Abstract
Lung cancer (LC) causes the majority of cancer-related deaths. Circular RNAs (circRNAs) were reported to play roles in cancers by targeting pro- and anti-oncogenic miRNAs. However, the mechanisms of circRNAs in LC progression and their prognostic value of treatment response remain unclear. By using next generation sequencing (NGS) of LC cell lines’ transcriptomes, we identified highly overexpressed hsa_circ_0000190 and hsa_circ_000164 as potential biomarkers. By using the highly sensitive RT-ddPCR method, these circRNAs were shown to be secreted by cell lines and were detected in human blood. Clinical validation by RT-ddPCR was carried out on 272 (231 LC patients and 41 controls) blood samples. Higher hsa_circ_0000190 levels were associated with larger tumor size (p < 0.0001), worse histological type of adenocarcinoma (p = 0.0028), later stage (p < 0.0001), more distant metastatic organs (p = 0.0039), extrathoracic metastasis (p = 0.0004), and poor survival (p = 0.047) and prognosis. Using liquid biopsy-based RT-ddPCR, we discovered the correlation between increased hsa_circ_0000190 plasma level (p < 0.0001) and higher programmed death-ligand 1 (PD-L1) level in tumor (p = 0.0283). Notably, long-term follow-up of the immunotherapy treated cases showed that upregulated plasma hsa_circ_0000190 level correlated with poor response to systemic therapy and immunotherapy (p = 0.0002, 0.0058, respectively). Secretory circRNAs are detectable in blood by LB-based RT-ddPCR and may serve as blood-based biomarkers to monitor disease progression and treatment efficacy.
Highlights
Introduction85% of Lung cancer (LC) cases belong to non-small-cell lung carcinoma (NSCLC) [1]
Lung cancer (LC) is the leading cause of cancer-related deaths throughout the world, and more than85% of LC cases belong to non-small-cell lung carcinoma (NSCLC) [1]
Increasing evidence has revealed that specific circRNAs, such as circRNA 100876 and hsa_circ_0013958, are upregulated in LC tissue comparing to adjacent normal tissue, little is known about the secreted circRNAs in patients’ peripheral blood [27,28]
Summary
85% of LC cases belong to non-small-cell lung carcinoma (NSCLC) [1]. The development of targeted therapies has led to significant improvement in the treatment efficacy for NSCLC, but the survival rate for advanced NSCLC still remains dismal [2]. The development of superior diagnostic and therapeutic approaches is critical for better understanding of the molecular pathogenesis of LC. Such advancements can contribute to the discovery of novel biomarkers for cancer detection and molecular treatment targets for LC, as well as more personalized treatment of LC patients
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