Role of Synaptojanin 2 in Glioma Cell Migration and Invasion

Chuang, Ya Yu; Tran, Nhan L.; Rusk, Nicole; Nakada, Mitsutoshi; Berens, Michael E.; Symons, Marc

doi:10.1158/0008-5472.can-04-2097

Cited by 145 publications

(148 citation statements)

References 40 publications

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“…High-grade gliomas exhibit aggressive behavior, which is manifested by rapid cellular migration under culture conditions in vitro (12,50). Using a standard "scratch" assay after the cells become confluent in culture dishes, we found that enhanced expression of miR-146a significantly reduced the rate of migration of Ink4a/Arf Ϫ/Ϫ Pten Ϫ/Ϫ Egfr vIII astrocytes compared to the same cells transduced with a control lentivirus (Fig.…”

Section: Egfr Activation and Pten Inactivation Synergistically Inducementioning

confidence: 85%

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: Egfr Activation and Pten Inactivation Synergistically Inducementioning

confidence: 85%

MicroRNA-146a Inhibits Glioma Development by Targeting Notch1

Mei

Bachoo²,

Zhang³

2011

Molecular and Cellular Biology

158

131

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“…Notably, our results contrast with those obtained in human glioma cells inhibiting Rac by small interfering RNA (siRNA)-mediated depletion. 28,29 One potential explanation for this discrepancy could be that compare to siRNA-mediated depletion of Rac1, the dominant negative Rac1 inhibits all isoforms of Rac (Rac1, Rac2 or Rac3) due to their high structural homology or other downstream signaling molecules. Therefore, it remains to be further studied the specific function of Rac1 in rat C6 glioma cells by siRNA-mediated depletion of Rac1, Rac2 or Rac3.…”

Section: Discussionmentioning

confidence: 99%

Dominant‐negative Rac increases both inherent and ionizing radiation‐induced cell migration in C6 rat glioma cells

Hwang

Jung

Jeong

et al. 2005

Intl Journal of Cancer

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Rho-like GTPases, including Cdc42, Rac1 and RhoA, regulate distinct actin cytoskeleton changes required for cell adhesion, migration and invasion. In the present study, we examined the role of Rac signaling in inherent migration, as well as radiation-induced migration, of rat glioma cells. Stable overexpression of dominantnegative Rac1N17 in a C6 rat glioma cell line (C6-RacN17) promoted cell migration, and ionizing radiation further increased this migration. Migration was accompanied by decreased expression of the focal adhesion molecules FAK and paxillin. Focal contacts and actin stress fibers were also reduced in C6-RacN17 cells. Downstream effectors of Rac include JNK and p38 MAP kinases. Irradiation transiently activated p38, JNK and ERK1/2 MAP kinases in C6-RacN17 cells, while p38 and JNK were constitutively activated in C6 control cells. Blocking JNK activity with JNK inhibitor SP600125 inhibited migration, suggesting that the JNK pathway may regulate radiation-induced, as well as inherent, migration of C6-RacN17 cells. Additionally, the radiation-induced migration increase was also inhibited by SB203580, a specific inhibitor of p38 MAP kinase. However, PD98059, a MEK kinase 1 inhibitor, failed to influence migration. This is the first evidence that suppression of Rac signaling may be involved in invasion or metastasis of glioma cells before and/or after radiotherapy. These data further suggest that radiotherapy for malignant glioma needs to be used with caution because of the potential for therapyinduced cell migration or invasion and that pharmacological inhibition of cell migration and invasion through targeting the Rac signaling pathway may represent a new approach for improving the therapeutic efficacy of radiotherapy for malignant glioma. ' 2005 Wiley-Liss, Inc.

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“…Interference with lamellipodia by the inhibition of Rac1 reduces migration. This also causes GBM cells to acquire a relatively round shape without extending cell processes (Chuang et al, 2004). In contrast, collapse of actin stress fiber formation by the inhibition of RhoA promotes migration (Salhia et al, 2005).…”

Section: Migration/invasionmentioning

confidence: 99%