In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3099-3099
Abstract:
Matrix metalloproteinase-9 (MMP-9) is one of the most prominent proteins associated with tumorigenesis and is a modulator of the tumor microenvironment during angiogenesis. Recently, it has been speculated that Syndecan-1, a transmembrane heparan sulfate-bearing proteoglycan, has a critical role in contributing to angiogenesis when associated with MMP-9. However, the mechanism behind their synergistic regulation is not fully understood. In the current study, we report that ionizing radiation (IR)-induced MMP-9 enhances Syndecan-1 shedding and tube-inducing ability of medulloblastoma cells. Furthermore, tumor angiogenesis is associated with higher MMP-9-Syndecan-1 interactions on both the cell surface and extracellular medium. Our results also revealed the existence of a novel regulatory mechanism where MMP-9 drives the suppression of miR-494, thereby resulting in enhanced Syndecan-1 shedding and angiogenesis. By employing bioinformatics and functional luciferase experiments, we demonstrated that 3’-UTR of Syndecan-1 mRNA is a direct target of miR-494. Moreover, from the in situ hybridization analysis, we found that MMP-9-specific shRNA (pM) treatment of mouse intracranial tumors resulted in elevated expression of miR-494. This negative correlation between MMP-9 and miR-494 levels was found to be dependent on the methylation status of the miR-494 promoter-associated CpG island region (-186 to -20), which was confirmed by bisulfite-sequencing and methylation-specific-PCR (MSP) analysis. Overall, our results demonstrate a previously unrecognized mechanism of angiogenesis regulation in medulloblastoma through which miR-494 modulates the transcription of radiation-induced angiogenesis promoting molecules and that MMP-9-Syndecan-1 activity creates a negative feedback loop by regulating the expression of miR-494. Citation Format: Swapna Asuthkar, Kiran Kumar Velpula, Christopher Gondi, Arun Kumar Nalla, Venkateswara Rao Gogineni, Jasti S. Rao. Radiation-induced angiogenesis is associated with MMP-9-miR-494-Syndecan-1 regulatory loop in medulloblastoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3099. doi:10.1158/1538-7445.AM2013-3099
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-3099
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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