Exosomes derived from pancreatic cancer cells induce osteoclast differentiation through the mir125a-5p/tnfrsf1b pathway

Abstract

Background: Pancreatic cancer (PC) was regarded as the 4th principal cause of cancer-related fatalities in the United States and patients usually suffered from severe nutrition deficiency, muscle wasting, as well as bone loss. In our previous research, we have found that PC-derived exosomes potentially initiate insulin resistance in skeletal muscle cells. However, the role of exosomes in the PC-related bone loss remains unknown. Methods: The effect of PC-derived exosomes on the osteoclast differentiation and femoral bone structure in the orthotopic xenograft mouse model were investigated. MiRNA expression profiles were detected and a dual luciferase experiment was conducted to identify the direct target of miRNA. Results: Our data showed that PC-derived exosomes significantly induced osteoclast differentiation and increased expression of NFAT2, TRAP, CTSK and MMP-9. The bone volume fraction and trabecular thickness of femur significantly reduced in osteoporotic model. Microarray analyses and luciferase reporter assay showed that the process was, at least partially, mediated by the miR-125a-5p/TNFRSF1B signaling pathways. Conclusion: According to the results, novel insights have been claimed the effect of exosomes derived from PC on bone deterioration and explained correlation between PC and cancer-related bone loss.