Landré Vivien, Antonov Alexey, Knight Richard, Melino Gerry
Medical Research Council Toxicology Unit, Leicester LE1 9HN, UK.
University of Rome Tor Vergata, Rome 00133, Italy.
Oncotarget. 2016 Mar 15;7(11):11785-802. doi: 10.18632/oncotarget.7600.
Glioblastoma Multiforme is one of the most highly metastatic cancers and constitutes 70% of all gliomas. Despite aggressive treatments these tumours have an exceptionally bad prognosis, mainly due to therapy resistance and tumour recurrence. Here we show that the transcription factor p73 confers an invasive phenotype by directly activating expression of POSTN (periostin, HGNC:16953) in glioblastoma cells. Knock down of endogenous p73 reduces invasiveness and chemo-resistance, and promotes differentiation in vitro. Using chromatin immunoprecipitation and reporter assays we demonstrate that POSTN, an integrin binding protein that has recently been shown to play a major role in metastasis, is a transcriptional target of TAp73. We further show that POSTN overexpression is sufficient to rescue the invasive phenotype of glioblastoma cells after p73 knock down. Additionally, bioinformatics analysis revealed that an intact p73/ POSTN axis, where POSTN and p73 expression is correlated, predicts bad prognosis in several cancer types. Taken together, our results support a novel role of TAp73 in controlling glioblastoma cell invasion by regulating the expression of the matricellular protein POSTN.
多形性胶质母细胞瘤是转移性最强的癌症之一，占所有胶质瘤的70%。尽管进行了积极治疗，但这些肿瘤的预后极差，主要原因是治疗耐药性和肿瘤复发。在此我们表明，转录因子p73通过直接激活胶质母细胞瘤细胞中POSTN（骨膜蛋白，HGNC:16953）的表达赋予侵袭性表型。敲低内源性p73可降低侵袭性和化疗耐药性，并促进体外分化。通过染色质免疫沉淀和报告基因分析，我们证明POSTN是一种整合素结合蛋白，最近已被证明在转移中起主要作用，它是TAp73的转录靶点。我们进一步表明，POSTN过表达足以挽救p73敲低后胶质母细胞瘤细胞的侵袭性表型。此外，生物信息学分析显示，POSTN和p73表达相关的完整p73/POSTN轴在几种癌症类型中预示着不良预后。综上所述，我们的结果支持TAp73通过调节基质细胞蛋白POSTN的表达在控制胶质母细胞瘤细胞侵袭中发挥新作用。
