ISSN: 1449-2288International Journal of Biological Sciences
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Int J Biol Sci 2024; 20(3):880-896. doi:10.7150/ijbs.90817 This issue Cite
Research Paper
Nε-(1-Carboxymethyl)-L-lysine/RAGE Signaling Drives Metastasis and Cancer Stemness through ERK/NFκB axis in Osteosarcoma
1. Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
2. Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
3. Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
4. Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
5. Department of Orthopedics, National Taiwan University Hospital, Taipei, Taiwan.
6. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
7. Department of Pediatrics, College of Medicine, National Taiwan University & Hospital, Taipei, Taiwan.
* These authors contributed equally to this study.
# These authors contributed equally to this study.
Abstract
Osteosarcoma is an extremely aggressive bone cancer with poor prognosis. Nε-(1-Carboxymethyl)-L-lysine (CML), an advanced glycation end product (AGE), can link to cancer progression, tumorigenesis and metastasis, although the underlying mechanism remains unclear. The role of CML in osteosarcoma progression is still unclear. We hypothesized that CML could promote migration, invasion, and stemness in osteosarcoma cells. CML and its receptor (RAGE; receptor for AGE) were higher expressed at advanced stages in human osteosarcoma tissues. In mouse models, which streptozotocin was administered to induce CML accumulation in the body, the subcutaneous tumor growth was not affected, but the tumor metastasis using tail vein injection model was enhanced. In cell models (MG63 and U2OS cells), CML enhanced tumor sphere formation and acquisition of cancer stem cell characteristics, induced migration and invasion abilities, as well as triggered the epithelial-mesenchymal transition process, which were associated with RAGE expression and activation of downstream signaling pathways, especially the ERK/NFκB pathway. RAGE inhibition elicited CML-induced cell migration, invasion, and stemness through RAGE-mediated ERK/NFκB pathway. These results revealed a crucial role for CML in driving stemness and metastasis in osteosarcoma. These findings uncover a potential CML/RAGE connection and mechanism to osteosarcoma progression and set the stage for further investigation.
Keywords: osteosarcoma, Nε-(1-Carboxymethyl)-L-lysine, cancer stemness, metastasis
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