Abstract
The critical role of the Hippo pathway has been recently investigated in various cancers, but little is known about its role in glioblastoma (GBM). In order to evaluate the clinical relevance of the Hippo pathway in GBM, we generated a core gene expression signature from four different previously-established silence of Hippo pathway (SOH) signatures. Based on a newly generated core SOH signature, a SOH and active Hippo pathway (AH) was predicted in GBM samples from The Cancer Genome Atlas (TCGA) and validated in a separate cohort. A comparative analysis was performed on multi-panel genomic datasets from TCGA and the possible association of SOH with immune activity and epithelial mesenchymal transition was also evaluated. The SOH signature was associated with poor prognosis in GBM in both cohorts. Expression levels of CTGF and CYR61, the most reliable and well-known downstream targets of YAP1, were markedly increased in the SOH subgroup of GBM patients. SOH signature was strongly associated with a high immune signature score and mesenchymal features. Genes differentially expressed between SOH and AH groups revealed many markers for inhibitory immune checkpoints and M2-polarized macrophages were upregulated in the SOH subgroup, suggesting that SOH may induce the resistance of cancer cells to host immune response in GBM. In summary, SOH is significantly associated with the poor prognosis of GBM patients and is possibly mediated by pro-tumoral immunosuppression.
Highlights
Glioblastoma (GBM) is the most deadly cancer that develops in the central nervous system.Since 2005, concomitant and maintenance treatment with temozolomide and radiotherapy has been the standard treatment for patients with newly diagnosed GBM [1]
The vast majority of genes in the core silence of Hippo (SOH) signature were upregulated in the SOH subgroups across the four cancer types, suggesting that many of these genes might be direct targets of YAP1/TAZ, which are best known as transcription activators
Once we had a core SOH signature that accurately reflected the inactivation of the Hippo pathway regardless of cancer type or organ site, we applied the signature to gene expression data from GBM
Summary
Glioblastoma (GBM) is the most deadly cancer that develops in the central nervous system. Since 2005, concomitant and maintenance treatment with temozolomide and radiotherapy has been the standard treatment for patients with newly diagnosed GBM [1]. The Hippo pathway is known to play a critical role in the regulation of tissue homeostasis, organ size control, and stem cell renewal [3,4]. An increasing number of reports have suggested that the Hippo pathway contributes to cancer development and progression [3,5]. The kinase complex, including STK3/4 (), SAV1, and LATS1/2, is the core functional component of the pathway, inhibiting the oncogenic transcription activators YAP1 and TAZ ( known as WWTR1) through phosphorylation
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