Abstract A77: Higher expression of lysyl oxidase family in GBM mesenchymal subtype and the clinical impact of LOXL3
Authors: Roseli Silva Soares, Talita Sousa Laurentino, Suely Kazue Nagahashi Marie, Sueli Mieko Oba-Shinjo
Journal: Clinical Cancer Research (2018)

Abstract Lysyl oxidade (LOX) is involved in cell motility, cell signaling, and gene regulation. We have previously described LOX increased expression and activity in diffusely infiltrative astrocytomas (da Silva et al., 2015), corroborating the role of LOX in migration, invasion, and angiogenesis of astrocytomas. Other members of lysyl oxidase family (LOXL1, LOXL2, LOXL3, and LOXL4) present similar structure and functions and, therefore, possible similar roles of LOX. For that reason, the purpose of our study was to characterize the expression levels of genes and proteins of lysyl oxidase family members in astrocytomas of different malignant grades. Additionally, gene expression levels were correlated with glioblastoma (GBM) molecular subtypes and the clinical endpoint of overall survival of GBM patients. Gene expression analysis were performed by quantitative real-time PCR in a series of 130 diffusely infiltrative astrocytomas and 22 samples of non-neoplastic brain. Gene expression data of our GBM cohort were analyzed according to molecular subtypes (classic, mesenchymal, and proneural) and were validated in TCGA cohorts (157 cases). Protein expressions coded by these genes were also analyzed by immunohistochemistry. Expression levels of all genes (LOXL1, LOXL2, LOXL3, and LOXL4) increased with the malignant grade of astrocytomas, GBM presenting the higher levels. LOXL1 and LOXL2 presented a higher expression in mesenchymal molecular GBM subtype, but with the statistical difference only for LOXL1 (p=0.0007, Kruskal-Wallis test) in our cohort. However, higher expression levels in mesenchymal subtype for all four genes (p=0.0003 for LOXL1, p&amp;lt;0.0001 for LOXL2 and LOXL3, and p=0.028 for LOXL4) were confirmed in the TCGA data. Positive correlations of expression levels among these four genes were observed in GBMs of mesenchymal subtype. When the expression levels were analyzed in relation to GBM patient outcome, only LOXL3 expression impacted in the overall survival. Patients with low expression presented longer survival time than those with higher LOXL3 expression. Protein expression levels of lysyl oxidase-like family members were also higher in glioblastoma samples, with both nuclear and cytoplasmic localization and endothelium staining. Altogether, higher expression of LOXL1-4 in GBM mesenchymal subtype and clinical impact of LOXL3 expression in GBMs overall survival indicate important roles of lysyl oxidase-like family in astrocytoma tumorigenesis. This work provides new insights for researchers aiming to design targeted therapies to control astrocytomas, especially GBM, which still presents poor prognosis nowadays, encouraging the search for new possible target therapies. Citation Format: Roseli Silva Soares, Talita Sousa Laurentino, Suely Kazue Nagahashi Marie, Sueli Mieko Oba-Shinjo. Higher expression of lysyl oxidase family in GBM mesenchymal subtype and the clinical impact of LOXL3 [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A77.