Non-coding RNAs in Hepatocellular Carcinoma

   

Houhong Wang^*

Citation: Wang H. Ubiquitination Modification in Hepatocellular Carcinoma. Adv Clin Med Res. 6(2):1-05.

Received: Setember 30, 2025  | Published: October 20, 2025

Copyright^© 2025 Genesis Pub by Wang H. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author(s) and source are properly credited.

DOI: https://doi.org/10.52793/ACMR.2025.6(2)-106

Abstract

Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality, is characterized by dysregulated gene expression networks. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), emerge as pivotal regulators of HCC pathogenesis. This retrospective analysis synthesizes evidence from 35 recent studies (PubMed, 2020–2025) to dissect the roles of ncRNAs in HCC diagnosis, prognosis, and therapy. Key findings reveal that dysregulated ncRNAs modulate critical pathways such as cell proliferation, metastasis, and immune evasion. Clinical data highlight ncRNAs like miR-21, HOTAIR, and CDR1as as promising biomarkers, while therapeutic strategies targeting ncRNA pathways show preclinical efficacy. This review underscores the translational potential of ncRNA research for improving HCC management.

Keywords

Ubiquitination; Hepatocellular carcinoma; Orchestrates protein; HCC pathogenesis.

Introduction

HCC accounts for over 90% of primary liver cancers, with a dismal 5-year survival rate due to late diagnosis and treatment resistance. Non-coding RNAs, once considered "junk RNA," are now recognized as essential regulators of gene expression. MicroRNAs (18–22 nt) repress mRNA translation or induce degradation, lncRNAs (>200 nt) modulate chromatin structure and signaling, and circRNAs (covalently closed loops) act as miRNA sponges or protein scaffolds. Dysregulation of these ncRNAs drives oncogenic pathways in HCC, making them attractive targets for precision medicine.

Methods

Literature search

A systematic PubMed search was conducted using keywords: ("hepatocellular carcinoma" OR "HCC") AND ("non-coding RNA" OR "microRNA" OR "lncRNA" OR "circRNA"). Inclusion criteria: English studies (2020–2025) reporting ncRNA functions in HCC with clinical/functional data. Exclusion criteria: reviews, non-HCC cancer studies, or non-English articles.

Data synthesis

Studies were categorized by ncRNA type (miRNA, lncRNA, circRNA), functional roles (proliferation, metastasis, therapy response), and clinical relevance (diagnosis, prognosis). Quantitative data (expression levels, survival outcomes, biomarker performance) were extracted and tabulated.

Results

MicroRNAs (miRNAs) in HCC

Oncogenic miRNAs

• miR-21: Overexpressed in 82% of HCC tissues (vs. 18% in normal liver, p<0.001), miR-21 promotes cell proliferation by targeting tumor suppressor PTEN and activating PI3K/AKT signaling. Serum miR-21 levels correlate with tumor size (r=0.62, p<0.01) and show 78% sensitivity for HCC diagnosis (Table 1).
• miR-221/222: Upregulated in metastatic HCC, these miRNAs enhance epithelial-mesenchymal transition (EMT) by downregulating p27 and p57, leading to increased invasion [1].

 

Tumor suppressive miRNAs

• miR-122: Liver-specific miRNA downregulated in HCC (65% of cases), miR-122 represses oncogenes like c-Myc and enhances sensitivity to sorafenib. Low miR-122 expression predicts poor overall survival (median OS: 16 vs. 28 months, p<0.001), (Table 3).

 

Long non-coding RNAs (lncRNAs) in HCC

Pro-tumor lncRNAs

• HOTAIR: Overexpressed in advanced HCC (TNM III/IV: 75% vs. I/II: 25%, p=0.008), HOTAIR promotes chromatin remodeling via interaction with PRC2, upregulating metastasis-related genes (MMP9, VEGF). HOTAIR-high patients exhibit 3-fold higher recurrence rate (Table 3).
• MALAT1: Elevated in sorafenib-resistant HCC cells, MALAT1 acts as a miRNA sponge for miR-143, releasing its target gene SNAIL to drive drug resistance [2].

 

Anti-tumor lncRNAs

• LINC00152: Downregulated in HCC, LINC00152 inhibits cell proliferation by recruiting HDAC1 to repress c-Myc transcription. Restoring LINC00152 reduces tumor growth by 40% in xenograft models [3].

 

Circular RNAs (circRNAs) in HCC

Oncogenic circRNAs

• CDR1as: Upregulated 3.5-fold in HCC tissues, CDR1as sponges miR-7 to activate EGFR signaling, promoting cell migration and invasion. High CDR1as expression correlates with vascular invasion (OR=2.3, 95% CI: 1.2–4.5, p=0.015), (Table 2).
• circRNA_0001649: Derived from the CCND1 locus, this circRNA binds to CDK4 to form a stable complex, accelerating G1/S transition in HCC cells [4].

 

Tumor suppressive circRNAs

• circRNA_000828: Downregulated in HCC, circRNA_000828 sequesters miR-214 to upregulate PTEN, inhibiting AKT phosphorylation and tumor growth [5].

 

Clinical relevance of ncRNA biomarkers

Diagnostic biomarkers

A panel of three miRNAs (miR-21, miR-155, miR-122) achieved an AUC-ROC of 0.89, outperforming AFP (AUC=0.72) in distinguishing HCC from cirrhosis (Table 1). Serum lncRNA HOTAIR levels also showed 82% specificity for early-stage HCC [5].

 

Prognostic biomarkers

Multivariate analysis identified miR-221 (HR=2.4, 95% CI: 1.5–3.8, p<0.001), HOTAIR (HR=1.9, 95% CI: 1.1–3.2, p=0.021), and CDR1as (HR=1.7, 95% CI: 1.0–2.8, p=0.045) as independent predictors of poor recurrence-free survival (Table 3).

 

Therapeutic implications

miRNA-targeted therapy

Lipid-nanoparticle delivery of miR-122 mimics suppressed tumor growth by 55% in nude mice, sensitizing HCC cells to chemotherapy [6]. Antagomir-21 reduced lung metastasis by 60% in orthotopic HCC models.

 

lncRNA/circRNA-targeted Strategies

siRNA against HOTAIR inhibited cell proliferation (IC50=20 nM) and induced apoptosis (25% vs. 5% in controls, (Table 4). CircRNA_0001649 inhibitors disrupted CDK4 binding, leading to G1 phase arrest in HepG2 cells [4].

 

Biomarker	Sample Type	Sensitivity	Specificity	AUC-ROC	Reference
miR-21	Serum	78%	85%	0.85	Zhang et al., 2021
miR-155	Plasma	82%	78%	0.87	Wu et al., 2022
miR-21+miR-122	Tissue	89%	91%	0.92	Wang et al., 2022