Emerging function and clinical significance of extracellular vesicle noncoding RNAs in lung cancer

Abstract

Lung cancer (LC) is a commonly diagnosed cancer with an unsatisfactory prognosis. Extracellular vesicles (EVs) are lipid bilayer-delimited particles that mediate cell-cell communication by transporting various biomacromolecules, such as nucleic acids, proteins, and lipids. Noncoding RNAs (ncRNAs), including microRNAs, circular RNAs, and long noncoding RNAs, are important noncoding transcripts that play critical roles in a variety of physiological and pathological processes, especially in cancer. ncRNAs have been verified to be packaged into EVs and transported between LC cells and stromal cells, regulating multiple LC malignant phenotypes, such as proliferation, migration, invasion, epithelial-mesenchymal transition, metastasis, and treatment resistance. Additionally, EVs can be detected in various body fluids and are associated with the stage, grade, and metastasis of LC. Herein, we summarize the biological characteristics and functions of EV ncRNAs in the biological processes of LC, focusing on their potential to serve as diagnostic and prognostic biomarkers of LC as well as their probable role in the clinical treatment of LC. EV ncRNAs provide a new perspective for understanding the mechanism underlying LC pathogenesis and development, which might benefit numerous LC patients in the future.

Keywords: clinical values; extracellular vesicle; lung cancer progression; noncoding RNA; prospective biomarkers.

Graphical abstract

Figure 1

Biology of EV ncRNAs (A) The biogenesis of ncRNAs and EVs. miRNA genes are transcribed into pri-miRNAs by RNA polymerase II (Pol II), and further cleaved by Drosha and DGCR8 to generate pre-miRNAs. After exporting into cytoplasm, pre-miRNAs are cleaved by Dicer to produce a miRNA duplex. Then the miRNA duplex loads on AGO. One strand of the duplex is selectively anchored into the AGO to form the RISC complex, thereby regulating the expression of target mRNA. circRNAs get their closed loop structures through back-splicing in nucleus. circRNAs are composed of extrons and/or introns depending on the methods of lariat-driven circularization, intron-pairing-driven circularization, and intron cyclization. lncRNA genes are transcribed through the mediation of Pol I/II to form lnc-pri-miRNAs, and are processed by RNase P/H to generate mature lncRNAs and pre-miRNAs. Mature ncRNAs are then sorted into MVBs. The MVBs are finally released as EVs in a Rab27b-dependent manner, or transported into lysosomes for degradation. (B) EVs can be internalized by recipient cells in different ways, such as phagocytosis, membrane fusion, clathrin-dependent endocytosis, caveolae-mediated endocytosis, and micropinocytosis. Once entering the recipient cells, EV ncRNAs exert their biological functions by acting as miRNA sponges, protein baits, protein scaffolds, and encoding proteins.

Figure 2

The participation of EV ncRNAs in lung cancer biology EV ncRNAs play important roles in lung cancer progression, such as cell proliferation, invasion, and migration (A), EMT and metastasis (B), angiogenesis (C), and treatment resistance (D).