RT info:eu-repo/semantics/article
T1 Differential regulation of microRNA-15a by radiation affects angiogenesis and tumor growth via modulation of acid sphingomyelinase
A1 Rana, Shushan
A1 Espinosa Diez, Cristina
A1 Ruhl, Rebecca
A1 Chatterjee, Namita
A1 Hudson, Clayton
A1 Fraile Bethencourt, María Eugenia
A1 Agarwal, Anupriya
A1 Khou, Sokchea
A1 Thomas, Charles R.
A1 Anand, Sudarshan
K1 MicroRNA
K1 Angiogénesis
K1 Esfingomielinasa ácida
K1 24 Ciencias de la Vida
AB 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.
PB Nature Research
SN 2045-2322
YR 2020
FD 2020
LK https://uvadoc.uva.es/handle/10324/47411
UL https://uvadoc.uva.es/handle/10324/47411
LA eng
NO Scientific Reports, 2020, vol. 10, n. 1
NO Producción Científica
DS UVaDOC
RD 27-dic-2024