Abstract
Non-small-cell lung cancer (NSCLC) constitutes approximately 80% of all diagnosed lung cancers, and diagnostic markers detectable in the plasma/serum of NSCLC patients are greatly needed. In this study, we established a pipeline for the discovery of markers using 9 transcriptome datasets from publicly available databases and profiling of six lung cancer cell secretomes. Thirty-one out of 312 proteins that overlapped between two-fold differentially expressed genes and identified cell secretome proteins were detected in the pooled plasma of lung cancer patients. To quantify the candidates in the serum of NSCLC patients, multiple-reaction-monitoring mass spectrometry (MRM-MS) was performed for five candidate biomarkers. Finally, two potential biomarkers (BCHE and GPx3; AUC = 0.713 and 0.673, respectively) and one two-marker panel generated by logistic regression (BCHE/GPx3; AUC = 0.773) were identified. A validation test was performed by ELISA to evaluate the reproducibility of GPx3 and BCHE expression in an independent set of samples (BCHE and GPx3; AUC = 0.630 and 0.759, respectively, BCHE/GPx3 panel; AUC = 0.788). Collectively, these results demonstrate the feasibility of using our pipeline for marker discovery and our MRM-MS platform for verifying potential biomarkers of human diseases.
Highlights
The up-regulated genes in cancer tissues were involved in protein binding, small molecule binding, carbohydrate derivative binding and transferase activity, while the down-regulated genes were concerned with protein binding, carbohydrate derivative binding, receptor activity, macromolecular complex binding and signaling receptor activity (Fig 2B)
The up-regulated genes were primarily compartmentalized in the cell and organelle parts and some were in the extracellular region, while the down-regulated genes were in the extracellular region and membrane part (Fig 2C)
Quantitative information on the differential gene expressions of tumor tissues and normal tissues were merged with cancer cell secretome data and patient’s plasma proteome data
Summary
Owing to its high metastatic potential and high mortality rate, lung cancer is one of the leading causes of cancer-related deaths worldwide and is broadly divided into two classes, small cell. Many have searched for potential NSCLC markers using various biological specimens, including cell lines, tissues, and serum/plasma at the discovery stage [2, 4,5,6,7,8,9]. We hypothesized that if some proteins show quantitative changes in cancer tissues compared to normal tissues and are present in the cell secretome, there would be a better chance of detecting those proteins in plasma/serum We challenged this hypothesis with NSCLC integrative tissue transcriptomes and cell secretomes, and the resulting candidates were verified using MRM-MS and ELISA to measure the concentrations of candidate proteins in plasma.
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