Abstract
Circulating microRNAs carried by exosomes have emerged as promising diagnostic biomarkers for cancer because of their abundant amount and remarkable stability in body fluids. Exosomal microRNAs in blood are typically quantified using the RNA isolation-qRT-PCR workflow, which cannot distinguish circulating microRNAs secreted by cancer cells from those released by non-tumor cells, making it potentially less sensitive in detecting cancer-specific microRNA biomarkers. We have developed a sensitive and simple tethered cationic lipoplex nanoparticles (tCLN) biochip to detect exosomal microRNAs in human sera. The tCLN biochip allows the discrimination of tumor-derived exosomes from their non-tumor counterparts, and thus achieves higher detection sensitivity and specificity than qRT-PCR. We have demonstrated the clinical utility of the tCLN biochip in lung cancer diagnosis using sera from normal controls, therapy-naive early stage and late stage non-small cell lung cancer (NSCLC) patients. Total five microRNAs (miR-21, miR-25, miR-155, miR-210, and miR-486) were selected as the biomarkers. Each microRNA biomarker measured by tCLN assay showed higher sensitivity and specificity in lung cancer detection than that measured by qRT-PCR. When all five microRNAs were combined, the tCLN assay distinguished normal controls from all NSCLC patients with sensitivity of 0.969, specificity of 0.933 and AUC of 0.970, and provided much better diagnostic accuracy than qRT-PCR (sensitivity = 0.469, specificity = 1.000, AUC = 0.791). Remarkably, the tCLN assay achieved absolute sensitivity and specificity in discriminating early stage NSCLC patients from normal controls, demonstrating its great potential as a liquid biopsy assay for lung cancer early detection.
Highlights
Lung cancer is the leading cause of cancer death in the United States
We have further evaluated the diagnostic performance of the tethered cationic lipoplex nanoparticles (tCLN) biochip using a relative large number of non-small cell lung cancer (NSCLC) patients and normal controls
No significant difference was observed in the size and number concentration of exosomes between normal controls and NSCLC patients (Supplementary Figure S1b)
Summary
Lung cancer is the leading cause of cancer death in the United States. The 5 year survival rate is ∼55% for early stage lung cancer but only 5% for late stage lung cancer, reflecting the urgent need for effective screening and early detection methods (Siegel et al, 2019). Exosomes carry many molecular cargos including microRNAs, mRNAs, DNA fragments and proteins from cells of origin (Kalluri, 2016; Xu et al, 2018). Exosomes, especially those released by tumor cells, are actively involved in cancer development, metastasis and drug resistance (Kalluri, 2016; Whiteside, 2016; Xu et al, 2018). A panel of circulating microRNAs including miR-21, miR-223, miR-155, and miR-126 were identified as potent biomarkers for lung cancer in a recent meta-analysis study involving 6919 lung cancer patients and 7064 controls (Yang et al, 2017)
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