Abstract
The p90 ribosomal S6 kinase (RSK) family, a downstream target of Ras/extracellular signal‐regulated kinase signaling, can mediate cross‐talk with the mammalian target of rapamycin complex 1 pathway. As RSK connects two oncogenic pathways in gliomas, we investigated the protein levels of the RSK isoforms RSK1–4 in nontumoral brain (NB) and grade I‐IV gliomas. When compared to NB or low‐grade gliomas (LGG), a group of glioblastomas (GBMs) that excluded long‐survivor cases expressed higher levels of RSK1 (RSK1hi). No difference was observed in RSK2 median‐expression levels among NB and gliomas; however, high levels of RSK2 in GBM (RSK2hi) were associated with worse survival. RSK4 expression was not detected in any brain tissues, whereas RSK3 expression was very low, with GBM demonstrating the lowest RSK3 protein levels. RSK1hi and, to a lesser extent, RSK2hi GBMs showed higher levels of phosphorylated RSK, which reveals RSK activation. Transcriptome analysis indicated that most RSK1hi GBMs belonged to the mesenchymal subtype, and RSK1 expression strongly correlated with gene expression signature of immune infiltrates, in particular of activated natural killer cells and M2 macrophages. In an independent cohort, we confirmed that RSK1hi GBMs exclude long survivors, and RSK1 expression was associated with high protein levels of the mesenchymal subtype marker lysosomal protein transmembrane 5, as well as with high expression of CD68, which indicated the presence of infiltrating immune cells. An RSK1 signature was obtained based on differentially expressed mRNAs and validated in public glioma datasets. Enrichment of RSK1 signature followed glioma progression, recapitulating RSK1 protein expression, and was associated with worse survival not only in GBM but also in LGG. In conclusion, both RSK1 and RSK2 associate with glioma malignity, but displaying isoform‐specific peculiarities. The progression‐dependent expression and association with immune infiltration suggest RSK1 as a potential progression marker and therapeutic target for gliomas.
Highlights
Gliomas are tumors of the central nervous system resulting from the malignant transformation of glial cells, their intermediate precursors, and neural stem cells (Huse and Holland, 2010; Zong et al, 2015)
This study demonstrates that RSK1, but not RSK2 or RSK3, expression and RSK1 activation increase during glioma progression
RSK2 protein expression do not increase during glioma progression, high RSK2 levels are associated with worse survival and RSK2 behaves as an independent prognostic marker when adjusted for IDH1 mutation status and treatment
Summary
Gliomas are tumors of the central nervous system resulting from the malignant transformation of glial cells, their intermediate precursors, and neural stem cells (Huse and Holland, 2010; Zong et al, 2015). Gliomas are classified into different grades (I–IV) according to their histological characteristics (Louis et al, 2016). High-grade gliomas, III and IV, are considered malignant (Lienhart et al, 2008). The incidence of malignant gliomas is 17 000 new cases per year (Omuro and DeAngelis, 2013). Astrocytomas are the most common type of gliomas. Grade IV astrocytoma, called glioblastoma (GBM, formerly called GBM multiforme), represents 82% of malignant gliomas. GBM is highly lethal, with the average patient surviving only 12–15 months. Standard treatment involves surgical resection when possible, but because of its infiltrative nature, GBMs cannot be completely removed. Almost all GBMs eventually recur and the mean disease progression time after treatment is 6.9 months (Omuro and DeAngelis, 2013)
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