Abstract
Lung cancer remains the leading cause of cancer-related death worldwide. Recently, extracellular vesicles such as exosomes have attracted considerable interest both as a source for theranostic biomarkers and an essential participant in lung cancer progression. However, how specific exosomal cargos, such as noncoding RNAs, are selectively packaged into exosomes and promote lung cancer progression remains unclear. In this study, we identified miR-665 as the most elevated exosomal miRNA from both non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) patients. We further demonstrated that lncRNA SCIRT was also increased in cancer cell exosomes and may facilitate the exosomal loading of miR-665 with the help of hnRNPA1. As a consequence, exosomal miR-665 promoted lung cancer cell invasion and migration by targeting Notch downstream transcription factor HEYL. In addition, we found that miR-665 and SCIRT were significantly upregulated in tumor tissue and plasma of patients with lung cancer, and both of them showed increased expression in metastatic disease samples. Our findings suggest that the exosomal transferring of miR-665 and SCIRT is a functional and mechanism-driven pathway that contributes to cancer progression and, thus, may provide novel diagnostic and therapeutic targets for lung cancer.
Highlights
Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related mortality among both men and women worldwide [1]
The aberrant expression of exosomal miRNAs is considered to be tightly involved in the pathogenesis of cancer, including metastasis, how specific miRNA species modulating intercellular communications in tumor microenvironment (TME) is still largely unknown
We identified miR-665 as the most highly expressed miRNAs in malignant pleural effusions (MPEs)-derived exosomes from both nonsmall-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) patients
Summary
Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related mortality among both men and women worldwide [1]. Great progress has been made in the management of lung cancer, such as EGFR tyrosine kinase inhibitors and ALK inhibitors, the prognosis of the disease remains poor owing to the presence of distant metastasis in more than half of the patients at the time of diagnosis [2]. The underlying mechanisms of the complex interplay between cancer cells and TME, especially cell-tocell communications, are still not fully understood. Accumulated evidence shows that cancer-derived exosomes can facilitate the reprogramming and intercellular communications in TME by transferring specific molecules [4, 5]. Among the molecular components carried in exosomes, microRNAs have attracted great attention due to their critical roles in cancer-related gene regulation and signal pathways. It has been reported that many exosomal miRNAs (exo-miRNAs) are associated with lung cancer metastasis [6,7,8]. Zhang et al [9] demonstrated that exosomal miR-193a-3p, miR-210-3p, and miR-5100
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