Abstract
BackgroundExtracellular vesicles (EVs) play important roles in intercellular communication through the delivery of their cargoes, which include proteins, lipids, and RNAs. Increasingly, multiple studies have reported the association between EV small non-coding RNAs and cancer, due to their regulatory functions in gene expression. Hence, analysis of the features of small non-coding RNA expression and their incorporation into EVs is important for cancer research.ResultsWe performed deep sequencing to investigate the expression of small RNAs in plasma EVs from lung adenocarcinoma (ADC) patients, lung squamous cell carcinoma (SQCC) patients, and healthy controls. Then, eighteen differently expressed miRNAs in plasma EVs was validated by QRT-PCR. The small RNA expression profiles of plasma EVs were different among lung ADC, SQCC patients, and healthy controls. And many small RNAs, including 5′ YRNA hY4-derived fragments, miR-451a, miR-122-5p, miR-20a-5p, miR-20b-5p, miR-30b-5p, and miR-665, were significantly upregulated in non-small cell lung cancer (NSCLC) EVs. And the cell viability assays indicated that hY4-derived fragments inhibited the proliferation of lung cancer cell A549. By comparing the cellular and EV expression levels of six miRNAs in NSCLC cells, we found that miR-451a and miR-122-5p were significantly downregulated in NSCLC cell lysates, while significantly upregulated in NSCLC EVs.ConclusionsThe differently expressed EV small RNAs may serve as potential circulating biomarkers for the diagnosis of NSCLC. Particularly, YRNA hY4-derived fragments can serve as a novel class of biomarkers, which function as tumor suppressors in NSCLC. Additionally, miR-451a and miR-122-5p may be sorted into NSCLC EVs in a selective manner.
Highlights
Extracellular vesicles (EVs) play important roles in intercellular communication through the delivery of their cargoes, which include proteins, lipids, and RNAs
We found no significant difference in small nucleolar RNA (snoRNA) fragments at the major peak or minor peak (18–24 nt), but the RPM of the CTRL group was slightly higher than ADC and squamous cell carcinoma (SQCC) at 30–42 nt hY4 RNA fragments are upregulated in non-small cell lung cancer (NSCLC) EVs and inhibit NSCLC cell proliferation To investigate the specific types and sequences of YRNA fragments that are upregulated in NSCLC plasma EVs, we analyzed the distribution of corresponding genes from the human genome (Fig. 4a–c)
We found that expression of miR-451a and miR-122-5p was significantly downregulated in NSCLC cell lysates, while significantly upregulated in NSCLC EVs, indicating that miR-451a and miR-122-5p may be selectively sorted into NSCLC EVs
Summary
Extracellular vesicles (EVs) play important roles in intercellular communication through the delivery of their cargoes, which include proteins, lipids, and RNAs. Increasingly, multiple studies have reported the association between EV small non-coding RNAs and cancer, due to their regulatory functions in gene expression. Analysis of the features of small non-coding RNA expression and their incorporation into EVs is important for cancer research. Extracellular vesicles (EVs) are membrane surrounded structures released by cells, and contain complex cargoes including nucleic acid, protein, and lipids [1]. Among the many types of molecules carried in exosomes, small RNAs, especially miRNAs, have attracted the most attention due to their roles in gene expression regulation. It has increasingly become clear that non-coding RNAs can be sorted into exosomes, protected from RNase degradation, and internalized by neighboring or distant cells, where they subsequently modulate cellular processes [8]
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