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Differential regulation of microRNA-15a by radiation affects angiogenesis and tumor growth via modulation of acid sphingomyelinase

Authors
  • Rana, Shushan1
  • Espinosa-Diez, Cristina2
  • Ruhl, Rebecca2
  • Chatterjee, Namita2
  • Hudson, Clayton2
  • Fraile-Bethencourt, Eugenia2
  • Agarwal, Anupriya2, 3
  • Khou, Sokchea2
  • Thomas, Charles R. Jr.1
  • Anand, Sudarshan1, 2
  • 1 Department of Radiation Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA , Portland (United States)
  • 2 Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA , Portland (United States)
  • 3 Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA , Portland (United States)
Type
Published Article
Journal
Scientific Reports
Publisher
Springer Nature
Publication Date
Mar 27, 2020
Volume
10
Issue
1
Identifiers
DOI: 10.1038/s41598-020-62621-8
Source
Springer Nature
License
Green

Abstract

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.

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