Exosome-Derived microRNA: Implications in Melanoma Progression, Diagnosis and Treatment

Abstract

Melanoma is a malignant and aggressive cancer, and its progression is greatly affected by interactions between melanoma cells and their surroundings. Exploration on mechanism of melanoma and improved diagnostic and therapeutic strategies are becoming increasingly important. Unlike extracellular messengers that mainly work on targeted cells through corresponding receptors, exosomes are essential intercellular messengers that deliver biologically active substances such as nucleic acids and proteins to target cells for cell-cell communication. Of them, microRNAs (miRNAs) are common and important exosomal components that can regulate the expression of a wide range of target genes. Accordingly, exosome-derived miRNAs play a significant role in melanoma progression, including invasion and metastasis, microenvironment establishment, angiogenesis, and immune escape. MiRNA signatures of exosomes are specific in melanoma patients compared to healthy controls, thus circulating miRNAs, especially exosomal miRNAs, become potential diagnostic markers and therapeutic targets for melanoma. This review aims to summarize recent studies on the role of exosomal miRNAs in melanoma as well as ongoing efforts in melanoma treatment.

Keywords: diagnosis; exosome; melanoma; microRNA; treatment.

Figure 1

Biogenesis of exosomes. (1) Cargoes are internalized to form early endosomes. (2) Cytoplasmic compartments are sorted into ILVs to form MVBs. (3) MVBs containing exosome cargo are transported to the plasma membrane through the cytoskeleton and microtubule network. (4) MVBs are docked with the plasma membrane through SNARE and Rab GTPases. (5) ILVs are released as exosomes by exocytosis. ESCRT, endosomal sorting complex required for transport; MVBs, multivesicular bodies; ILVs, intraluminal vesicles; PM, Plasma membrane; SNARE, soluble NSF attachment protein receptors.

Figure 2

Generation of miRNAs and their sorting mechanisms. In the nucleus, miRNA is first transcribed by polymerase II to produce Pri-miRNA. The ribonuclease type III enzyme Drosha processes Pri-miRNAs to produce hairpin precursors (pre-miRNAs) composed of about 70 nucleotides. Pre-miRNA hairpins are exported to the cytoplasm by EXPORTIN5 and Rnase Ⅲ protein Dicer further works Pre-miRNA into 19–25 nt miRNA double stranded structure. The two less stable strands of the double strand are merged into a multi-protein nuclease complex, the RNA-induced silencing complex (RISC). Mature miRNAs are sorted into exosomes through five mechanisms: (1) Sphingomyelinase 2-dependent pathway. (2) miRNA motifs dependent pathway. (3) 3′-end modification of miRNA-dependent pathway. (4) Endogenous RNA-mediated pathway. (5) miRISC-related pathways. AGO: argonaute RISC catalytic component; GW182, trinucleotide repeat containing adaptor 6A; hnRNPA2B1, heterogeneous nuclear ribonucleoprotein A2/B1; miRISC, miRNA induced silencing complex; MVB, multivesicular body; ILV, intraluminal vesicle.

Figure 3

Roles of exosome-derived miRNAs in melanoma invasion and metastasis. Exosomes derived from high metastatic melanoma cells promote melanoma invasion and metastasis through delivering miRNAs into low metastatic melanoma cells to increase the invasive ability of the latter, or into the fibroblasts or the melanocytes to generate the pro-invasive surroundings.

Figure 4

Roles of exosome-derived miRNAs in melanoma microenvironment. Exosomal miRNAs generate a melanoma-friendly microenvironment through inducing fibroblasts and macrophages into cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), respectively.

Figure 5

Roles of exosome-derived miRNAs in melanoma angiogenesis. On the one side, exosome-derived miRNAs regulate melanoma microenvironment to facilitate angiogenesis through working on fibroblasts or melanoma cells. On the other sides, exosomal miRNAs from melanoma can be uptaken directly by endothelial cells to induce angiogenesis.

Figure 6

Roles of exosome-derived miRNAs in melanoma immune escape. MiRNAs derived from melanoma exosomes could suppress the abilities of CD8⁺ T cells and Th1 cells to target and attack melanoma cells, encourage the development of tumor-associated macrophages, and reduce the antitumor immunity of melanoma, all of which ultimately contribute to immune escape.