Abstract
ObjectAt present, there are few effective treatment options available to patients suffering from osteosarcoma (OS). Clarifying the signaling pathways that govern OS oncogenesis may highlight novel approaches to treating this deadly form of cancer. Recent experimental evidence suggests that the transmembrane protein tetraspanin-9 (Tspan9) plays a role in tumor development. This study was thus formulated to assess the molecular role of Tspan9 as a regulator of OS cell metastasis.MethodsGene expression in OS cell lines was evaluated via qRT-PCR, while CCK-8, colony formation, Transwell, and wound healing assays were used to explore the in vitro proliferative, invasive, and migratory activities of OS cells. The relationship between Tspan9 and in vivo OS cell metastasis was assessed by injecting these cells into the tail vein of nude mice. Interactions between the Tspan9 and integrin β1 proteins were explored through mass spectrometric and co-immunoprecipitation, and Western blotting to assess the functional mechanisms whereby Tspan9 shapes OS pathogenesis.ResultsBoth primary OS tumors and OS cell lines commonly exhibited Tspan9 upregulation, and the knockdown of this tetraspanin suppressed the migration, invasion, and epithelial-mesenchymal transition (EMT) activity in OS cells, whereas Tspan9 overexpression resulted in opposite phenotypes. Tumor lung metastasis were significantly impaired in mice implanted with HOS cells in which Tspan9 was downregulated as compared to mice implanted with control HOS cells. Tspan9 was also found to interact with β1 integrin and to contribute to OS metastasis via the amplification of integrin-mediated downstream FAK/Ras/ERK1/2 signaling pathway.ConclusionThese data suggest that Tspan9 can serve as a promising therapeutic target in OS.
Highlights
Osteosarcoma (OS) is the most prevalent form of primary bone malignancy affecting children and adolescences, most commonly manifesting in the epiphyseal region of the proximal tibia and distal femur [1]
Both primary OS tumors and OS cell lines commonly exhibited Tspan9 upregulation, and the knockdown of this tetraspanin suppressed the migration, invasion, and epithelial-mesenchymal transition (EMT) activity in OS cells, whereas Tspan9 overexpression resulted in opposite phenotypes
Tumor lung metastasis were significantly impaired in mice implanted with HOS cells in which Tspan9 was downregulated as compared to mice implanted with control HOS cells
Summary
Osteosarcoma (OS) is the most prevalent form of primary bone malignancy affecting children and adolescences, most commonly manifesting in the epiphyseal region of the proximal tibia and distal femur [1]. No biomarkers or therapeutic targets specific for OS have been identified or leveraged in a clinical context, and there is a clear need to further explore the molecular mechanisms governing OS pathogenesis and metastasis in order to design more effective treatments capable of prolonging the survival of affected patients. 33 human tetraspanins have been identified and found to be expressed in most tissues, including Tspan, CD63, CD82, and CD151 [7]. These tetraspanins can bind with surface proteins and other molecules at the plasma membrane in tetraspanin-enriched membrane microdomains (TEMs). Receptor molecules, and other signaling intermediaries, tetraspanins can activate downstream signaling to control key physiological processes including apoptosis, adhesion, differentiation, oncogenesis, and metastatic tumor progression [8–10]
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