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Aberrant expression of RSK1 characterizes high-grade gliomas with immune infiltration

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Hajj, Glaucia N. M. [1, 2] ; da Silva, Fernanda F. [1] ; de Bellis, Barbara [1] ; Lupinacci, Fernanda C. S. [1] ; Bellato, Hermano M. [1] ; Cruz, Juvanier R. [3] ; Segundo, Claudionor N. C. [4] ; Faquini, V, Igor ; Torres, Leuridan C. [3, 5] ; Sanematsu, I, Paulo ; Begnami, Maria D. [6] ; Martins, Vilma R. [1, 2] ; Roffe, Martin [1, 2]
Número total de Autores: 13
Afiliação do(s) autor(es):
[1] AC Camargo Canc Ctr, Int Res Ctr, Rua Tagua 440, Sao Paulo, SP - Brazil
[2] Natl Inst Sci & Technol Oncogen, Sao Paulo, SP - Brazil
[3] Hosp Canc Pernambuco, Dept Clin Oncol, Recife, PE - Brazil
[4] V, Hosp Restauracao, Dept Neurosurg, Recife, PE - Brazil
[5] Faquini, Igor, V, Inst Med Integral Prof Fernando Figueira, Translat Res Lab Prof CA Hart, Recife, PE - Brazil
[6] AC Camargo Canc Ctr, Dept Pathol, Sao Paulo, SP - Brazil
Número total de Afiliações: 6
Tipo de documento: Artigo Científico
Fonte: MOLECULAR ONCOLOGY; v. 14, n. 1, p. 159-179, JAN 2020.
Citações Web of Science: 0

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. (AU)

Processo FAPESP: 15/15451-3 - Estudo da Regulação e Função da família das RSKs em Glioblastomas
Beneficiário:Martín Roffé
Modalidade de apoio: Auxílio à Pesquisa - Regular
Processo FAPESP: 18/17796-6 - Controle traducional no câncer - Parte II
Beneficiário:Glaucia Noeli Maroso Hajj
Modalidade de apoio: Auxílio à Pesquisa - Regular