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

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, such as IP10, 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.

High expression of SMPD4 promotes liver cancer and is associated with poor prognosis

“…The mouse model of colorectal cancer found that inhibiting miR-15a increased the expression of SMPD1, promoted rapid apoptosis of endothelial cells, and inhibited tumor growth. An analysis of 182 patients with CRC showed that patients with low SMPD1 [19] expression were associated with poor prognosis. Lin et al [20] found that SMPD2 expression in exosomes inhibited HCC growth by decreasing the sphingomyelin/ceramide ratio.…”

Mechanisms of microRNA action in rectal cancer radiotherapy

“…Rb overexpression has also been shown to reverse radiation resistance induced by miR-622 in vitro. [37] The results reported by Rana et al [38] suggest that the activation of acid sphingolipids (sphingomyelin phosphodiesterase 1, SMPD1) and the production of ceramides are key processes in the regulation of apoptosis in response to cellular stress, including radiation. Low expression levels of miR-15a upregulate SMPD1 levels, inducing apoptosis and increasing radiosensitivity.…”