Interplay between VEGF-A and cMET signaling in human vestibular schwannomas and schwann cells

Dilwali, Sonam; Roberts, Daniel S.; Stanković, Konstantina M.

doi:10.4161/15384047.2014.972765

Cited by 33 publications

(39 citation statements)

References 15 publications

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“…In recent years, bevacizumab VEGF-A antagonists have been safely used in human alone or with chemotherapy combined [37]. Another previous study was found the interaction between VEGF-A and c-Met signaling in human Schwann cells and vestibular schwannomas [38], which consistent our study. Therefore, we hypothesized that VEGF-A is one of the miR-4316 target genes.…”

Section: Discussionsupporting

confidence: 91%

MicroRNA-4316 inhibits gastric cancer proliferation and migration via directly targeting VEGF-A

et al. 2020

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Background and aims: microRNAs (miRNAs) have been reported to regulate proliferation and migration by downregulating the expression of target genes. The aims of this study were to investigate whether miR-4316 inhibited proliferation and migration by downregulating vascular endothelial growth factor A (VEGF-A) and its clinical significance in gastric cancer (GC). Methods: The clinical tissues of the GC patients for miR-4316 and VEGF-A were detected by qRT-PCR. The protein levels of VEGF-A and c-Met were determined by western blotting. Cell Proliferation, migration, and colony forming assays were conducted to show whether miR-4316 affects proliferation by CCK-8, migration by transwell, wound healing and colony formation assays. The bioinformatic methods and luciferase reporter assay were applied to detect the relationship between miRNA and VEGF-A on its targeting 3-untranslated regions (3-UTRs). CCK-8, colony formation, wound healing, and transwell assay were performed to explore the function of miR-4316. Results: The results of qRT-PCR indicated that miR-4316 expression level was significantly downregulated in human GC tissues and GC cell lines compared with their control. miR-4316 inhibited proliferation, migration and colony formation in GC cell lines by reducing VEGF-A. And western blot results indicated that miR-4316 significantly inhibited GC through repressing VEGF-A and c-Met. The investigation of Luciferase assay indicated that VEGF-A is a direct target gene of miR-4316. Conclusions: miR-4316 suppressed proliferation and migration of GC through the VEGF-A gene. MiR-4316 acts as a tumor suppressor by targeting VEGF-A and this indicated that MiR-4316 might be a potential therapeutic target for GC.

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Section: Discussionsupporting

confidence: 91%

MicroRNA-4316 inhibits gastric cancer proliferation and migration via directly targeting VEGF-A

et al. 2020

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“…We also investigated the mechanisms of miR-1-mediated tumor suppression in VS. VEGFA is a key regulator of angiogenesis and exerts important effects on tumor growth and metastasis (Carmeliet, 2005). Previous study has revealed that VEGFA signaling is aberrantly up-regulated in VS (Cayé-Thomasen et al, 2005;Koutsimpelas et al, 2012), and knockdown of VEGFA decreases proliferation in primary human VS cell cultures (Dilwali et al, 2015). In our study, raised miR-1 expression in HEI-193 cells reduced VEGFA protein levels, and a dual-luciferase reporter assay showed that miR-1 directly bound the 3'-UTR of VEGFA.…”

Section: Discussionsupporting

confidence: 57%

“…Current treatment modalities include microsurgical removal and stereotactic radiosurgery, but complications from such interventions are not uncommon (Arthurs et al, 2011). Recently, several genes and pathways associated with VS, including NF2 (Chen et al, 2014), vascular endothelial growth factor A (VEGFA; Koutsimpelas et al, 2012;Dilwali et al, 2015), and PI3K/AKT (Jacob et al, 2008), have been identified. However, the molecular events involved in the development of this condition are not well understood.…”

Section: Introductionmentioning

confidence: 99%

miR-1 association with cell proliferation inhibition and apoptosis in vestibular schwannoma by targeting VEGFA

et al. 2016

Genet. Mol. Res.

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A growing body of research has demonstrated the tumor suppressive function of microRNA (miR)-1 in many cancers. Our study aimed to investigate its role in vestibular schwannoma (VS). We examined miR-1 expression in 95 VS specimens and 79 normal vestibular nerves using quantitative real-time polymerase chain reaction. Moreover, miR-1 mimics, miR-1 inhibitors, and negative control oligonucleotides were transfected into HEI-193 human VS cells to investigate the functional significance of miR-1 expression in this condition at a cellular level. Finally, the role of vascular endothelial growth factor A (VEGFA) in miR-1-mediated HEI-193 cell growth was confirmed. miR-1 levels were significantly reduced in VS specimens compared with normal vestibular nerve tissues (P < 0.001). In addition, low levels of miR-1 were associated with larger tumor volumes. In functional assays, miR-1 suppressed HEI-193 cell proliferation and colony formation, and enhanced apoptosis. VEGFA was verified as a target gene of miR-1, and VEGFA overexpression partially negated the effects of miR-1 on HEI-193 cells. These findings suggest that miR-1 suppresses VS growth by targeting VEGFA, and should be considered as a potential therapeutic target for treatment of this condition.

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“…cMET activation can directly induce tumor angiogenesis by promoting endothelial cell proliferation, migration, and survival (38). Recent studies in VS cells also reported cross-talk between HGF/cMET and VEGF pathways: cMET targeting decreases VEGF and VEGF receptor 2 expression, while VEGF inhibition reduces cMET expression (21,39,40). However, in our animal studies, cMET blockade did not change VEGF expression; consequently, cMET blockade did not affect vessel density, perfusion, or tumor oxygenation.…”

Section: Discussioncontrasting

confidence: 44%

“…More importantly, increasing evidence implicates cMET as a major mechanism of resistance to chemotherapy, RT, and targeted therapies (16)(17)(18). In human sporadic VSs, the expression of cMET has been detected (19,20), and it has been found to be elevated in comparison to normal nerve tissues (21). However, whether cMET and HGF expression and activation correlate with schwannoma progression is not known.…”

Section: Significancementioning

confidence: 99%

Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models

Zhao

Liu

Zhang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Neurofibromatosis type II (NF2) is a disease that needs new solutions. Vestibular schwannoma (VS) growth causes progressive hearing loss, and the standard treatment, including surgery and radiotherapy, can further damage the nerve. There is an urgent need to identify an adjunct therapy that, by enhancing the efficacy of radiation, can help lower the radiation dose and preserve hearing. The mechanisms underlying deafness in NF2 are still unclear. One of the major limitations in studying tumor-induced hearing loss is the lack of mouse models that allow hearing testing. Here, we developed a cerebellopontine angle (CPA) schwannoma model that faithfully recapitulates the tumor-induced hearing loss. Using this model, we discovered that cMET blockade by crizotinib (CRZ) enhanced schwannoma radiosensitivity by enhancing DNA damage, and CRZ treatment combined with low-dose radiation was as effective as high-dose radiation. CRZ treatment had no adverse effect on hearing; however, it did not affect tumor-induced hearing loss, presumably because cMET blockade did not change tumor hepatocyte growth factor (HGF) levels. This cMET gene knockdown study independently confirmed the role of the cMET pathway in mediating the effect of CRZ. Furthermore, we evaluated the translational potential of cMET blockade in human schwannomas. We found that human NF2-associated and sporadic VSs showed significantly elevated HGF expression and cMET activation compared with normal nerves, which correlated with tumor growth and cyst formation. Using organoid brain slice culture, cMET blockade inhibited the growth of patient-derived schwannomas. Our findings provide the rationale and necessary data for the clinical translation of combined cMET blockade with radiation therapy in patients with NF2.

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Interplay between VEGF-A and cMET signaling in human vestibular schwannomas and schwann cells

Cited by 33 publications

References 15 publications

MicroRNA-4316 inhibits gastric cancer proliferation and migration via directly targeting VEGF-A

MicroRNA-4316 inhibits gastric cancer proliferation and migration via directly targeting VEGF-A

miR-1 association with cell proliferation inhibition and apoptosis in vestibular schwannoma by targeting VEGFA

Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models

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