Non-Coding RNAs as Potential Diagnostic/Prognostic Markers for Hepatocellular Carcinoma

Abstract

The increasing incidence of hepatocellular carcinoma (HCC), together with the poor effectiveness of the available treatments, make early diagnosis and effective screening of utmost relevance. Liquid biopsy represents a potential novel approach to early HCC detection and monitoring. The identification of blood markers has many desirable features, including the absence of any significant risk for the patients, the possibility of being used as a screening tool, and the ability to perform multiple tests, thus allowing for the real-time monitoring of HCC evolution. Unfortunately, the available blood markers for HCC have several limitations, mostly related to specificity and sensitivity. In this context, employing non-coding RNAs (ncRNAs) may represent an interesting and novel diagnostic approach. ncRNAs, which include, among others, micro interfering RNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), regulate human gene expression via interactions with their target mRNA. Notably, their expression can be altered in HCC, thus reflecting disease status. In this review, we discuss some notable works that describe the use of miRNAs, lncRNAs, and circRNAs as HCC biomarkers. Despite some open aspects related to ncRNA use, the presented works strongly support the potential effectiveness of these molecules as diagnostic/prognostic markers for HCC.

Keywords: circRNA; diagnosis; hepatocellular carcinoma; lncRNA; miRNA; prognosis.

Figure 1

miRNA biogenesis and functions. In the cell nucleus, a long precursor named pri-miRNA is processed by the enzyme Drosha to pre-miRNA; this, in turn, is exported to the cytoplasm by the Exportin 5 enzyme. Here, the DICER enzyme produces double-stranded mature RNA (miRNA). The miRNA antisense strand is then loaded onto RISC, allowing for the recognition of the target mRNA, resulting in translation inhibition (via an imperfect base pairing) or mRNA degradation (via perfect base pairing). Recent findings indicate that via direct/indirect mechanisms, miRNA can also promote gene expression. This figure was created with BioRender.com (accessed on 23 September 2024).

Figure 2

LncRNA biogenesis and functions. LncRNAs can be spliced, capped, and poly-adenylated. Following transcription, they assume a three-dimensional (3D) structure responsible for the biological effects, such as the recruitment of transcription activators/repressors to the promoters of their target genes, thus regulating gene expression; the inhibition of miRNA activity via the sponging effect; and the ability to act as scaffolds for protein to support the formation of protein complexes. This figure was created with BioRender.com (accessed on 23 September 2024).

Figure 3

CircRNA biogenesis and functions. Although circRNAs have multiple biogenesis mechanisms, a common one is represented by back-splicing. Back-splicing can be induced by protein-dimerization, sequence complementarity of flanking introns, and exon-skipping mechanisms. Following the formation of a circular RNA, circRNA is exported into the cytoplasm, where it can bind miRNAs via complementary regions; undergo translation to generate small peptides; and interact with proteins, gene promoters, and specific mRNAs. This figure was created with BioRender.com (accessed on 23 September 2024).

Figure 4

Extracellular vesicles. Extracellular vesicles (EVs) are a heterogeneous group of lipid bilayer particles synthesized and secreted by different cell types into the extracellular environment. EVs encapsulate various bioactive molecules, such as proteins, lipids, and nucleic acids. Nowadays, it is known that EVs can contain ncRNAs and can deliver these molecules to distant cells both under physiological and pathological conditions. This figure was created with BioRender.com (accessed on 23 September 2024).