Insights about exosomal circular RNAs as novel biomarkers and therapeutic targets for hepatocellular carcinoma

Abstract

One of the most prevalent pathological types of Primary Liver Cancer (PLC) is the Hepatocellular Carcinoma (HCC) poses a global health issue. The high recurrence and metastasis rate of HCC, coupled with a low 5-year survival rate, result in a bleak prognosis. Exosomes, small extracellular vesicles released by various cells, contain diverse non-coding RNA molecules, including circular RNAs (circRNAs), which play a significant role in intercellular communication and can impact HCC progression. Studies have revealed the potential clinical applications of exosomal circRNAs as biomarkers and therapeutic targets for HCC. These circRNAs can be transferred via exosomes to nearby non-cancerous cells, thereby regulating HCC progression and influencing malignant phenotypes, such as cell proliferation, invasion, metastasis, and drug resistance. This review provides a comprehensive overview of the identified exosomal circRNAs, highlighting their potential as non-invasive biomarkers for HCC, and suggesting new perspectives for HCC diagnosis and treatment. The circRNA from exosomal organelles promotes metastasis and immune scape because of their unique chirality which is different from the Biomolecular Homochirality.

Keywords: biomarker; cancer therapy; circRNA; exosomes; hepatocellular carcinoma.

FIGURE 1

The biogenesis of exosomes and the function of circRNAs in HCC. The cytoplasmic membrane internalizes extracellular components through endocytosis, forming early endosomes. During endosome maturation, they are classified as intraluminal vesicles (ILV) within the endosome. The endosomal membrane further folds to form multivesicular bodies (MVB) that contain ILVs. Selectively or passively, various cellular contents such as RNA (including mRNA, circRNA, and other ncRNAs), DNA, and lipids are integrated into the vesicles. Subsequently, MVBs can either fuse with lysosomes for degradation or merge with the plasma membrane to release the ILVs, now called exosomes, into the extracellular fluid, where they perform their physiological functions. Exosomal circRNAs play an important role in tumour development. CircRNAs regulate the transcription of HCC target genes by acting as a microRNA sponges to impair microRNA function and protect target mRNAs from degradation. CircRNAs also bind to RNA-binding proteins (RBPs) to regulate the expression of relevant genes. CircRNAs interact with proteins to affect their structure and activity. Some circRNAs contain an internal ribosome entry site (IRES) element, in which the AUG site serves as a template for coding peptides or proteins.

FIGURE 2

The regulatory role of exosomal circRNAs in HCC. CircRNAs are delivered by exosomes from donor cells to recipient cells, and affect the progression of HCC by competitively binding miRNAs and acting on downstream target genes. Exosomal circRNAs are involved in mediating the malignant phenotype of HCC, such as immune evasion (A), angiogenesis (B), HCC cell proliferation and metastasis (C), metabolism (D), and drug resistance (E).