Exosomes Derived from Pancreatic Cancer Cells Induce Osteoclast Differentiation Through the miR125a-5p/TNFRSF1B Pathway

Yizhao Zhou,1,2,* Yi Zhu,1,2,* Xin Dong,1,2,* Guodong Cao,1,2 Yongzhou Li,1,2 Yiqun Fan,3 Qing Chen,1,2 Haolei Cai,1,2 Yulian Wu1,2 1Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Surgery, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yulian WuDepartment of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, People’s Republic of ChinaTel/Fax +86-571-87784604Email yulianwu@zju.edu.cnBackground: 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