RESUMEN
Toll-like receptors (TLRs) are the first to identify disturbances in the immune system, recognizing pathogens such as bacteria, fungi, and viruses. Since the inflammation process plays an important role in several diseases, TLRs have been considered potential therapeutic targets, including treatment for cancer. However, TLRs' role in cancer remains ambiguous. This study aims to analyze the expression levels of plasmatic cell membrane TLRs (TLR1, TLR2, TLR4, TLR5, and TLR6) in human astrocytomas the most prevalent tumors of CNS different grades (II-IV). We demonstrated that TLR expressions were higher in astrocytoma samples compared to non-neoplastic brain tissue. The gene and protein expressions were observed in GBM cell lines U87MG and A172, proving their presence in the tumor cells. Associated expressions between the known heterodimers TLR1-TLR2 were found in all astrocytoma grades. In GBMs, the mesenchymal subtype showed higher levels of TLR expressions in relation to classical and proneural subtypes. A strong association of TLRs with the activation of cell cycle process and signaling through canonical, inflammasome and ripoptosome pathways was observed by in silico analysis, further highlighting TLRs as interesting targets for cancer treatment.
Asunto(s)
Astrocitoma/metabolismo , Neoplasias Encefálicas/metabolismo , Membrana Celular/metabolismo , Receptores Toll-Like/metabolismo , Encéfalo/metabolismo , Línea Celular Tumoral , Técnica del Anticuerpo Fluorescente , Humanos , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor Toll-Like 1/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 5/metabolismo , Receptor Toll-Like 6/metabolismoRESUMEN
The CXCR7, a new receptor for CXCL12 with higher affinity than CXCR4 has raised key issues on glioma cell migration. The aim of this study is to investigate the CXCR7 mRNA expression in diffuse astrocytomas tissues and to evaluate its interactions with CXCR4 and HIF1α expression and IDH1 mutation. CXCR7, CXCR4 and HIF1α mRNA expression were evaluated in 129 frozen samples of astrocytomas. IDH1 mutation status was analyzed with gene expressions, matched with clinicopathological parameters and overall survival time. Protein expression was analyzed by immunohistochemistry in different grades of astrocytoma and in glioma cell line (U87MG) by confocal microscopy. There was significant difference in the expression levels of the genes studied between astrocytomas and non-neoplasic (NN) controls (p < 0.001). AGII showed no significant correlation between CXCR7/HIF1α (p = 0.548); there was significant correlation between CXCR7/CXCR4 (p = 0.042) and CXCR7/IDH1 (p = 0.008). GBM showed significant correlations between CXCR7/CXCR4 (p = 0.002), CXCR7/IDH1 (p < 0.001) and CXCR7/HIF1α (p = 0.008). HIF1α overexpression was associated with higher expressions of CXCR7 (p = 0.01) and CXCR4 (p < 0.0001), while IDH1 mutation was associated with lower CXCR7 (p = 0.009) and CXCR4 (p = 0.0005) mRNA expressions. Protein expression increased with malignancy and in U87MG cell line was mainly localized in the cellular membrane. CXCR7 was overexpressed in astrocytoma and correlates with CXCR4 and IDH1 in AGII and CXCR4, IDH1 and HIF1α in GBM. Overexpression HIF1α was related with higher expressions of CXCR7 and CXCR4, otherwise IDH1 mutation related with lower expression of both genes. No association between CXCR7 and CXCR4 expression and survival data was related.