Abstract
MicroRNA contribute to tumor radiation resistance, which is an important clinical problem, and thus we are interested in identifying and characterizing their function. We demonstrate that miR-620 contributes to radiation resistance in cancer cells by increasing proliferation, and decreasing the G2/M block. We identify the hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (HPGD/15-PGDH) tumor suppressor gene as a direct miR-620 target, which results in increased prostaglandin E2 (PGE2) levels. Furthermore, we show that siRNA targeting of HPGD or administration of exogenous PGE2 recapitulates radioresistance. Targeting of the EP2 receptor that responds to PGE2 using pharmacological or genetic approaches, abrogates radioresistance. Tumor xenograft experiments confirm that miR-620 increases proliferation and tumor radioresistance in vivo. Regulation of PGE2 levels via targeting of HPGD by miR-620 is an innovative manner by which a microRNA can induce radiation resistance.
Highlights
Over 50% of cancer patients will receive radiotherapy as part of their treatment
MiR are an integral contributor to tumor radiation response, and elucidation of their function is essential to understanding this clinical problem
We provide novel evidence that miR-620 can promote radiation resistance in a range of cancer cells, including those that are inherently more radioresistant
Summary
Despite delivery of a radical course of radiotherapy, tumor recurrences can occur, due to cellular mediators that promote radiation resistance [1], and this, in turn, can result in a more aggressive phenotype including increased proliferative capacity, nodal metastases, and poor prognosis [2,3,4]. To address this important clinical problem, a better understanding of the molecular mediators of resistance is required. A single miR may exhibit pleotropic effects due to regulation of multiple target mRNA Their expression is known to be dysregulated in malignancies, and they are believed to contribute towards the pathogenesis of cancer [5]. Dicer and Drosha, which are essential enzymes involved in processing miR, are known to be involved in activation of the DNA damage response (DDR) [9], further supporting the importance of miR in mediating cellular response to ionizing radiation. miR have been demonstrated to regulate radiosensitivity through targeting essential components of the DDR such as www.impactjournals.com/oncotarget
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