Exosomal miRNAs in hepatocellular carcinoma development and clinical responses

Abstract

Hepatocellular carcinoma remains the sixth most lethal malignancy in the world. While HCC is often diagnosed via current biomarkers at a late stage, early detection of HCC has proven to be very difficult. Recent studies have focused on using exosomal miRNAs in clinical diagnostics and therapeutics, because they have improved stability in exosomes than as free miRNAs themselves. Exosomal miRNAs act through novel mechanisms for inducing cellular responses in a variety of biological circumstances. Dysregulated expression of miRNAs in exosomes can also accelerate HCC progression, including cell proliferation and metastasis, via alteration of a network of genes. Growing evidence demonstrates that exosomal miRNAs can affect many aspects of physiological and pathological conditions in HCC and indicates that miRNAs in exosomes can not only serve as sensitive biomarkers for cancer diagnostics and recurrence but can also potentially be used as therapeutics to target HCC progression. In this review, we summarize the latest findings between exosomal miRNAs and HCC, in order to better comprehend the functions and applications in HCC. Moreover, we discuss critical issues to consider when developing anti-tumor exosomal miRNAs as a novel therapeutic strategy for treating HCC in the clinic.

Keywords: Diagnosis; Exosome; Hepatocellular carcinoma; miRNAs.

Fig. 1

Exosomal miR-122 from adipose tissue-derived mesenchymal stem cells (AMSCs) could inhibit the proliferation of recipient HepG2 cells and enhance HCC chemosensitivity in vivo. This diagram shows the experimental platform that has been tested using HepG2 cells to modulate their sensitivity to chemotherapeutics

Fig. 2

The process of miRNA-mediated treatment envisioned for future application in HCC patients. Based on experimental data generated using cell lines, a comparable approach for engineering exosomes containing miRNA cocktails can be tailored to the patient-specific needs. This approach has many technical hurdles to overcome but has great promise as future therapy for HCC with fewer side effects. Selecting and culturing appropriate cells to produce enough exosomes is a first priority. Second, endogenous and exogenous packaging of desired miRNAs into exosomes is important. The former would need to be done by transfecting miRNA over-expressing vectors into donor cells, while the latter would require transferring miRNA mimics into isolated exosomes or via electroporation. Transporting exosomes to the liver by intra-venous delivery or direct intra-tumoral injection is also a major objective