Abstract
Medulloblastoma is the most common malignant brain tumor of childhood, with great potential to metastasize. However, the mechanisms of how medulloblastoma develops and progresses remain to be elucidated. The present study assessed the role of long noncoding RNA LOXL1-AS1 (lncRNA LOXL1-AS1) in the cell proliferation and metastasis in human medulloblastoma. It was initially found that LOXL1-AS1 was significantly overexpressed in clinical medulloblastoma tissues compared with the adjacent noncancerous tissues. LOXL1-AS1 was also highly expressed in medulloblastoma at advanced stages and differentially expressed in a series of medulloblastoma cell lines. Knockdown of LOXL1-AS1 using shRNAs significantly inhibited cell viability and colony formation capacities in D283 and D341 cells. Moreover, the cell proportion in the S phase was significantly increased, while the cell proportion in the G2/M phase was decreased after knockdown of LOXL1-AS1 in D283 cells and D341 cells. Cell cycle arrest led to eventual cell apoptosis by LOXL1-AS1 knockdown. Moreover, in a xenograft model of human medulloblastoma, knockdown of LOXL1-AS1 significantly inhibited tumor growth and promoted tumor cell apoptosis. In addition, knockdown of LOXL1-AS1 inhibited cell migration and reversed epithelial-to-mesenchymal transition (EMT). Western blot analysis further revealed that knockdown of LOXL1-AS1 decreased the phosphorylated levels of PI3K and AKT without affecting their total protein levels. These results suggest that LncRNA LOXL1-AS1 promoted the proliferation and metastasis of medulloblastoma by activating the PI3K-AKT pathway, providing evidence that knockdown of LncRNA LOXL1-AS1 might be a potential therapeutic strategy against medulloblastoma.
Highlights
Medulloblastoma is the most common malignant brain tumor of childhood characterized with frequent extraneural metastasis [1]
Forty percent of patients suffering from medulloblastoma were found to have distant metastasis at diagnosis [14], making it a real challenge to treat this malignancy
LOXL1-AS1 is a recently identified long noncoding RNAs (lncRNAs) that is critically associated with cellular stress response [13], but there is a lack of expression data for LOXL1AS1, especially in tumor tissues
Summary
Medulloblastoma is the most common malignant brain tumor of childhood characterized with frequent extraneural metastasis [1]. Other critical lncRNAs significantly associated with medulloblastoma remain to be elucidated. LOXL1-AS1 expression is significantly altered in response to oxidative stress in human lens epithelial cells and in response to cyclic mechanical stress in human Schlemm’s canal endothelial cells [13], supporting a functional role for the lncRNA LOXL1-AS1 in cellular stress response. The role of LOXL1-AS1 in human tumorigenesis remains unknown, so the present study aimed to investigate the expression profile and functional role of LOXL1-AS1 in medulloblastoma. To this end, the LOXL1-AS1 level was initially evaluated in clinical medulloblastoma tissues and in a series of medulloblastoma cell lines. The PI3K/AKT pathway was regulated by LOXL1-AS1, which might suggest a regulatory mechanism contributing to LOXL1-AS1-mediated medulloblastoma progression
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