscriptionally downregulate EZH2 expression. On the other hand, PIK3CA alterations facilitate the activation of Akt which phosphorylates EZH2 on Ser21, precluding the trimethylation of histone H3 in K27. Remarkably the increased expression of miR101 or miR138 and the expression of Ser21-phosphorylated EZH2 are good prognostic factors regarding non-muscle invasive bladder cancer recurrence and progression. Collectively, this study provides molecular evidences indicating that the gene expression rewiring occurring in primary bladder tumors, associated with increased EZH2 expression and activity and mediating the increased recurrence and progression risk, are prevented by PIK3CA-dependent signaling. This molecular process may have deep implications in the management of bladder cancer patients and in the design of novel molecularly targeted therapeutic approaches.
肿瘤复发和进展的高发生率是非肌肉浸润性膀胱癌的一个主要临床问题。先前的数据表明，EZH2依赖性信号传导介导了这些过程，而PIK3CA基因的频繁改变（拷贝数增加和突变）可预测复发率降低。在此，我们使用临床样本和膀胱癌细胞系表明，EZH2依赖性和PIK3CA依赖性信号通路之间存在功能相互作用。一方面，PIK3CA改变介导了两种miRNA，即miR-101和miR-138的表达增加，它们在转录后下调EZH2表达。另一方面，PIK3CA改变促进了Akt的激活，Akt使EZH2的Ser21位点磷酸化，从而阻止组蛋白H3在K27位点的三甲基化。值得注意的是，miR101或miR138的表达增加以及Ser21磷酸化的EZH2的表达是非肌肉浸润性膀胱癌复发和进展的良好预后因素。总的来说，这项研究提供了分子证据，表明原发性膀胱肿瘤中发生的基因表达重排，与EZH2表达和活性增加相关并介导复发和进展风险增加，可被PIK3CA依赖性信号传导阻止。这一分子过程可能对膀胱癌患者的管理以及新型分子靶向治疗方法的设计具有深远意义。
