Yes-Associated Protein 1 Is Widely Expressed in Human Brain Tumors and Promotes Glioblastoma Growth

Abstract

The hippo pathway and its downstream mediator yes-associated protein 1 (YAP1) regulate mammalian organ size in part through modulating progenitor cell numbers. YAP1 has also been implicated as an oncogene in multiple human cancers. Currently, little is known about the expression of YAP1 either in normal human brain tissue or in central nervous system neoplasms. We used immunohistochemistry to evaluate nuclear YAP1 expression in the fetal and normal adult human brains and in 264 brain tumors. YAP1 was expressed in fetal and adult brain regions known to harbor neural progenitor cells but there was little YAP1 immunoreactivity in the adult cerebral cortex. YAP1 protein was also readily detected in the nuclei of human brain tumors. In medulloblastoma, expression varied between histologic subtypes and was most prominent in nodular/desmoplastic tumors. In gliomas it was frequently expressed in infiltrating astrocytomas and oligodendrogliomas, but rarely in pilocytic astrocytomas. Using a loss of function approach we show that YAP1 promoted growth of glioblastoma cell lines in vitro. High levels of YAP1 mRNA expression were associated with aggressive molecular subsets of glioblastoma and with a non-significant trend toward reduced mean survival in human astrocytoma patients. These findings suggest that YAP1 may play an important role in normal human brain development and that it could represent a new target in human brain tumors.

SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status

“…48 Matrix metalloproteases (MMPs 7 and 20) have a central role in cell proliferation, migration, differentiation, angiogenesis, apoptosis and host defences and YAP1 is the critical downstream regulatory target in the Hippo signaling pathway, having a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. 49,50 By contrast, the genes contained in the 13q32.1 HZD have not been yet associated with a role in cancer disease. The HZD located at 8p11.23-p11.22 and found in two MGUS patients is also of particular interest, as it contains only the ADAM3A gene, in which HZD has recently been reported in pediatric high-grade glioma and diffuse intrinsic pontine gliomas.…”

PTPN14 is required for the density-dependent control of YAP1

“…Overexpression of YAP1 leads to loss of contact inhibition and increases the organ size (Huang et al 2005;Camargo et al 2007). Dysregulation of YAP1 has been identified in various types of cancer (Yuan et al 2008;Liu et al 2010;Wu et al 2010;Orr et al 2011;Zhang et al 2011;Diep et al 2012). Because of its crucial function in tissue growth and tumor development, YAP1 and its regulation have been studied extensively.…”

Expression and Yes-Associated Protein in Gastric Adenocarcinoma and Inhibitory Effects of its Knockdown on Gastric Cancer Cell Proliferation and Metastasis

“…YAP is also widely expressed in human brain tumors and esophageal squamous cell carcinoma, and promotes tumor growth. It is indicated that YAP is a putative oncogene and represents a potential diagnostic and therapeutic target (10,11).…”