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Sci Rep. 2019 Dec 2;9(1):18101. doi: 10.1038/s41598-019-54843-2.

OPN promotes the aggressiveness of non-small-cell lung cancer cells through the activation of the RON tyrosine kinase.

Hao C1,2,3,4, Cui Y3, Chang S1,2, Huang J1,2, Birkin E3, Hu M5, Zhi X5, Li W4, Zhang L6, Cheng S7,8, Jiang WG9,10,11.

Author information

1
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
2
Beijing Key Laboratory of Cancer & Metastasis Research, Capital Medical University, Beijing, 100069, China.
3
Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK.
4
Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
5
Department of Thoracic Surgery, Beijing Xuanwu Hospital, Capital Medical University, Beijing, China.
6
Department of Thoracic Surgery, Peking University School of Oncology and Beijing Cancer Hospital & Institute, Beijing, 100142, P.R. China.
7
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. chengs@ccmu.edu.cn.
8
Beijing Key Laboratory of Cancer & Metastasis Research, Capital Medical University, Beijing, 100069, China. chengs@ccmu.edu.cn.
9
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. jiangw@cf.ac.uk.
10
Beijing Key Laboratory of Cancer & Metastasis Research, Capital Medical University, Beijing, 100069, China. jiangw@cf.ac.uk.
11
Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK. jiangw@cf.ac.uk.

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.

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