NEDD9, a novel target of miR-145, increases the invasiveness of glioblastoma

Speranza, Maria C.; Frattini, Véronique; Pisati, Federica; Kapetis, Dimos; Porrati, Paola; Eoli, Marica; Pellegatta, Serena; Finocchiaro, Gaetano

doi:10.18632/oncotarget.547

Cited by 80 publications

(61 citation statements)

References 44 publications

(58 reference statements)

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“…Related to this, a recent study showed that higher-level NEDD9 in lower-grade glioma tumors is associated with reduced progression-free survival (12). In agreement with this, analysis of REMBRANDT data presented here demonstrated an association between NEDD9 expression and survival when all glioma tumors were grouped together.…”

Section: Discussionsupporting

confidence: 90%

“…For example, one such classification scheme defines cells as proneural, proliferative, and mesenchymal, with corresponding increase in aggressiveness (30). Potentially, NEDD9 expression may prove to be more prominent in one of these subclasses, particularly given recent reports suggesting a correlation between NEDD9 and nestin expression in glioma (12). We observed a striking inverse relationship between NEDD9 expression and patient survival in the subset of neuroblastomas that lack N-myc amplification.…”

Section: Discussionmentioning

confidence: 58%

“…Uniquely among the Cas family proteins, NEDD9 was required for the invasion of U87MG glioblastoma cells through brain homogenates (11). NEDD9 is elevated in high-grade glioma cells and high-level expression in low-grade glioma correlated with significantly poorer prognosis and increased invasion (12). In contrast, the morphologic regulation of invasive neuroblastoma is comparatively less well defined.…”

Section: Introductionmentioning

confidence: 99%

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NEDD9 Regulates 3D Migratory Activity Independent of the Rac1 Morphology Switch in Glioma and Neuroblastoma

Zhong

Bach

Shum

et al. 2014

Molecular Cancer Research

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Metastasizing tumor cells must transmigrate the dense extracellular matrix that surrounds most organs. The use of three-dimensional (3D) collagen gels has revealed that many cancer cells can switch between different modes of invasion that are characterized by distinct morphologies (e.g., rounded vs. elongated). The adhesion protein NEDD9 has the potential to regulate the switch between elongated and rounded morphologies; therefore, its role was interrogated in the invasion switch of glioblastoma and neuroblastoma tumors that similarly derive from populations of neural crest cells. Interestingly, siRNA-mediated depletion of NEDD9 failed to induce cell rounding in glioma or neuroblastoma cells, contrasting the effects that have been described in other tumor model systems. Given that Rac1 GTPase has been suggested to mediate the switch between elongated and rounded invasion, the functionality of the Rac1 morphology switch was evaluated in the glioma and neuroblastoma cells. Using both dominant-negative Rac1 and Rac1-specific siRNA, the presence of this morphologic switch was confirmed in the neuroblastoma, but not in the glioma cells. However, in the absence of a morphologic change following NEDD9 depletion, a significant decrease in the cellular migration rate was observed. Thus, the data reveal that NEDD9 can regulate 3D migration speed independent of the Rac1 morphology switch.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

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NEDD9 Regulates 3D Migratory Activity Independent of the Rac1 Morphology Switch in Glioma and Neuroblastoma

Zhong

Bach

Shum

et al. 2014

Molecular Cancer Research

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“…Despite indications that several miRNAs, including miR-20a, miR-199a-3p, miR-143 and so forth, are involved in the development and progression of OS (8)(9)(10), their exact role remains largely unknown. Previously, miR-145 was identified as a tumor-suppressive miRNA in multiple types of cancers, including lung, glioma, ovarian, colon, gastric, bladder, prostate and breast cancer, as well as in OS (11)(12)(13)(14)(15)(16)(17). However, the detailed regulatory mechanism underlying the effects of miR-145 in OS cells remains unclear.…”

Section: Introductionmentioning

confidence: 99%

microRNA-145 inhibits osteosarcoma cell proliferation and invasion by targeting ROCK1

Lei

Xie

Wang

et al. 2014

Molecular Medicine Reports

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Abstract. Osteosarcoma (OS), a malignant mesenchymal sarcoma, is the most frequent primary bone tumor, with a peak incidence in young children and adolescents. The downregulation of microRNA-145 (miRNA/miR-145) has previously been identified to be associated with the aggressiveness and metastasis of OS. However, the detailed regulatory mechanism by which miR-145 inhibits OS remains largely unknown. The present study demonstrated that miR-145 was significantly downregulated in OS tissues and KHOS and U2OS cell lines. Rho-associated protein kinase 1 (ROCK1), a key regulator of actin cytoskeleton reorganization, was identified as a novel target of miR-145. Ectopic expression of miR-145 notably suppressed the protein expression of ROCK1 without affecting its mRNA level. Furthermore, the expression of ROCK1 was significantly increased in the OS tissues and in the KHOS and U2OS cells. It was further demonstrated that the overexpression of miR-145 downregulated KHOS and U2OS cell proliferation and invasion, which was reversed by restoration of ROCK1. To the best of our knowledge, the present study demonstrates for the first time that, as a tumor suppressor, miRNA-145 inhibits OS cell proliferation and invasion, at least in part by directly targeting ROCK1. These results indicate that miR-145 may be a potential candidate for the diagnosis and treatment of OS. IntroductionOsteosarcoma (OS) mainly arises from the metaphysis of the long bones of adolescents and young adults. OS is the most common primary malignant tumor and is associated with high morbidity (1). Despite wide tumor excision combining multi-agent chemotherapy and radiotherapy, the five-year survival rate of patients with recurrent or metastatic OS remains at ~30% (2). Although recent studies have focused on the molecular pathogenesis of OS (3), its detailed molecular mechanisms have not been fully elucidated. As a result, the identification of novel molecular candidates and/or targets is crucial for the development of effective therapeutic strategies to improve the prognosis of OS.microRNAs (miRNA/miRs) are small non-coding RNA molecules with 18-25 nucleotides, which mainly negatively regulate gene expression by suppressing translation via binding to the 3' untranslated region (3'UTR) of their target genes (4). Previously, miRNAs have been demonstrated to have crucial roles in various physiological and pathological processes, including the development and progression of malignant tumors (5). In fact, it has been demonstrated that miRNAs function as oncogenes or tumor suppressors in cellular proliferation, apoptosis, differentiation, migration and invasion in various cancer cells (6,7). Despite indications that several miRNAs, including miR-20a, miR-199a-3p, miR-143 and so forth, are involved in the development and progression of OS (8-10), their exact role remains largely unknown. Previously, miR-145 was identified as a tumor-suppressive miRNA in multiple types of cancers, including lung, glioma, ovarian, colon, gastric, bladder, prostate and breast cancer, ...

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“…MiR-145 has been shown to be involved in the control of cell proliferation and apoptosis, stem cell differentiation and neural development. MiR-145 has been deemed a tumor-suppressive gene, as demonstrated by the observation that miR-145 expression is significantly lower in a variety of human cancers, including breast cancer, colon cancer, hepatocellular carcinoma, lung cancer, prostate cancer and ovary carcinomas [12][13][14][15][16][17][18][19][20]. MiR-145 acts as a tumor inhibitor by inhibiting the expression of many oncogenic genes.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-145 Suppresses Osteosarcoma Metastasis via Targeting MMP16

Chen

Huang

Zhang

et al. 2015

Cell Physiol Biochem

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Background: Metastasis is a leading cause of mortality for osteosarcoma (OS) patients, and its molecular pathological mechanisms remain to be elucidated. Previous studies have suggested a significant role of microRNAs (miRNAs) in the control of cancel cell migration and invasion. Methods: Real-time PCR was used to screen the differentially expressed miRNAs between OS with or without metastasis, and miR-145 underexpression was observed in metastatic OS. Luciferase assay was performed to validate the target gene. Results: Further, we identified three genes, MMP16, ADAM17 and metadherin, as possible targets of miR-145. We identified MMP16 as a target gene of miR-145 and ruled out ADAM17 and metadherin as targets in OS using a dual luciferase reporter system. Subsequently, we determined and compared the expression level of MMP16 in human OS samples and showed that the mRNA and protein levels of MMP16 were significantly up-regulated in primary OS with metastasis compared with those without metastasis. We also altered miR-145 expression by transfecting OS cells with miR-145 mimics or inhibitors. MMP16 expression was similarly downregulated in the cells transfected with miR-145 mimics or MMP16-specific siRNA, and the invasive and migratory capability of those cells was significantly suppressed compared with negative controls. MMP16 expression was consistently significantly upregulated in the cells transfected with miR-145 inhibitors, and the invasive and migratory capability of those cells was significantly promoted compared with negative controls. Conclcusion: Our results suggest that miR-145 functions as a tumor metastasis suppressor gene by down-regulating MMP16 and may be a potential target in osteosarcoma treatment.

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NEDD9, a novel target of miR-145, increases the invasiveness of glioblastoma

Cited by 80 publications

References 44 publications

NEDD9 Regulates 3D Migratory Activity Independent of the Rac1 Morphology Switch in Glioma and Neuroblastoma

NEDD9 Regulates 3D Migratory Activity Independent of the Rac1 Morphology Switch in Glioma and Neuroblastoma

microRNA-145 inhibits osteosarcoma cell proliferation and invasion by targeting ROCK1

MicroRNA-145 Suppresses Osteosarcoma Metastasis via Targeting MMP16

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