SPARC overexpression combined with radiation retards angiogenesis by suppressing VEGF-A via miR‑410 in human neuroblastoma cells
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Published on: February 17, 2019
Jerusha Boyineni1, Smita Tanpure1, Manu Gnanamony1
1Department of Internal Medicine, University of Illinois College of Medicine, Peoria, IL 61605, USA.
Abstract:
Neuroblastoma (NB) is the most common extra-cranial solid tumor in children and despite aggressive therapy survival rates remain low. One of the contributing factors for low survival rates is aggressive tumor angiogenesis, which is known to increase due to radiation, one of the standard therapies for neuroblastoma. Therefore, targeting tumor angiogenesis can be a viable add-on therapy for the treatment of neuroblastomas. In the present study, we demonstrate that overexpression of secreted protein acidic and rich in cysteine (SPARC) suppresses radiation induced angiogenesis in SK-N‑BE(2) and NB1691 neuroblastoma cells. We observed that overexpression of SPARC in SK-N-BE(2) and NB1691 cells reduced radiation induced angiogenesis in an in vivo mouse dorsal skin model and an ex vivo chicken CAM (chorioallantoic-membrane) model and also reduced tumor size in subcutaneous mouse tumor models of NB. We also observed that SPARC overexpression reduces VEGF-A expression, in SK-N-BE(2) and NB1691 NB cells via miR-410, a VEGF-A targeting microRNA. SPARC overexpression alone or in combination with miR-410 and radiation was shown to be effective at reducing angiogenesis. Moreover, addition of miR-410 inhibitors reversed SPARC mediated inhibition of VEGF-A in NB1691 cells but not in SK-N-BE(2) NB cells. In conclusion, the present study demonstrates that the overexpression of SPARC in combination with radiation reduced tumor angiogenesis by downregulating VEGF-A via miR-410.
Insights
Secreted protein acidic and rich in cysteine (SPARC) overexpression suppresses radiation-induced tumor angiogenesis in neuroblastoma. This approach, targeting VEGF-A via miR-410, offers a potential new therapy for this common childhood cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Neuroblastoma (NB) is a common pediatric cancer with low survival rates, partly due to aggressive tumor angiogenesis.
- Radiation therapy, a standard NB treatment, can paradoxically enhance tumor angiogenesis.
- Targeting tumor angiogenesis presents a potential strategy to improve NB treatment outcomes.
Purpose of the Study:
- To investigate the role of secreted protein acidic and rich in cysteine (SPARC) in suppressing radiation-induced angiogenesis in neuroblastoma.
- To elucidate the molecular mechanisms by which SPARC affects angiogenesis, including its interaction with VEGF-A and miR-410.
- To evaluate the therapeutic potential of SPARC overexpression, alone or in combination with radiation and miR-410 modulation, for neuroblastoma treatment.
Main Methods:
- Overexpression of SPARC in SK-N-BE(2) and NB1691 neuroblastoma cell lines.
- Assessment of radiation-induced angiogenesis using in vivo mouse dorsal skin and ex vivo chicken CAM models.
- Tumor size evaluation in subcutaneous mouse tumor models.
- Analysis of VEGF-A and miR-410 expression levels.
- Inhibition of miR-410 to assess its role in SPARC-mediated effects.
Main Results:
- SPARC overexpression significantly suppressed radiation-induced angiogenesis in both in vitro and in vivo models.
- SPARC overexpression reduced tumor size in neuroblastoma mouse models.
- SPARC overexpression led to decreased VEGF-A expression, mediated by miR-410.
- Combined SPARC overexpression with miR-410 and radiation demonstrated efficacy in reducing angiogenesis.
Conclusions:
- SPARC overexpression is a potent suppressor of radiation-induced angiogenesis in neuroblastoma.
- The mechanism involves the downregulation of VEGF-A through the miR-410 pathway.
- SPARC, in combination with radiation and potentially miR-410 modulation, represents a promising therapeutic strategy for neuroblastoma.
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