Epigenetic-Mediated Dysfunction of the Bone Morphogenetic Protein Pathway Inhibits Differentiation of Glioblastoma-Initiating Cells

Lee, Jeongwu; Son, Myung Jin; Woolard, Kevin D.; Donin, Nicholas M.; Li, Aiguo; Cheng, Chui H.; Kotliarova, Svetlana; Kotliarov, Yuri; Walling, Jennifer; Ahn, Susie; Kim, Misuk; Totonchy, Mariam B.; Cusack, Thomas R.; Ene, Cristian; Ma, Huaxian; Su, Qin; Zenklusen, Jean C.; Zhang, Wei; Maric, Dragan; Fine, Howard A.

doi:10.1016/j.ccr.2007.12.005

Cited by 409 publications

(382 citation statements)

References 53 publications

(76 reference statements)

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“…The results of a recent study (26), similar to our findings, showed that IFN-β induces the phosphorylation of STAT3 in glioma cells and thereby activates STAT3-mediated miR-21 transcription in a luciferase reporter gene system. Our findings support the hypothesis that STAT3 activation exerts a cytostatic or antiproliferative effect in some types of cells (34)(35)(36)(37); however, the role of STAT3 activation is debatable because its overactivation has been reported to be oncogenic in some cell lines (38,39). Loffler et al showed that IL-6-dependent STAT3 activates the transcription of miR-21 in multiple myeloma cells.…”

Section: Discussionsupporting

confidence: 88%

The Modulation of MicroRNAs by Type I IFN through the Activation of Signal Transducers and Activators of Transcription 3 in Human Glioma

Ohno

Natsume

Kondo

et al. 2009

Molecular Cancer Research

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Type I IFNs are involved in double-stranded RNA responses. Here, we investigated the possibility that IFN-β may induce or downregulate cellular microRNAs (miRNA) in human neoplasms and thereby use the RNA interference system to show antitumor effects. Because of its known connection to glioma biology, we focused on miR-21 among seven miRNAs influenced by IFN-β. We analyzed the effect of IFN-β treatment on miR-21 expression in glioma cells and intracranial glioma xenografts. IFN-β treatment reduced miR-21 expression in glioma cells markedly, and IFN-β administration suppressed the growth of glioma-initiating cell-derived intracranial tumors. The levels of primary miR-21 gene transcripts, precursor miR-21, and mature miR-21 decreased 6 hours after the addition of IFN-β, indicating that the reduction in miR-21 levels was due to transcriptional suppression. We did reporter assays to elucidate the IFN-β-mediated suppression of miR-21; the addition of signal transducers and activators of transcription 3 (STAT3)-expressing vectors induced the IFN-β-mediated suppression of miR-21, whereas STAT3-inhibiting agents inhibited the miR-21 suppression. Thus, the results of our study show that the downregulation of miR-21 contributes to the antitumor effects of IFN-β and that miR-21 expression is negatively regulated by STAT3 activation. These results highlight the importance of understanding the transcriptional regulation of the miRNAs involved in

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Section: Discussionsupporting

confidence: 88%

The Modulation of MicroRNAs by Type I IFN through the Activation of Signal Transducers and Activators of Transcription 3 in Human Glioma

Ohno

Natsume

Kondo

et al. 2009

Molecular Cancer Research

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“…Germ line mutations of BMPR1A have been associated with juvenile polyposis in humans and produce a significantly higher risk of gastrointestinal cancer (33). BMPR1B homozygous null mice are viable; however, mutants exhibit skeletal defects (34), and BMPR1B is epigenetically silenced in some patientderived tumor-initiating glioblastoma cell lines (35). A recent study indicated that lower BMPR1B expression was observed in breast cancer tissues with poor prognosis, and the decreased expression of BMPR1B resulted in increased cell proliferation in breast cancer cells in vitro, which suggested that BMPR1B mediated a repressive effect on breast cancer cells (36).…”

Section: Discussionmentioning

confidence: 99%

The Activation of MEK/ERK Signaling Pathway by Bone Morphogenetic Protein 4 to Increase Hepatocellular Carcinoma Cell Proliferation and Migration

Chiu

Kuo

et al. 2012

Molecular Cancer Research

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Hepatocellular carcinoma (HCC) is one of the most common visceral malignancies worldwide, with a very high incidence and poor prognosis. Bone morphogenesis protein 4 (BMP4), which belongs to the TGF-b superfamily of proteins, is a multifunctional cytokine, which exerts its biologic effects through SMAD-and non-SMADdependent pathways, and is also known to be involved in human carcinogenesis. However, the effects of the BMP4 signaling in liver carcinogenesis are not yet clearly defined. Here, we first show that BMP4 and its receptor, BMPR1A, are overexpressed in a majority of primary HCCs and that it promotes the growth and migration of HCC cell lines in vitro. We also establish that BMP4 can induce HCC cyclin-dependent kinase (CDK)1 and cyclin B1 upregulation to accelerate cell-cycle progression. Our study indicates that the induction of HCC cell proliferation is independent of the SMAD signaling pathway, as Smad4 knockdown of HCC cell lines still leads to the upregulation of CDK1 and cyclin B1 expression after BMP4 treatment. Using mitogen-activated protein/extracellular signalregulated kinase (MEK) selective inhibitors, the induction of CDK1, cyclin B1 mRNA and protein were shown to be dependent on the activation of MEK/extracellular signal-regulated kinase (ERK) signaling. In vivo xenograft studies confirmed that the BMPR1A-knockdown cells were significantly less tumorigenic than the control groups. Our findings show that the upregulation of BMP4 and BMPR1A in HCC promotes the proliferation and metastasis of HCC cells and that CDK1 and cyclin B1 are important SMAD-independent molecular targets in BMP4 signaling pathways, during the HCC tumorigenesis. It is proposed that BMP4 signaling pathways may have potential as new therapeutic targets in HCC treatment. Mol Cancer Res; 10(3); 415-27. Ó2012 AACR. IntroductionHepatic cancer, particularly hepatocellular carcinoma (HCC), is one of the most common tumors worldwide and the third most common cause of cancer-related deaths. Diagnosis of advanced stage of HCC is a devastating experience for both patients and family. More than 80% of HCC cases originate in developing countries (1, 2). Chronic infections with hepatitis B virus or hepatitis C virus are responsible for the majority of HCC cases in those countries, especially in Asia (3, 4). Other risk factors include prolonged

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“…BMPs were identified based on their ability to promote ectopic cartilage and bone formation (2). BMPs function through conserved type I and type II transmembrane receptors and Smad-dependent and -independent pathways, to regulate a range of biological processes in a highly context-dependent manner (1,(3)(4)(5). Disruption of these pathways can lead to various diseases including cancer (6).…”

Section: Introductionmentioning

confidence: 99%

Induction of estrogen receptor α-36 expression by bone morphogenetic protein 2 in breast cancer cell lines

Wang

Huang

Baowei

et al. 2012

Molecular Medicine Reports

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Abstract. The expression of estrogen receptor-α (ERα) is one of the most important diagnostic and prognostic factors of breast cancer. Recently, ERα-36 has been identified as a novel variant of ER-α. ERα-36 lacks intrinsic transcription activity and mainly mediates non-genomic estrogen signaling. Bone morphogenetic proteins (BMPs) are recognized as key factors during the control of cell fate and cancer development. However, the correlation between BMP and the ER signaling pathway remains unclear. In this study, we show that BMP2, a member of the BMP family, is a novel inducer of ERα-36 expression in breast cancer cells. As shown by western blot assays, the upregulation of ERα-36 by BMP2 was significant. In MDA-MB-231 cells which are ERα-66-negative, BMP2 was able to induce the expression of ERα-36 in a dose-dependent manner, and the RNA interference assay indicated a correlation between BMP2 and ERα-36 expression. BMP2 inhibited the growth of MCF-7 and MDA-MB-231 cells; however, the inhibitory effect was antagonized by tamoxifen, suggesting that the ER signal was involved. The growth of MDA-MB-231 cells was stimulated by 17-β-estradiol (E2) after BMP2 induction, even though the cells were previously insensitive to E2. These results suggest that BMP2 induces ERα-36 expression and alters tumor resistance to endocrine therapy by changing the expression profile of ERs.

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Epigenetic-Mediated Dysfunction of the Bone Morphogenetic Protein Pathway Inhibits Differentiation of Glioblastoma-Initiating Cells

Cited by 409 publications

References 53 publications

The Modulation of MicroRNAs by Type I IFN through the Activation of Signal Transducers and Activators of Transcription 3 in Human Glioma

The Modulation of MicroRNAs by Type I IFN through the Activation of Signal Transducers and Activators of Transcription 3 in Human Glioma

The Activation of MEK/ERK Signaling Pathway by Bone Morphogenetic Protein 4 to Increase Hepatocellular Carcinoma Cell Proliferation and Migration

Induction of estrogen receptor α-36 expression by bone morphogenetic protein 2 in breast cancer cell lines

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