Radiation suppresses liver metastases via exosome secretion in pancreatic cancer cells.

Abstract

Pancreatic cancer (PC) is difficult to treat because of its radio-resistance and metastases. Radiotherapy modifies the tumor microenvironment (TME) and affects PC progression. Exosomes are produced in response to radiation, but their nature and mechanisms of action are unclear. We investigated how exosomes from irradiated PC cells (IR-Exo) regulated metastasis both in vitro and in vivo. We isolated exosomes from three human PC cell lines: MIAPaCa-2, BxPC3, and Panc-1. The uptake of IR-Exo by irradiated PC cells decreased the migration and invasion capacities of all PC cell lines in vitro. Additionally, IR-Exos prevented liver metastasis induced by MIAPaCa-2 cells in vivo We detected 2,565 miRNAs in exosomes in a microarray. Seventeen of these genes were differentially expressed between the exosomes isolated from non-irradiated cells (0 Gy-Cells) and IR-Exo. miR-3160-5p was the most upregulated miRNA in IR-Exo. Transfection of miR-3160-5p into PC cells decreased cell migration and invasion. Furthermore, expression of Repulsive Guidance Molecule BMP Co-Receptor B (RGMB), a target molecule of miR-3160-5p, was significantly decreased by the addition of miR-3160-5p. Knockdown of RGMB expression significantly prevented cell migration and invasion. Thus, irradiation increases exosomal miR-3160-5p expression and inhibits cell migration and invasion via a decrease in RGMB expression. This points toward new treatment targets or biomarkers.