Abstract
Lysyl oxidase (LOX) is involved in vital biological processes such as cell motility, cell signaling and gene regulation. Deregulation of this protein can contribute to tumor formation and progression. Although it is known that LOX is involved in invasion, proliferation and tumor migration in other types of tumors, studies of LOX in astrocytomas of different grades are scarce. The purpose of our study was to characterize LOX, BMP1 and HIF1A expression by real-time PCR in astrocytomas with WHO grades I to IV compared to non-neoplastic brain tissue. IDH1 mutational status was determined by PCR and sequencing. LOX protein expression was also analyzed by immunohistochemistry. LOX functional analyses were performed using siRNA knockdown and the specific inhibitor BAPN in two glioblastoma cell lines. The expression levels of LOX, BMP1 and HIF1A were correlated and analyzed according to IDH1 mutation status and to the clinical end-point of overall survival of glioblastoma patients. The results demonstrate that increased expression and activity of LOX, BMP1 and HIF1A were positively correlated with the malignant grade of astrocytomas. LOX protein expression also increased according to the degree of malignancy, with localization in the cytoplasm and nucleus and staining observed in endothelial cells. Glioblastoma with a mutation in IDH1 expressed lower levels of LOX in the nucleus, and IDH1-mutated cases showed lower LOX expression levels when compared to wild-type IDH1 cases. LOX knockdown and inhibition by BAPN in U87MG and A172 cell lines affected migration, invasion and soft agar colony formation. Taken together, these results corroborate the role of LOX in the migration, invasion and angiogenesis of astrocytomas. Furthermore, LOX expression is influenced by IDH1 mutational status. This work provides new insights for researchers aiming to design targeted therapies to control astrocytomas.
Highlights
Astrocytomas are the most common primary brain tumors
Lysyl oxidase (LOX), bone morphogenic protein-1 (BMP1) and HIF1A expression analysis by qRT-Polymerase chain reaction (PCR) showed great variability in astrocytomas of all malignant grades when compared to non-neoplastic samples
No difference was found in LOX expression level between AGI, AGII and AGIII when compared to non-neoplastic samples
Summary
Astrocytomas are the most common primary brain tumors. The World Health Organization (WHO) classifies astrocytomas into four malignant grades: grade I, or pilocytic astrocytoma; grade II, or low-grade astrocytoma (AGII), grade III, or anaplastic astrocytoma (AGIII); and PLOS ONE | DOI:10.1371/journal.pone.0119781 March 19, 2015LOX Expression in Astrocytomas grade IV astrocytoma or glioblastoma (AGIV or GBM) [1]. Astrocytomas are the most common primary brain tumors. Infiltrative astrocytomas (AGII-GBM) have the ability to invade the surrounding normal brain tissue, hampering tumor resection. GBM, the most malignant and frequent brain tumor in adults, can be divided into two subgroups: primary GBM, which arises de novo, and secondary GBM, which results from the progression of a lower grade astrocytoma [2,3]. Mutations in the gene that encodes isocitrate dehydrogenase 1 (IDH1) have been reported in diffuse gliomas, including WHO grades II and III astroglial and oligodendroglial lineages [4,5,6,7,8]. IDH1 mutations are strong predictors of a more favorable prognosis and serve as a highly selective molecular marker of secondary GBM that complements clinical criteria for distinguishing secondary GBM from primary GBM [9,10,11]
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