Abstract
Lung cancer is one of the most common human cancers both in incidence and mortality, with prognosis particularly poor in metastatic cases. Metastasis in lung cancer is a multifarious process driven by a complex regulatory landscape involving many mechanisms, genes, and proteins. Membrane proteins play a crucial role in the metastatic journey both inside tumor cells and the extra-cellular matrix and are a viable area of research focus with the potential to uncover biomarkers and drug targets. In this work we performed membrane proteome analysis of highly and poorly metastatic lung cells which integrated genomic, proteomic, and transcriptional data. A total of 1,762 membrane proteins were identified, and within this set, there were 163 proteins with significant changes between the two cell lines. We applied the Tied Diffusion through Interacting Events method to integrate the differentially expressed disease-related microRNAs and functionally dys-regulated membrane protein information to further explore the role of key membrane proteins and microRNAs in multi-omics context. Has-miR-137 was revealed as a key gene involved in the activity of membrane proteins by targeting MET and PXN, affecting membrane proteins through protein–protein interaction mechanism. Furthermore, we found that the membrane proteins CDH2, EGFR, ITGA3, ITGA5, ITGB1, and CALR may have significant effect on cancer prognosis and outcomes, which were further validated in vitro. Our study provides multi-omics-based network method of integrating microRNAs and membrane proteome information, and uncovers a differential molecular signatures of highly and poorly metastatic lung cancer cells; these molecules may serve as potential targets for giant-cell lung metastasis treatment and prognosis.
Highlights
Lung cancer remains the leading cause of cancer-related mortality in the world, with an overall 5-year survival rate of 18% (Siegel et al, 2017)
We focused on has-miR-137, which was up-regulated in the highmetastatic (95D) cell line and increases invasion and metastasis of non-small cell lung cancer (NSCLC) cells (Chang et al, 2017) Four up-regulated membrane proteins, HGF, CTNNB1, ITGB1, and ITGA4, involved in focal adhesion pathway, were linked to has-miR-137 by two mediation genes – PXN and MET (Figure 2B)
High expression of CDH2 (HR = 1.2874, 95% CI: 1.0425–1.5898, p = 0.0279), epidermal growth factor receptor (EGFR) (HR = 1.2927, 95% CI: 1.0496–1.5921, p = 0.0166), ITGA3 (HR = 1.2965, 95% CI: 1.0202–1.6477, p = 0.0379), ITGB1 (HR = 1.5930, 95% CI: 1.2906–1.9663, p = 2.1922e−05), and ITGA5 (HR = 1.4656, 95% CI: 1.1836–1.8148, p = 5.8933e−04) was negatively associated with overall survival (OS) in NSCLC patients
Summary
Lung cancer remains the leading cause of cancer-related mortality in the world, with an overall 5-year survival rate of 18% (Siegel et al, 2017). In 2016, over 155,000 people died from lung cancer in the United States alone (Siegel et al, 2017). These low survival rates are partly due to the fact that over 50% of patients are diagnosed at a later stage, for which the 5-year survival is only 4%. 80–85% of lung cancer cases are non-small cell lung cancer (NSCLC), and the remaining 15–20% are small-cell lung cancer cases (Giaccone and Zucali, 2008). The prognosis is poor in metastatic cases -only ∼1% of such NSCLC patients will survive five or more years (Borghaei et al, 2017)
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