Abstract
Osteopontin (OPN) is identified as a diagnostic and prognostic biomarker of tumor progression and metastasis. In non-small-cell lung cancer (NSCLC), the functions of OPN have not been well characterized. The current study sought to investigate the clinical implications of OPN expression in NSCLC and the role of OPN in the aggressiveness of the lung cancer cells. Using a proteomics approach, we identified that phospho-RON (p-RON) was one of the most remarkably up-regulated proteins in OPN-overexpressing cells. The levels of OPN and RON transcripts were unveiled as independent prognostic indicators of survival in NSCLC (p = 0.001). Higher levels of OPN, RON and p-RON proteins were observed in tumor tissues. Knock down of the OPN gene suppressed the migration and invasion abilities of the A549 lung cancer cells which endogenously expresses OPN. While ectopic expression of OPN in the SK-MES-1 lung cancer cells increased levels of cellular invasion and migration. In addition, these changes were accompanied by a phosphorylated activation of RON. Small-molecule inhibition of RON or siRNA silencing of RON significantly reduced OPN-induced migration and invasion of lung cancer cells and had an inhibitory effect on the OPN-mediated cell epithelial-mesenchymal transition. Our study suggests that in NSCLC, the aberrant expression of OPN can be considered as an independent survival indicator and is associated with disease progression. OPN plays a crucial role in promoting migration and invasion properties of lung cancer cells through its phosphorylation activation of the RON signaling pathway, implying its potential as a therapeutic target in the treatment of NSCLC.
Highlights
Lung cancer is one of the most prevalent and lethal cancers worldwide
By IHC, our data indicated that higher levels of OPN, Recepteur d’Origine Nantais (RON) and p-RON (Y1238 + Y1239) were expressed in the non-small-cell lung cancer (NSCLC) tissues compared with the paired adjacent normal tissues (p < 0.01, respectively) (Fig. 1c)
RON and p-RON were mainly located on lung epithelial cell membranes and cytoplasm in adjacent normal tissues, while in cancer tissues, their expressions were mainly detected in the cytoplasm of lung cancer cells
Summary
Lung cancer is one of the most prevalent and lethal cancers worldwide. Non-small-cell lung cancer (NSCLC) accounts for approximately 80–90% of all lung cancer[1]. Aberrant expression of RON is associated with tumor stage, poor prognosis and invasiveness in many cancer types[22]. Recent studies indicate that RON may be a potent biomarker of tumor progression, metastasis and prognosis[31]. We examined the in vitro biological functions of OPN in human lung cancer cell lines (namely A549 and SK-MES-1) after gene knockdown and ectopic expression, respectively. Our protein microarray analysis data established the link between OPN expression and the activation of RON in lung cancer cells, which led us to further investigate the combined prognostic value of RON and the regulation of RON signaling pathways by OPN in the aggressiveness of NSCLC cells
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