Abstract
Osteosarcoma, a common aggressive and malignant cancer, appears in the musculoskeletal system among young adults. The major cause of mortality in osteosarcoma was the recurrence of lung metastases. However, the molecular mechanisms of metastasis involved in osteosarcomas remain unclear. Recently, CXCL1 and CXCR2 have been crucial indicators for lung metastasis in osteosarcoma by paracrine releases, suggesting the involvement of directing neutrophils into tumor microenvironment. In this study, overexpression of CXCL1 has a positive correlation with the migratory and invasive activities in osteosarcoma cell lines. Furthermore, the signaling pathway, CXCR2/FAK/PI3K/Akt, is activated through CXCL1 by promoting vascular cell adhesion molecule 1 (VCAM-1) via upregulation of nuclear factor-kappa B (NF-κB) expression and nuclear translocation. The in vivo animal model further demonstrated that CXCL1 serves as a critical promoter in osteosarcoma metastasis to the lung. The correlated expression of CXCL1 and VCAM-1 was observed in the immunohistochemistry staining from human osteosarcoma specimens. Our findings demonstrate the cascade mechanism regulating the network in lung metastasis osteosarcoma, therefore indicating that the CXCL1/CXCR2 pathway is a worthwhile candidate to further develop treatment schemas.
Highlights
Among all bone malignancy diagnoses with children and young adults, osteosarcoma is the most common primary and aggressive malignant neoplasm [1, 2]
The current study showed that the CXCL1 could signal the CXCR2/focal adhesion kinase (FAK)/phosphatidylinositol-3kinase (PI3K)/Akt/nuclear factor-kappa B (NF-kB) pathway to increase vascular cell adhesion molecule 1 (VCAM-1) expression and subsequently upregulate the metastasis ability of human osteosarcoma cells
CXCL1-enhanced VCAM-1 protein levels could be suppressed by pretreating respective pathway inhibitors (Figures 4G–I). These findings indicated that CXCL1-triggered cell migration and VCAM-1 expression were regulated through the FAK/PI3K/Akt/NF-kB pathway in osteosarcoma cells
Summary
Among all bone malignancy diagnoses with children and young adults, osteosarcoma is the most common primary and aggressive malignant neoplasm [1, 2]. CXCL1 secretion could enhance the invasion and metastasis of several types of cancer cells [22,23,24,25]; in contrast, silencing or knockdown of CXCL1 could inhibit tumor growth in hepatocellular carcinoma [26] and colorectal cancer liver metastasis [27]. These studies conspicuously indicate that CXCL1 is a crucial indicator in the progress of cancer invasion and metastasis. The role and related mechanisms of CXCL1 in osteosarcoma remain unclear
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