1. School of Medicine, China Medical University, Taichung, Taiwan.
2. Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan.
3. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
4. Department of Medical Education and Research, China Medical University Beigang Hospital, Yunlin, Taiwan.
5. Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan.
6. Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan.
7. Department of Orthopaedic Surgery, China Medical University Beigang Hospital, Yunlin, Taiwan.
8. Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
9. Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
10. Ph.D. Program for Cancer Molecular Biology and Drug Discovery, and Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
11. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
12. Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.
#Equal contributions to this work.
Osteosarcoma is a highly mortal bone tumor, with a high metastatic potential, promoted in part by the enzyme procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2). Increasing level of PLOD2 in osteosarcoma tissue correlates with lymphatic and distant metastasis. The adipokine apelin (APLN) is also found in different cancers and APLN upregulation promotes angiogenesis and metastasis, but its effects on osteosarcoma metastasis are uncertain. We explored APLN functioning in metastatic osteosarcoma. An analysis of records from the Gene Expression Omnibus (GEO) database showed higher levels of APLN expression in osteosarcoma tissue than in normal tissue. Similarly, levels of APLN and PLOD2 mRNA synthesis were upregulated in osteosarcoma tissue. Levels of APLN and PLOD2 protein correlated positively with osteosarcoma clinical stages. APLN increased PLOD2 expression in human osteosarcoma cell lines and cell migration via the mammalian Sterile 20-like kinase 1 (MST1), monopolar spindle-one-binder protein (MOB)1, and YAP cascades, and through hsa_circ_0000004 functioning as a sponge of miR-1303. We also found that knockdown of APLN antagonized lung metastasis in mice with osteosarcoma. APLN may be a therapeutic target in osteosarcoma metastasis.
Keywords: Apelin, PLOD2, metastasis, osteosarcoma