Expression of microRNA-146 suppresses NF-κB activity with reduction of metastatic potential in breast cancer cells

Bhaumik, Dipa; Scott, Gary K.; Schokrpur, Shiruyeh; Patil, Christopher K.; Campisi, Judith; Benz, Christopher C.

doi:10.1038/onc.2008.171

Cited by 574 publications

(489 citation statements)

References 25 publications

(35 reference statements)

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“…Unexpectedly, our study reveals that, instead of promoting gliomagenesis through its upregulation, miR-146a rather plays an inhibitory role in restricting the formation of glioma stem-like cells and tumor burden. This result is consistent with a demonstrated role of miR-146a in other cancers, such as pancreatic and breast cancers, where it inhibits cancer progression and invasion (8,26,33). A recent report also showed a positive correlation of miR-146a expression with the survival time of gastric cancer patients (25).…”

Section: Discussionsupporting

confidence: 74%

“…A recent report also showed a positive correlation of miR-146a expression with the survival time of gastric cancer patients (25). Furthermore, the overexpression of miR-146a inhibits the proliferation and survival of breast, prostate, and pancreatic cancer cells through the downregulation of other targets in these cells, including ROCK1, EGFR, and MTA-2 (8,33,34). Our study adds Notch1 as a major target of miR-146a in glioma cells.…”

Section: Discussionmentioning

confidence: 77%

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MicroRNA-146a Inhibits Glioma Development by Targeting Notch1

Mei

Bachoo²,

Zhang³

2011

Molecular and Cellular Biology

158

131

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Dysregulated epidermal growth factor receptor (EGFR) signaling through either genomic amplification or dominant-active mutation (EGFR vIII ), in combination with the dual inactivation of INK4A/ARF and PTEN, is a leading cause of gliomagenesis. Our global expression analysis for microRNAs revealed that EGFR activation induces miR-146a expression, which is further potentiated by inactivation of PTEN. Unexpectedly, overexpression of miR-146a attenuates the proliferation, migration, and tumorigenic potential of Ink4a/Arf ؊/؊ Pten ؊/؊ Egfr vIII murine astrocytes. Its ectopic expression also inhibits the glioma development of a human glioblastoma cell line in an orthotopic xenograft model. Such an inhibitory function of miR-146a on gliomas is largely through downregulation of Notch1, which plays a key role in neural stem cell maintenance and is a direct target of miR-146a. Accordingly, miR-146a modulates neural stem cell proliferation and differentiation and reduces the formation and migration of glioma stem-like cells. Conversely, knockdown of miR-146a by microRNA sponge upregulates Notch1 and promotes tumorigenesis of malignant astrocytes. These findings indicate that, in response to oncogenic cues, miR-146a is induced as a negative-feedback mechanism to restrict tumor growth by repressing Notch1. Our results provide novel insights into the signaling pathways that link neural stem cells to gliomagenesis and may lead to new strategies for treating brain tumors.Gliomas are the most frequently observed brain tumors, with glioblastoma multiforme (GBM) being the most common and aggressive form in adults (35). Despite major therapeutic improvements made by combining neurosurgery, chemotherapy, and radiotherapy, the prognosis and survival rate for patients with GBM is still extremely poor (7). The deadly nature of GBM originates from explosive growth and invasive behavior, which are fueled by dysregulation of multiple signaling pathways. Epidermal growth factor receptor (EGFR) activation, in cooperation with loss of tumor suppressor functions, such as mutations in Ink4a/Arf and Pten genes, constitutes a lesion signature for GBM (4). Such dysregulated genetic pathways are sufficient to transform neural stem cells (NSCs) or astrocytes into cancer stem-like cells. This gives rise to highgrade malignant gliomas with a pathological phenotype resembling human GBM (5, 59). However, the downstream events underlying these genetic dysregulations in gliomagenic cells have not been fully elucidated.MicroRNAs are 20-to 22-nucleotide noncoding RNA molecules that have emerged as key players in controlling NSC self-renewal and differentiation (11,57). Aberrant expression of miRNAs, such as miR-21, miR-124, and miR-137, is linked to glioma formation (49). miR-199b-5p and miR-34a impair cancer stem-like cells through the negative regulation of several components of the Notch pathway in brain tumors (18,21). The Notch pathway is an evolutionarily conserved signaling pathway that plays an important role in neurogenesis (3, 10, 23). Upon bindi...

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 77%

MicroRNA-146a Inhibits Glioma Development by Targeting Notch1

Mei

Bachoo²,

Zhang³

2011

Molecular and Cellular Biology

158

131

View full text Add to dashboard Cite

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“…This conclusion is in agreement with previous studies, suggesting that inhibition of miR-146a activity could promote tumor growth and metastasis (Bhaumik et al, 2008;Lin et al, 2008;Hurst et al, 2009;Xia et al, 2009). In addition, down-regulation of miR-146a expression by the c-Myc oncogenic transcription factor was previously observed in human and mouse B cell lymphomas .…”

Section: Methodssupporting

confidence: 83%

miR-146ais a significant brake on autoimmunity, myeloproliferation, and cancer in mice

Boldin¹,

Taganov²,

Rao³

et al. 2011

J Cell Biol

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Excessive or inappropriate activation of the immune system can be deleterious to the organism, warranting multiple molecular mechanisms to control and properly terminate immune responses. MicroRNAs (miRNAs), 22-nt-long noncoding RNAs, have recently emerged as key posttranscriptional regulators, controlling diverse biological processes, including responses to non-self. In this study, we examine the biological role of miR-146a using genetically engineered mice and show that targeted deletion of this gene, whose expression is strongly up-regulated after immune cell maturation and/or activation, results in several immune defects. Collectively, our findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation.

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“…The present data that several tumor suppressor miRs are induced by LMP1 and the downregulation of TCL1 through miR-29b adds another mechanistic clue as to cytostasis provoked by this protein in B lymphoma cells. In this context, it is interesting to note that miR146a, upregulated by LMP1, is implicated in metastasis inhibition (Bhaumik et al, 2008;Hurst et al, 2009). Taken together, this suggests that LMP1 can promote normal B-cell growth and that of murine fibroblasts, and yet is capable of inhibiting growth of B lymphoma cells.…”

Section: Ebv Lmp1 Regulates Tcl1 Through Mir-29bmentioning

confidence: 97%

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

et al. 2009

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Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1) is noted for its transforming potential. Yet, it also acts as a cytostatic and growth-relenting factor in Burkitt's lymphoma (BL) cells. The underlying molecular mechanisms of the growth inhibitory property of LMP1 have remained largely unknown. In this study, we show that LMP1 negatively regulates a major oncogene, TCL1, in diffuse large B-cell lymphoma (DLBCL) and BL cells. MicroRNA (miR) profiling of LMP1 transfectants showed that among others, miR-29b, is upregulated. LMP1 diminished TCL1 by inducing miR29b through C-terminus activation region 1 (CTAR1) and CTAR2. miR-29b locked nucleic acid (LNA) antisense oligonucleotide transfection into LMP1-expressing cells reduced miR-29b expression and consequently reconstituted TCL1, suggesting that LMP1 negatively regulates TCL1 through miR-29b upregulation. The miR-29b increase by LMP1 was due to an increase in the cluster pri-miR-29b1-a transcription, derived from human chromosome 7. Using pharmacological inhibitors, we found that p38 mitogen-activated protein kinase-activating function of LMP1 is important for this effect. The ability of LMP1 to negatively regulate TCL1 through miR-29b might underlie its B-cell lymphoma growth antagonistic property. As LMP1 is also important for B-cell transformation, we suggest that the functional dichotomy of this viral protein may depend on a combination of levels of its expression, lineage and differentiation of the target cells and regulation of miRs, which then directs the outcome of the cellular response.

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Expression of microRNA-146 suppresses NF-κB activity with reduction of metastatic potential in breast cancer cells

Cited by 574 publications

References 25 publications

MicroRNA-146a Inhibits Glioma Development by Targeting Notch1

MicroRNA-146a Inhibits Glioma Development by Targeting Notch1

miR-146ais a significant brake on autoimmunity, myeloproliferation, and cancer in mice

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

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