Exosomal Non-Coding RNAs: Regulatory and Therapeutic Target of Hepatocellular Carcinoma

Abstract

Exosomes are small extracellular vesicles secreted by most somatic cells, which can carry a variety of biologically active substances to participate in intercellular communication and regulate the pathophysiological process of recipient cells. Recent studies have confirmed that non-coding RNAs (ncRNAs) carried by tumor cell/non-tumor cell-derived exosomes have the function of regulating the cancerous derivation of target cells and remodeling the tumor microenvironment (TME). In addition, due to the unique low immunogenicity and high stability, exosomes can be used as natural vehicles for the delivery of therapeutic ncRNAs in vivo. This article aims to review the potential regulatory mechanism and the therapeutic value of exosomal ncRNAs in hepatocellular carcinoma (HCC), in order to provide promising targets for early diagnosis and precise therapy of HCC.

Keywords: early diagnosis; exosomes; hepatocellular carcinoma; non-coding RNAs; precise therapy; tumor microenvironment.

Figure 1

Exosome biogenesis within endosomal system. Early endosomes are formed by the fusion of endocytic vesicles, further transformed into late endosomes/MVBs through inward budding of the membrane (packing the cargo into ILVs). ILVs protein sorting has two methods, ESCRT-dependent and ESCRT-independent. ESCRT-0, ESCRT-I, ESCRT-II and ESCRT-III are the four components of the ESCRT. They generalize the substrate on the inwardly budding endosomal membrane. Subsequently, a part of MVBs is fused with lysosomes to be degraded, while another part of MVBs can be fused with the plasma membrane to release ILVs into the extracellular space, now called exosomes. In addition, Rab27A and Rab27B are important mediators leading MVBs to the periphery of cells, and the SNARE complex helps MVBs fuse with the plasma membrane.

Figure 2

Interaction network between exosomal ncRNAs and tumor microenvironment of HCC. Tumor cell/non-tumor cell-derived exosomes regulate the malignant biological behaviors of HCC through targeted cargo transportation. 1) Angiogenesis: upregulated lnc MALAT1, miR-638, EIF3C, circ100338 promote the angiogenesis in tumor microenvironment and HCC cell proliferation/blood-metastasis. 2) Drug resistance: upregulated miR-32-5p and lnc H19 are involved in mediating the drug resistance of HCC cells. 3) Metabolic reprogramming: upregulated c-Myc and circFBLIM1 induce aerobic glycolysis (Warburg Effect) of HCC cells. Upregulated miR-23 and circ-DB promote the transformation of fat cells into tumor-associated tumor cells (CAAs). 4) Immune escape: upregulated lnc TUC339 induces the repolarization of macrophages from M1 to M2, and the upregulation of miR-23a-3p can promote PD-L1/PD1 binding and induce T cell apoptosis.