Expression analysis of stem cell-related genes reveal OCT4 as a predictor of poor clinical outcome in medulloblastoma

Rodini, Carolina Oliveira; Suzuki, Daniela Emi; Saba-Silva, Najsla; Cappellano, Andréa; Souza, Jorge Estefano Santana de; Cavalheiro, Sérgio; Toledo, Sílvia Regina Caminada de; Okamoto, Oswaldo Keith

doi:10.1007/s11060-011-0647-9

Cited by 44 publications

(46 citation statements)

References 22 publications

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“…After reviewing the abstracts, only 25 studies were preliminarily included and were further assessed by reading full text [14][15][16][17][18][19][20][21][22][23][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. Fifteen studies were then excluded for other types of gliomas or the lack of usable data [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42], and ten studies were finally included into the meta-analysis [14][15][16][17][18][19][20][21][22][23]. Those t...…”

Section: Study Selection and Description Of Included Studiesmentioning

confidence: 99%

High CD133 Expression Is Associated with Worse Prognosis in Patients with Glioblastoma

Zhang

Chen

et al. 2015

Mol Neurobiol

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The CD133 antigen has been identified as a putative stem cell marker in gliomas. However, the prognostic significance of CD133 expression in glioblastoma patients remained controversial. A meta-analysis of published data was performed to comprehensively assess the prognostic role of CD133 expression in glioblastoma patients. Publications assessing the prognostic significance of CD133 expression in glioblastoma patients were identified in PubMed, Embase, and Web of Science up to November 2014. The pooled hazard ratio (HR) with 95% confidence interval (95% CI) was calculated using meta-analysis to evaluate the prognostic significance of CD133 expression in glioblastoma. Ten studies with a total of 715 glioblastoma patients were included into the meta-analysis. Overall, high CD133 expression was associated with poorer overall survival in patients with glioblastoma (HR = 1.96, 95% CI 1.46-2.64, P < 0.001). In addition, high CD133 expression was also associated with poorer progression-free survival in patients with glioblastoma (HR = 2.03, 95% CI 1.43-2.88, P < 0.001). Meta-analyses of studies with high quality showed that high CD133 expression was associated with both poorer overall survival (HR = 2.39, 95% CI 1.77-3.23, P < 0.001) and poorer progression-free survival (HR = 2.17, 95% CI 1.60-2.94, P < 0.001) in patients with glioblastoma. Meta-analysis of studies with adjusted estimates further showed that high CD133 expression was an independent prognostic factor of glioblastoma. High CD133 expression is associated with worse prognosis in patients with glioblastoma. More prospective studies with well-design are needed to confirm this finding.

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Section: Study Selection and Description Of Included Studiesmentioning

confidence: 99%

High CD133 Expression Is Associated with Worse Prognosis in Patients with Glioblastoma

Zhang

Chen

et al. 2015

Mol Neurobiol

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“…Tumor processing, respective clinical data, and cDNA preparation were previously described [9]. This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction.…”

Section: Tumor Collection and Data Analysismentioning

confidence: 99%

“…In germ cell tumours [7], enhanced expression of OCT4 has been associated with increased malignant potential [8]. High OCT4 expression also predicts unfavorable clinical outcome in medulloblastoma and gastric cancer [9,10]. Lin28b, an RNA-binding protein, has been implicated in the genesis of Wilms tumor [11] and gliomas [12], as well as recurrence of hepatocellular carcinoma [13], and aggressiveness of breast carcinoma [14].…”

Section: Introductionmentioning

confidence: 99%

“…A previous study revealed abnormal expression of stemness genes in medulloblastoma, the most common type of malignant embryonal tumor arising in the central nervous system of children under four years of age [9]. As a type of primitive neuroectodermal tumor, medulloblastoma is thought to arise from immature cells during early cerebellum development [19,20].…”

Section: Introductionmentioning

confidence: 99%

“…A significant proportion of medulloblastoma patients do not respond adequately to available treatments, usually consisting of surgery followed by radiotherapy and classic chemotherapy [21]. Given that aberrantly elevated OCT4 expression has been correlated with poor survival of medulloblastoma patients [9], it prompted us to investigate whether L1TD1, a downstream target of OCT4, would be relevant to the aggressiveness of this important pediatric brain tumor.…”

Section: Introductionmentioning

confidence: 99%

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Embryonic Stem Cell-Related Protein L1TD1 Is Required for Cell Viability, Neurosphere Formation, and Chemoresistance in Medulloblastoma

Santos

Silva

Rodini

et al. 2015

Stem Cells and Development

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Misexpression of stem cell-related genes may occur in some cancer cells, influencing patient's prognosis. This is the case of medulloblastoma, a common and clinically challenging malignant tumor of the central nervous system, where expression of the pluripotency factor, OCT4, is correlated with poor survival. A downstream target of OCT4, L1TD1 (LINE-1 type transposase domain-containing protein 1 family member), encodes a novel embryonic stem cell (ESC)-related protein involved in pluripotency and self-renewal of ESCs. L1TD1 is still poorly characterized and its expression pattern and function in cancer cells are virtually unknown. Although normally restricted to non-neoplastic undifferentiated cells and germ cells, we found that high L1TD1 expression also occurs in medulloblastoma cells, reaching levels similar to those found in ESCs, and is correlated with poor prognosis. Conversely to what is reported during normal cell differentiation, when differentiated cells remain healthy, despite L1TD1 downregulation, depletion of L1TD1 protein levels by targeted gene silencing significantly reduced medulloblastoma cell viability, inhibiting cell proliferation and inducing apoptosis. More strikingly, L1TD1 depletion downregulated expression of the neural stem cell markers, CD133 and Nestin, inhibited neurosphere generation capability, and sensitized medulloblastoma cells to temozolomide and cisplatin, two chemotherapeutic agents of clinical relevance in medulloblastoma treatment. Our findings provide insights about the contribution of pluripotency-related genes to a more aggressive tumor phenotype through their involvement in the acquisition of stem-like properties by cancer cells and point out L1TD1 as a potential therapeutic target in malignant brain tumors.

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miR‐367 as a therapeutic target in stem‐like cells from embryonal central nervous system tumors

et al. 2019

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Aberrant expression of the pluripotency factor OCT4A in embryonal tumors of the central nervous system (CNS) is a key factor that contributes to tumor aggressiveness and correlates with poor patient survival. OCT4A overexpression has been shown to up‐regulate miR‐367, a microRNA (miRNA) that regulates pluripotency in embryonic stem cells and stem‐like aggressive traits in cancer cells. Here, we show that (a) miR‐367 is carried in microvesicles derived from embryonal CNS tumor cells expressing OCT4A; and (b) inhibition of miR‐367 in these cells attenuates their aggressive traits. miR‐367 silencing in OCT4A‐overexpressing tumor cells significantly reduced their proliferative and invasive behavior, clonogenic activity, and tumorsphere generation capability. In vivo, targeting of miR‐367 through direct injections of a specific inhibitor into the cerebrospinal fluid of Balb/C nude mice bearing OCT4A‐overexpressing tumor xenografts inhibited tumor development and improved overall survival. miR‐367 was also shown to target SUZ12, one of the core components of the polycomb repressive complex 2 known to be involved in epigenetic silencing of pluripotency‐related genes, including POU5F1, which encodes OCT4A. Our findings reveal possible clinical applications of a cancer stemness pathway, highlighting miR‐367 as a putative liquid biopsy biomarker that could be further explored to improve early diagnosis and prognosis prediction, and potentially serve as a therapeutic target in aggressive embryonal CNS tumors.

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Expression analysis of stem cell-related genes reveal OCT4 as a predictor of poor clinical outcome in medulloblastoma

Cited by 44 publications

References 22 publications

High CD133 Expression Is Associated with Worse Prognosis in Patients with Glioblastoma

High CD133 Expression Is Associated with Worse Prognosis in Patients with Glioblastoma

Embryonic Stem Cell-Related Protein L1TD1 Is Required for Cell Viability, Neurosphere Formation, and Chemoresistance in Medulloblastoma

miR‐367 as a therapeutic target in stem‐like cells from embryonal central nervous system tumors

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