Effect of exosomal miRNA on cancer biology and clinical applications

Abstract

Exosomes, extracellular vesicles with diameters ranging from 30 to 150 nm, are widely present in various body fluids. Recently, microRNAs (miRNAs) have been identified in exosomes, the biogenesis, release, and uptake of which may involve the endosomal sorting complex required for transport (ESCRT complex) and relevant proteins. After release, exosomes are taken up by neighboring or distant cells, and the miRNAs contained within modulate such processes as interfering with tumor immunity and the microenvironment, possibly facilitating tumor growth, invasion, metastasis, angiogenesis and drug resistance. Therefore, exosomal miRNAs have a significant function in regulating cancer progression. Here, we briefly review recent findings regarding tumor-derived exosomes, including RNA sorting and delivering mechanism. We then describe the intercommunication occurring between different cells via exosomal miRNAs in tumor microenvironmnt, with impacts on tumor proliferation, vascularization, metastasis and other biological characteristics. Finally, we highlight the potential role of these molecules as biomarkers in cancer diagnosis and prognosis and tumor resistance to therapeutics.

Keywords: Angiogenesis; Biomarkers; Cancer; Exosomal miRNAs; Metastasis.

Fig. 1

The sorting mechanism of exosomal miRNA MiRNA genes are transcribed into primary miRNAs (pri-miRNA) by Pol-II. Then with the catalytic action of DGCR8 and Drosha complex, pri-RNA are transmitted into pre-miRNA, which are exported out of the nucleus by exportin5 complex. In the cytoplasm, the pre-miRNAs are digested by the Dicer complex into double-stranded miRNAs, which turn to be single-stranded ones, mature miRNAs, in the next step by Helicase. Mature miRNAs are sorted into exosomes via four potential modes: a the miRISC-related pathway; b nSMase2-dependent pathway; c miRNA motif and sumoylated hnRNPs-dependent pathway; d 3’miRNA sequence-dependent pathway. e Knockdown of Rab27 or their effectors, SYTL4 and EXPH5, could inhibit secretion of exosomes in HeLa cells. f Both the tumor repressor protein p53 and its downstream effector TSAP6 could enhance exosome production

Fig. 2

Exosomal miRNA in Cancer. a The first general mechanism is that cancer cells export exosomal miRNA to parent surrounding cancer cells. b The second general mechanism is that primary tumor cells can communicate with other cells via exosomal miRNAs in the tumor microenvironment. c The third general mechanism is that exosomes derived from normal cells alter the behavior of tumor cells. d The forth general mechanism is that exosomes derived from cells infected with virus to influencr normal cells oncology and themselves