Genome-Wide Profiling Identified a Set of miRNAs that Are Differentially Expressed in Glioblastoma Stem Cells and Normal Neural Stem Cells

Lang, Ming-Fei; Shen, Yang; Zhao, Chunnian; Sun, Guoqiang; Murai, Kiyohito; Wu, Xiwei; Wang, Jinhui; Gao, Hanlin; Brown, Christine E.; Liu, Xiaoxuan; Zhou, Jiehua; Peng, Ling; Rossi, John J.; Shi, Yanhong

doi:10.1371/journal.pone.0036248

Cited by 104 publications

(83 citation statements)

References 45 publications

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“…Overexpression of CSMD1 in melanoma cells resulted in reduced migration and proliferation and induced apoptosis. In addition, xenografted tumours expressing CSMD1 resulted in reduction of tumour weight and size (15) Of note, reduced mRNA CSMD1 expression has been identified in glioblastoma stem cells compared to neural stem cells (16). Downregulation of CSMD1 was linked to up regulation of the microRNAs miR-10a and miRNA10b which formed an inhibitory complex with the 3'UTR of CSMD1 (16).…”

Section: Loss Of Csmd1 Expression Disrupts Mammary Duct Formation Whimentioning

confidence: 99%

“…In addition, xenografted tumours expressing CSMD1 resulted in reduction of tumour weight and size (15) Of note, reduced mRNA CSMD1 expression has been identified in glioblastoma stem cells compared to neural stem cells (16). Downregulation of CSMD1 was linked to up regulation of the microRNAs miR-10a and miRNA10b which formed an inhibitory complex with the 3'UTR of CSMD1 (16). Similarly high levels of miRNA-10b associated with low levels of CSMD1 expression were identified in hepG2 hepatocellular carcinoma cells (17).…”

Section: Loss Of Csmd1 Expression Disrupts Mammary Duct Formation Whimentioning

confidence: 99%

“…CSMD1 is located on chromosome 8p23, a region that is frequently deleted in different types of cancer (1,(6)(7)(8)(9)(10). In addition, reduced CSMD1 mRNA and protein expression has been observed in different cancers (11)(12)(13)(14)(15)(16)(17). An array comparative genomic hybridization study revealed a high rate of loss of 8p23.2 containing the CSMD1 gene in advanced prostrate cancer samples.…”

Section: Introductionmentioning

confidence: 99%

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Loss of CSMD1 expression disrupts mammary duct formation while enhancing proliferation, migration and invasion

et al. 2017

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Abstract. The CUB and sushi multiple domains 1 (CSMD1) gene maps to chromosome 8p23, a region deleted in many cancers. Loss of CSMD1 expression is associated with poor prognosis in breast cancer suggesting that it acts as a tumour suppressor in this cancer. However, the function of CSMD1 is largely unknown. Herein, we investigated CSMD1 functions in cell line models. CSMD1 expression was suppressed in MCF10A and LNCaP cells using short hairpin RNA. Functional assays were performed focusing on the 'normal' MCF10A cell line. Suppression of CSMD1 significantly increased the proliferation, cell migration and invasiveness of MCF10A cells compared to shcontrols. shCSMD1 cells also showed significantly reduced adhesion to Matrigel and fibronectin. In a three-dimensional Matrigel model of MCF10A cells, reduced CSMD1 expression resulted in the development of larger and more poorly differentiated breast acini-like structures that displayed impaired lumen formation. Loss of CSMD1 expression disrupts a model of mammary duct formation while enhancing proliferation, migration and invasion. Our data suggest that CSMD1 is involved in the suppression of a transformed phenotype. IntroductionCUB and sushi multiple domains-1 (CSMD1) is a very large gene which contains 71 exons that span over 2 Mb of genomic DNA on chromosome 8p23 (1). Multiple splice variants exist for CSMD1 and these encode proteins of varying length. The largest transcript is 14.3 kb long and this encodes a 3,565 amino acid protein (1). The full-length protein is a membrane protein with an extracellular region containing 14 CUB and 28 sushi domains, a single transmembrane domain and a short cytoplasmic domain that contains a putative tyrosine phosphorylation site. CSMD1 belongs to the CSMD gene family whose members also include the structurally similar proteins CSMD2 and CSMD3 (1-3). The function of CSMD1 is largely unknown. Although CSMD1 has been shown to inhibit C3 deposition onto the surface of cells leading to the inhibition of the classical complement pathway (4,5). The structure of CSMD1 predicts that CSMD1 is a receptor for unknown ligand(s) and is involved in signal transduction (1).CSMD1 is believed to act as a tumour suppressor based on a number of observations. CSMD1 is located on chromosome 8p23, a region that is frequently deleted in different types of cancer (1,6-10). In addition, reduced CSMD1 mRNA and protein expression has been observed in different cancers (11-17). An array comparative genomic hybridization study revealed a high rate of loss of 8p23.2 containing the CSMD1 gene in advanced prostrate cancer samples. A further small real-time PCR study identified a decrease in CSMD1 mRNA levels in higher stage prostrate cancer samples (11). Similarly reduced CSMD1 expression at the mRNA level has been identified in colorectal cancer associated with reduced patient survival (12). Furthermore, somatic mutations were detected in CSMD1 in 11% (6/54) of colorectal cancer patients along side DNA methylation and allele loss, predominantly in early onset ...

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Section: Loss Of Csmd1 Expression Disrupts Mammary Duct Formation Whimentioning

confidence: 99%

Section: Loss Of Csmd1 Expression Disrupts Mammary Duct Formation Whimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of CSMD1 expression disrupts mammary duct formation while enhancing proliferation, migration and invasion

et al. 2017

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“…However, many tumors had overexpression of the PTBP1 transcript ( Figure 6A) and protein ( Figure 6B) without gene amplification. Neuron-specific microRNA miR-124, which plays an important role in neurogenesis (80) and is repressed in high-grade gliomas (81)(82)(83) to enhance stem-like traits and invasiveness (84), directly targets PTBP1 during nervous system development (44). Our analysis of miR-124 expression in a panel of patient-derived BTSCs revealed consistently lower levels of miR-124 in glioblastoma-derived BTSCs and tumor cell cultures than were seen in normal brain and, in turn, showed higher levels of PTBP1 expression in the BTSCs and tumor cultures ( Figure 6D).…”

Section: Figurementioning

confidence: 99%

Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

et al. 2014

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Tissue-specific alternative splicing is critical for the emergence of tissue identity during development, yet the role of this process in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily conserved, alternative exons that represent only a minority of the total alternative exons identified. Many of these conserved exons have functional features that influence signaling pathways to profound biological effect. Here, we determined that lineage-specific splicing of a brain-enriched cassette exon in the membrane-binding tumor suppressor annexin A7 (ANXA7) diminishes endosomal targeting of the EGFR oncoprotein, consequently enhancing EGFR signaling during brain tumor progression. ANXA7 exon splicing was mediated by the ribonucleoprotein PTBP1, which is normally repressed during neuronal development. PTBP1 was highly expressed in glioblastomas due to loss of a brain-enriched microRNA (miR-124) and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that glioblastoma cells inherit the trait from a potential tumor-initiating ancestor and that these cells exploit this trait through accumulation of mutations that enhance EGFR signaling. Our data illustrate that lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates tumor suppressor functions and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones.

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“…Currently, the treatment strategies for glioblastoma mainly include surgery, chemotherapy and radiation therapy; however, the overall median survival time of patients is only ~15 months (2). To improve the quality of life in patients with glioblastoma, research is focusing on its pathogenesis and novel therapeutic targets such as microRNAs (miRNAs) (3).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of miR-124 promotes the growth and invasiveness of glioblastoma cells involving upregulation of PPP1R13L

Zhao

Yang-de

2013

International Journal of Molecular Medicine

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Abstract. plays an important role in regulating growth, invasiveness, stem-like traits, differentiation and apoptosis of glioblastoma cells. PPP1R3L, an inhibitory member of the apoptosis-stimulating protein of p53 family (IASPP), is also able to affect growth, cell cycle progression, metastasis and apoptosis of various types of cancer. To investigate the regulation of PPP1R13L expression by miR-124 and their effects on proliferation, cell cycle transition and invasion in glioblastoma cells, U251 and U373 glioblastoma cells were transfected with miR-124 mimics, its negative control (NC) or an inhibitor. We found that miR-124 was downregulated in glioblastoma tissues, and inversely regulated PPP1R13L expression in U251 and U373 glioblastoma cells. PPP1R13L was found to be a direct target of miR-124 in glioblastoma cells. Overexpression of miR-124 inhibited proliferation, G1/S transition and invasiveness in glioblastoma cells. miR-124 downregulation-mediated malignant progression of glioblastoma was partly attributed to increased PPP1R13L expression. Consequently, our findings provide a molecular basis for the role of miR-124/PPP1R13L in the progression of human glioblastoma and suggest a novel target for the treatment of glioblastoma.

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Genome-Wide Profiling Identified a Set of miRNAs that Are Differentially Expressed in Glioblastoma Stem Cells and Normal Neural Stem Cells

Cited by 104 publications

References 45 publications

Loss of CSMD1 expression disrupts mammary duct formation while enhancing proliferation, migration and invasion

Loss of CSMD1 expression disrupts mammary duct formation while enhancing proliferation, migration and invasion

Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

Downregulation of miR-124 promotes the growth and invasiveness of glioblastoma cells involving upregulation of PPP1R13L

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