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High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells.

ABSTRACT: Medulloblastoma is a highly aggressive pediatric brain tumor, in which sporadic expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However the contribution of specific OCT4 isoforms to tumor aggressiveness is still poorly understood. Here, we report that medulloblastoma cells stably overexpressing the OCT4A isoform displayed enhanced clonogenic, tumorsphere generation, and invasion capabilities. Moreover, in an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic OCT4A effects were expression-level dependent and accompanied by distinct chromosomal aberrations. OCT4A overexpression in medulloblastoma cells also induced a marked differential expression of non-coding RNAs, including poorly characterized long non-coding RNAs and small nucleolar RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer.

SUBMITTER: da Silva PBG

PROVIDER: S-EPMC5386677 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells.

da Silva Patrícia Benites Gonçalves PBG Teixeira Dos Santos Márcia Cristina MC Rodini Carolina Oliveira CO Kaid Carolini C Pereira Márcia Cristina Leite MCL Furukawa Gabriela G da Cruz Daniel Sanzio Gimenes DSG Goldfeder Mauricio Barbugiani MB Rocha Clarissa Ribeiro Reily CRR Rosenberg Carla C Okamoto Oswaldo Keith OK

Oncotarget 20170301 12

Medulloblastoma is a highly aggressive pediatric brain tumor, in which sporadic expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However the contribution of specific OCT4 isoforms to tumor aggressiveness is still poorly understood. Here, we report that medulloblastoma cells stably overexpressing the OCT4A isoform displayed enhanced clonogenic, tumorsphere generation, and invasion capabilities. Moreover, in an orthotopic metastatic model of medul ...[more]

PMID: 28186969

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Project description:Medulloblastoma is a highly aggressive pediatric brain tumor, in which expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However, the contribution of OCT4 transcript variants to tumor aggressiveness is still poorly understood. In this study, we found that transcripts encoding OCT4A, but not OCT4B or OCT4B1, were significantly correlated with LIN28A expression, which encodes another well-known pluripotency factor. LIN28A was found to specifically bind OCT4A transcripts and interact with poly(A) binding protein and RNA helicase A in polysomal fractions of medulloblastoma cells, favoring increased OCT4A protein levels in these cells. Medulloblastoma cells stably overexpressing OCT4A displayed significantly enhanced clonogenic activity, tumorsphere generation and invasion capability, as well as increased tumorigenicity. In an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic effects of OCT4A were found to be expression-level dependent and accompanied by distinct subchromosomal aberrations and differential expression of newly discovered, still poorly characterized, non-coding RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer. Total RNA of 2-3 clones of each cell line (Control and OCT4A overexpression) was extracted with the RNeasy Mini kit (Qiagen), following the manufacturerâs protocol. Gene expression profiling was carried out independently for each sample using Affymetrix GeneChipÂ® Human Gene 2.0 ST whole-transcript arrays (Affymetrix, Santa Clara, CA, USA). The quality control and normalization of data were processed by AffymetrixÂ® Expression Console Software (Affymetrix). Differentially expressed genes were identified with the One-Way ANOVA, with a p-value cutoff of 0.05, using Transcriptome Analysis Console v3.0 (Affymetrix).

Project description:Medulloblastoma is one of the most prevalent solid tumors found in children, occurring in the brain's posterior fossa. The standard treatment protocol involves maximal resection surgery followed by craniospinal irradiation and chemotherapy. Despite a long-term survival rate of 70%, wide disparities among patients have been observed. The identification of pertinent targets for both initial and recurrent medulloblastoma cases is imperative. Both primary and recurrent medulloblastoma are marked by their aggressive infiltration into surrounding brain tissue, robust angiogenesis, and resistance to radiotherapy. While the significant role of integrin-αvβ3 in driving these characteristics has been extensively documented in glioblastoma, its impact in the context of medulloblastoma remains largely unexplored. Integrin-αvβ3 was found to be expressed in a subset of patients with medulloblastoma. We investigated the role of integrin-αvβ3 using medulloblastoma-derived cell lines with β3-subunit depletion or overexpression both in vitro and in vivo settings. By generating radioresistant medulloblastoma cell lines, we uncovered an increased integrin-αvβ3 expression, which correlated with increased susceptibility to pharmacologic integrin-αvβ3 inhibition with cilengitide, a competitive ligand mimetic. Finally, we conducted single-photon emission computed tomography (SPECT)/MRI studies on orthotopic models using a radiolabeled integrin-αvβ3 ligand (99mTc-RAFT-RGD). This innovative approach presents the potential for a novel predictive imaging technique in the realm of medulloblastoma. Altogether, our findings lay the foundation for employing SPECT/MRI to identify a specific subset of patients with medulloblastoma eligible for integrin-αvβ3-directed therapies. This breakthrough offers a pathway toward more targeted and effective interventions in the treatment of medulloblastoma.SignificanceThis study demonstrates integrin-αvβ3's fundamental role in medulloblastoma tumorigenicity and radioresistance and the effect of its expression on cilengitide functional activity.

Dataset Information

High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells.

Publications

High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells.

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