2024-03-28T23:55:03Zhttps://uvadoc.uva.es/oai/requestoai:uvadoc.uva.es:10324/474112022-07-18T09:32:46Zcom_10324_1134com_10324_931com_10324_894col_10324_1213
Differential regulation of microRNA-15a by radiation affects angiogenesis and tumor growth via modulation of acid sphingomyelinase
Rana, Shushan
Espinosa Diez, Cristina
Ruhl, Rebecca
Chatterjee, Namita
Hudson, Clayton
Fraile Bethencourt, María Eugenia
Agarwal, Anupriya
Khou, Sokchea
Thomas, Charles R.
Anand, Sudarshan
MicroRNA
Angiogénesis
Esfingomielinasa ácida
24 Ciencias de la Vida
Producción Científica
Activation of acid sphingomyelinase (SMPD1) and the generation of ceramide is a critical regulator of apoptosis in response to cellular stress including radiation. Endothelial SMPD1 has been shown to regulate tumor responses to radiation therapy. We show here that the SMPD1 gene is regulated by a microRNA (miR), miR-15a, in endothelial cells (ECs). Standard low dose radiation (2 Gy) upregulates miR-15a and decreases SMPD1 levels. In contrast, high dose radiation (10 Gy and above) decreases miR-15a and increases SMPD1. Ectopic expression of miR-15a decreases both mRNA and protein levels of SMPD1. Mimicking the effects of high dose radiation with a miR-15a inhibitor decreases cell proliferation and increases active Caspase-3 & 7. Mechanistically, inhibition of miR-15a increases inflammatory cytokines, activates caspase-1 inflammasome and increases Gasdermin D, an effector of pyroptosis. Importantly, both systemic and vascular-targeted delivery of miR-15a inhibitor decreases angiogenesis and tumor growth in a CT26 murine colorectal carcinoma model. Taken together, our findings highlight a novel role for miR mediated regulation of SMPD1 during radiation responses and establish proof-of-concept that this pathway can be targeted with a miR inhibitor.
This work was supported by US NIH (grant R01HL137779 and R01HL143803) to S.A
ASTRO (Grant ID 534775)
2021-07-14T10:59:13Z
2021-07-14T10:59:13Z
2020
info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
Scientific Reports, 2020, vol. 10, n. 1
2045-2322
https://uvadoc.uva.es/handle/10324/47411
10.1038/s41598-020-62621-8
1
Scientific Reports
10
2045-2322
eng
https://www.nature.com/articles/s41598-020-62621-8
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by-nc-nd/4.0/
© Nature Research
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Nature Research
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http://creativecommons.org/licenses/by-nc-nd/4.0/
UVaDOC. Repositorio Documental de la Universidad de Valladolid
https://uvadoc.uva.es/handle/10324/47411