Abstract
Simple SummaryHigher neutrophil-derived cytokine lipocalin-2 (LCN2) expression possesses a versatile role in a myriad of cancers, but little is known about the role of LCN2 on osteosarcoma metastasis. In this study, we demonstrated that higher LCN2 inhibited cellular motility, migration, and invasion of osteosarcoma cells. Moreover, the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was decreased by LCN2 knockdown. Conclusively, LCN2 inhibits osteosarcoma cell metastasis by suppressing MET via the mitogen-activated protein kinases/ERK kinase (MEK)–ERK pathway.Higher neutrophil-derived cytokine lipocalin-2 (LCN2) expression possesses a versatile role in a myriad of cancers, but little is known about the role of LCN2 on osteosarcoma metastasis. In this study, we demonstrated that higher LCN2 inhibited cellular motility, migration, and invasion of osteosarcoma cells. Moreover, using RNA sequencing technology, we found that LCN2 repressed MET gene expression in U2OS cells. Manipulation of LCN2 levels influenced the migratory potential of osteosarcoma cells as cellular migration was enhanced by transfecting with vectors containing a constitutively active LCN2 cDNA and recombinant human LCN2. Moreover, the phosphorylation of mitogen-activated protein kinases/extracellular signal-regulated kinase (ERK) kinase (MEK) 1/2 and ERK 1/2 was decreased by LCN2 knockdown. Furthermore, the use of ERK inhibitor (U0126) and activator (tBHQ) confirmed that the pharmaceutic inhibition of MEK–ERK augmented the LCN2-mediated MET suppression and migration of U2OS and HOS cells. Conclusively, LCN2 inhibits osteosarcoma cell metastasis by suppressing MET via the MEK–ERK pathway.
Highlights
Cancer, associated with high mortality and disability rates, is one of the world’s largest health problems
Our results expectedly showed inconsistent LCN2 mRNA and protein expressions in different cell lines: lower LCN2 mRNA and protein expressions were observed in HOS, MG-63, and Saos-2 cells; and the highest expressions were observed in U2OS cells, which showed about 10 times more of them in HOS, MG-63, and Saos-2 cells in reverse transcription–polymerase chain reaction (RT–PCR) (Figure 1A,B)
Microculture Tetrazolium Colorimetric (MTT) assay and flow cytometry showed that overexpression of LCN2 in HOS cells and silencing of LCN2 in U2OS cells up to 6 days did not increase the incidence of apoptosis, as evidenced by the absence of significant changes in the cell cycle (Figure 1D,E)
Summary
Cancer, associated with high mortality and disability rates, is one of the world’s largest health problems. Because the high rate of metastasis is a defining feature of osteosarcoma, its metastasis rate is responsible for the great majority of treatment failures and high mortality rates. Surgical en bloc resection or amputation of the diseased limb to achieve a complete radical excision had been the most common form of treatment for most osteosarcomas prior to metastasis [3], whereas 80% of patients had pulmonary metastasis (perhaps undetectable) at the time of presentation [4,5]. The combination of surgery and chemotherapy for osteosarcoma has increased long-term survival chances to approximately 68% through limb salvaging surgeries based on radiological staging, surgical techniques, and new chemotherapy protocols [3,6]. Potent metastatic transfer to the lungs is still the main target of development of new therapeutic targets for anti-metastasis of osteosarcoma
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