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Functional role of LOXL3 in glioblastoma

Grant number: 21/01207-4
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2021
Effective date (End): January 31, 2024
Field of knowledge:Health Sciences - Medicine
Principal researcher:Sueli Mieko Oba Shinjo
Grantee:Talita de Sousa Laurentino
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Astrocytomas are tumors originated from astrocytic cells of the central nervous system and are the most frequent tumors among gliomas (tumors originating from glial cells). Initially, the World Health Organization classified astrocytomas according to malignancy, based on histological characteristics (grade I to IV astrocytomas), although molecular characteristics were later incorporated into the classification. Glioblastoma (GBM), grade IV, is the most common glioma and has the worst prognosis. Among the overerexpressed genes in GBM, our laboratory verified the members of the LOX family, responsible for catalyzing the collagen and elastin cross-links. In addition, Kaplan Meier curve analysis showed that the high expression of LOXL3 impacted negatively on overall survival of patients. For this reason, during the master's thesis project, Transient gene silencing of LOXL3 with siRNA in GBM U87MG cell line was performed to better understand the function of this gene. LOXL3 colocalized with mitochondria and LOLX3 silencing changed the mitochondrial cellular distribution, which changed from a more perinuclear location to one closer to regions of cell adhesion points. Furthermore, RNAseq analysis showed that U87MG cells with LOXL3 silencing demonstrated an increase of in the expression of genes encoding proteins of the extracellular matrix and cell adhesion, and a decrease in the expression of related genes in the processes of endocytosis and lysosome formation, and MAPK-binding proteins related to focal adhesion. Functional assays showed that cells silenced for LOXL3 presented decrease cell viability and increased cell adhesion and cell death by apoptosis. The expression of LOXL3 is positively regulated in several types of tumor, and its different functions have already been associated with cell migration and metastasis, maintenance of genomic stability and promotion of proliferation in melanoma, and invasion and survival of patients with gastric cancer. However, no study has described the role of LOXL3 in astrocytomas and its involvement with mitochondria and vesicle traffic processes. Therefore, this study aims to study the involvement of LOXL3 with mitochondrial, migration / adhesion processes, and with vesicle traffic in a cell model with LOXL3 silencing by CRISPR / Cas 9, which will allow different approaches, including in vivo models, for a better understanding of the functional role of LOXL3 in GBM. (AU)

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