Open AccessAberrant expression of RSK1 characterizes high‐grade gliomas with immune infiltration
Author(s) -
M. Hajj Glaucia N.,
Silva Fernanda F.,
Bellis Bárbara,
Lupinacci Fernanda C. S.,
Bellato Hermano M.,
Cruz Juvanier R.,
Segundo Claudionor N. C.,
Faquini Igor V.,
Torres Leuridan C.,
Sanematsu Paulo I.,
Begnami Maria D.,
Martins Vilma R.,
Roffé Martín
Publication year - 2020
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12595
Subject(s) - biology , ribosomal s6 kinase , transmembrane protein , glioma , microbiology and biotechnology , gene isoform , immune system , kinase , cancer research , phosphorylation , p70 s6 kinase 1 , gene , protein kinase b , immunology , genetics , receptor
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 (RSK1 hi ). No difference was observed in RSK2 median‐expression levels among NB and gliomas; however, high levels of RSK2 in GBM (RSK2 hi ) 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. RSK1 hi and, to a lesser extent, RSK2 hi GBMs showed higher levels of phosphorylated RSK, which reveals RSK activation. Transcriptome analysis indicated that most RSK1 hi 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 RSK1 hi 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.