Exosomal microRNAs as Biomarkers and Therapeutic Targets for Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second most common cause of cancer-related death globally. This type of liver cancer is frequently detected at a late stage by current biomarkers because of the high clinical and biological heterogeneity of HCC tumours. From a plethora of molecules and cellular compounds, small nanoparticles with an endosomal origin are valuable cancer biomarkers or cargos for novel treatments. Despite their small sizes, in the range of 40-150 nm, these particles are delimited by a lipid bilayer membrane with a specific lipid composition and carry functional information-RNA, proteins, miRNAs, long non-coding RNAs (lncRNAs), or DNA fragments. This review summarizes the role of exosomal microRNA (miRNA) species as biomarkers in HCC therapy. After we briefly introduce the exosome biogenesis and the methods of isolation and characterization, we discuss miRNA's correlation with the diagnosis and prognosis of HCC, either as single miRNA species, or as specific panels with greater clinical impact. We also review the role of exosomal miRNAs in the tumourigenic process and in the cell communication pathways through the delivery of cargos, including proteins or specific drugs.

Keywords: exosomes; hepatocellular carcinoma; miRNA.

Figure 1

Extracellular vesicles’ biogenesis, transport, and membrane fusion. The first stage, membrane budding, integrates receptors that are transferred into early endosomes. MVB formation (stage 2) and sorting take place in the late exosome. Detailed ESCRT-dependent and ESCRT-independent pathways are presented in insets. MVBs are transported via microtubules and motor proteins, and fuse with the cellular membrane using SNARE, synaptotagmin proteins, and actin filaments. The pathway proposed for miRNA sorting using sumoylated HnNPA2b1 protein is also illustrated.

Figure 2

Roles of exosomal miRNAs in HCC progression. HCC cells secrete exosomes and affect proliferation by transferring miR-744, miR-21, and miR-26a into neighbouring cells. Angiogenesis is stimulated by miR-210, which blocks the SMAD4 and STAT6 pathways, while apoptosis is activated by miR-31 and miR-451. Inhibition of GNMT by miR-224 promotes the proliferation and invasion of HCC cells. miR-155 secretion increases under hypoxic conditions.