Role of Exosomal Noncoding RNAs in Lung Carcinogenesis

Lung cancer is the major cause of cancer death worldwide. Novel, recently discovered classes of noncoding RNAs (ncRNAs) have diverse functional and regulatory activities and increasing evidence suggests crucial roles for deregulated ncRNAs in the onset and progression of cancer, including lung cancer. Exosomes are small extracellular membrane vesicles of endocytic origin that are released by many cells and are found in most body fluids. Tumor-derived exosomes mediate tumorigenesis by facilitating tumor growth and metastasis. MicroRNAs (miRNAs) are a subclass of ncRNAs that are present in exosomes. miRNAs are taken up by neighboring or distant cells and modulate various functions of recipient cells. Here, the authors review exosome-derived ncRNAs with a focus on miRNAs and their role in lung cancer biology.

Potential modes for sorting of miRNAs into exosomes: (1) Mature miRNAs can interact with assembly proteins to form a complex called miRISC, which includes target miRNA, miRNA-repressible mRNA, GW182 protein, and miRNA effector protein argonaute 2 (AGO2, which was initially identified as membrane associated). Active miRISCs are recruited into GW-bodies that are physically associated with MVBs and this may represent a method of loading miRNAs into exosomes. (2) The protein hnRNP specifically binds to the 3′ regions of miRNA sequences and controls their loading into exosomes. (3) 3′-end adenylated miRNAs directly sort into EVs. miRNAs release as exosomes and uptake by recipient cell: (a) MVBs are released by exocytosis and fuse with the plasma membrane leading to the release of exosomes. (b) EVs uptake by recipient cells through phagocytosis.