Emerging role of exosomal microRNA in liver cancer in the era of precision medicine; potential and challenges

Abstract

Exosomal microRNAs (miRNAs) have great potential in the fight against hepatocellular carcinoma (HCC), the fourth most common cause of cancer-related death worldwide. In this study, we explored the various applications of these small molecules while analyzing their complex roles in tumor development, metastasis, and changes in the tumor microenvironment. We also discussed the complex interactions that exist between exosomal miRNAs and other non-coding RNAs such as circular RNAs, and show how these interactions coordinate important biochemical pathways that propel the development of HCC. The possibility of targeting exosomal miRNAs for therapeutic intervention is paramount, even beyond their mechanistic significance. We also highlighted their growing potential as cutting-edge biomarkers that could lead to tailored treatment plans by enabling early identification, precise prognosis, and real-time treatment response monitoring. This thorough analysis revealed an intricate network of exosomal miRNAs lead to HCC progression. Finally, strategies for purification and isolation of exosomes and advanced biosensing techniques for detection of exosomal miRNAs are also discussed. Overall, this comprehensive review sheds light on the complex web of exosomal miRNAs in HCC, offering valuable insights for future advancements in diagnosis, prognosis, and ultimately, improved outcomes for patients battling this deadly disease.

Keywords: cancer biomarker; exosomal miRNAs; exosomes; hepatocellular carcinoma(HCC); liver cancer; non-coding RNAs.

SCHEME 1

Pictorial representation of exosome isolation and the various roles of exosomal-miRNA. Exosomes are isolated from biological fluids or serum samples using various methods and the multiple functions of microRNA derived from exosomes have been illustrated. Created with BioRender.com.

FIGURE 1

Schematic illustration shows that exosome biogenesis in cells begins with budding to the inner side of the plasma membrane, which allows for the generation of early endosomes. Next, the endosome sorting complex protein family required for transport (ESCRT) promotes the formation of late endosomes that collect various microparticles and apoptotic contents, including nucleic acids, proteins, and lipids, ultimately leading to the formation of multivesicular bodies (MVBs). Finally, MVBs amalgamate with the plasma membrane to form exosomes, which are secreted into the extracellular environment by exocytosis. Adapted from Dai et al., 2020 with copyright permission under the terms of the CC-BY-NC-ND 4.0 license.

FIGURE 2

Schematic sketch of signaling pathways linked to carbohydrate and lipid metabolism. The orange arrows depict the part of the pathway that builds glucose and plasma triacylglycerol from the byproducts of the tricarboxylic acid cycle (TCA) and the glycolytic cycle. Some of the representative miRNAs that play vital roles in the metabolism of carbohydrates and lipids are highlighted in green color. Adapted from Paul et al., 2021 with copyright permission, Elsevier.

FIGURE 3

Overview of the role of microRNA (e.g., MiR-223) in normal liver physiology and pathobiology. Adapted from Ye et al., 2018, with copyright permission under the terms of the CC-BY-NC-ND 4.0 license.

FIGURE 4

Overview of the potential therapeutic application of exosomes for cancer diagnostics and treatment. Adapted from Syn et al., 2017, with copyright permission, Elsevier. (A) Targeted drug delivery approches. (B) Immunotheraputic apprachs.