De Smet Frederik, Saiz Rubio Mirian, Hompes Daphne, Naus Evelyne, De Baets Greet, Langenberg Tobias, Hipp Mark S, Houben Bert, Claes Filip, Charbonneau Sarah, Delgado Blanco Javier, Plaisance Stephane, Ramkissoon Shakti, Ramkissoon Lori, Simons Colinda, van den Brandt Piet, Weijenberg Matty, Van England Manon, Lambrechts Sandrina, Amant Frederic, D'Hoore André, Ligon Keith L, Sagaert Xavier, Schymkowitz Joost, Rousseau Frederic
The Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
VIB Center for Brain and Disease Research, Leuven, Belgium.
J Pathol. 2017 May;242(1):24-38. doi: 10.1002/path.4872. Epub 2017 Mar 23.
Although p53 protein aggregates have been observed in cancer cell lines and tumour tissue, their impact in cancer remains largely unknown. Here, we extensively screened for p53 aggregation phenotypes in tumour biopsies, and identified nuclear inclusion bodies (nIBs) of transcriptionally inactive mutant or wild-type p53 as the most frequent aggregation-like phenotype across six different cancer types. p53-positive nIBs co-stained with nuclear aggregation markers, and shared molecular hallmarks of nIBs commonly found in neurodegenerative disorders. In cell culture, tumour-associated stress was a strong inducer of p53 aggregation and nIB formation. This was most prominent for mutant p53, but could also be observed in wild-type p53 cell lines, for which nIB formation correlated with the loss of p53's transcriptional activity. Importantly, protein aggregation also fuelled the dysregulation of the proteostasis network in the tumour cell by inducing a hyperactivated, oncogenic heat-shock response, to which tumours are commonly addicted, and by overloading the proteasomal degradation system, an observation that was most pronounced for structurally destabilized mutant p53. Patients showing tumours with p53-positive nIBs suffered from a poor clinical outcome, similar to those with loss of p53 expression, and tumour biopsies showed a differential proteostatic expression profile associated with p53-positive nIBs. p53-positive nIBs therefore highlight a malignant state of the tumour that results from the interplay between (1) the functional inactivation of p53 through mutation and/or aggregation, and (2) microenvironmental stress, a combination that catalyses proteostatic dysregulation. This study highlights several unexpected clinical, biological and therapeutically unexplored parallels between cancer and neurodegeneration. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
尽管在癌细胞系和肿瘤组织中已观察到p53蛋白聚集物，但其在癌症中的影响仍 largely未知。在此，我们在肿瘤活检中广泛筛选p53聚集表型，并确定转录无活性的突变型或野生型p53的核包涵体（nIBs）是六种不同癌症类型中最常见的聚集样表型。p53阳性nIBs与核聚集标记物共染色，并具有神经退行性疾病中常见的nIBs分子特征。在细胞培养中，肿瘤相关应激是p53聚集和nIB形成的强烈诱导剂。这在突变型p53中最为显著，但在野生型p53细胞系中也可观察到，其中nIB形成与p53转录活性丧失相关。重要的是，蛋白质聚集还通过诱导高激活的致癌热休克反应（肿瘤通常依赖于此）以及使蛋白酶体降解系统过载，加剧了肿瘤细胞中蛋白质稳态网络的失调，这一现象在结构不稳定的突变型p53中最为明显。显示p53阳性nIBs肿瘤的患者临床预后较差，类似于p53表达缺失的患者，并且肿瘤活检显示与p53阳性nIBs相关的蛋白质稳态表达谱存在差异。因此，p53阳性nIBs突出了肿瘤的一种恶性状态，这种状态是由（1）通过突变和/或聚集导致的p53功能失活与（2）微环境应激之间的相互作用引起的，这种组合催化了蛋白质稳态失调。本研究突出了癌症与神经退行性变之间一些意想不到的临床、生物学和治疗上未探索的相似之处。版权所有© 2017大不列颠及爱尔兰病理学会。由John Wiley & Sons, Ltd.出版。
