Background Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality globally, and its progression is associated with various factors, including parasitic infections such as Clonorchis sinensis (C. sinensis). Although C. sinensis infection has been implicated in HCC, the molecular mechanisms, particularly the role of microRNAs (miRNAs), remain poorly understood. This study aims to fill this gap by investigating the miRNA expression profiles in C. sinensis+ and C. sinensis− HCC tissues. Method We performed miRNA sequencing on HCC tissues from C. sinensis+ and C. sinensis− patients, followed by bioinformatics analyses to identify differentially expressed miRNAs (DEMs) and their target genes. Gene Ontology (GO) enrichment analysis was conducted to explore relevant biological processes, while a competitive endogenous RNA (ceRNA) network was constructed to investigate the interactions among miRNAs, long noncoding RNAs (lncRNAs), and messenger RNAs (mRNAs). Additionally, we performed survival analysis using Gene Expression Profiling Interactive Analysis 2 (GEPIA2) based on the The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort and assessed the clinical relevance of DEMs. Key miRNAs identified from this analysis were further validated through quantitative real‑time polymerase chain reaction (qRT-PCR) assays to confirm their expression in MHCC97H. Results Our research identified significant miRNA dysregulation in C. sinensis+ HCC tumors compared with C. sinensis− HCC tumors. Notably, miR-143-3p, miR-10a-5p, and miR-100-5p were upregulated in C. sinensis+ HCC, contributing to immune responses and tumor progression, while let-7 family members and miR-221-3p were downregulated, affecting metabolic pathways. GO enrichment analysis highlighted the involvement of developmental processes, immune system regulation, and metabolic reprogramming in C. sinensis+ HCC. The construction of a ceRNA network revealed key interactions between miRNAs, lncRNAs, and mRNAs in C. sinensis+ HCC, suggesting regulatory mechanisms that could be potential therapeutic targets. Additionally, validation through qRT-PCR confirmed these findings, highlighting miRNA dysregulation as a critical factor in C. sinensis+ HCC progression. Conclusions This study provides novel insights into the role of miRNAs in C. sinensis-infected HCC progression. The findings highlight the critical role of miRNA dysregulation in the progression of C. sinensis-associated HCC, emphasizing the potential for therapeutic interventions targeting these molecular alterations in affected patients. Graphical Abstract

The microRNA landscape and regulatory network in Clonorchis sinensis-infected hepatocellular carcinoma: implications for tumor progression

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2025年2月21日

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Caibiao Wei,
Junxian Chen,
Taijun Huang,
Lingling Zhou,
Yulong Xu,
Qiumei Lin,
Yuling Qin,
Zeli Tang,
Weilong Yang,
Min Fang

摘要

Background

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality globally, and its progression is associated with various factors, including parasitic infections such as Clonorchis sinensis (C. sinensis). Although C. sinensis infection has been implicated in HCC, the molecular mechanisms, particularly the role of microRNAs (miRNAs), remain poorly understood. This study aims to fill this gap by investigating the miRNA expression profiles in C. sinensis⁺ and C. sinensis⁻ HCC tissues.

Method

We performed miRNA sequencing on HCC tissues from C. sinensis⁺ and C. sinensis⁻ patients, followed by bioinformatics analyses to identify differentially expressed miRNAs (DEMs) and their target genes. Gene Ontology (GO) enrichment analysis was conducted to explore relevant biological processes, while a competitive endogenous RNA (ceRNA) network was constructed to investigate the interactions among miRNAs, long noncoding RNAs (lncRNAs), and messenger RNAs (mRNAs). Additionally, we performed survival analysis using Gene Expression Profiling Interactive Analysis 2 (GEPIA2) based on the The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort and assessed the clinical relevance of DEMs. Key miRNAs identified from this analysis were further validated through quantitative real‑time polymerase chain reaction (qRT-PCR) assays to confirm their expression in MHCC97H.

Results

Our research identified significant miRNA dysregulation in C. sinensis⁺ HCC tumors compared with C. sinensis⁻ HCC tumors. Notably, miR-143-3p, miR-10a-5p, and miR-100-5p were upregulated in C. sinensis⁺ HCC, contributing to immune responses and tumor progression, while let-7 family members and miR-221-3p were downregulated, affecting metabolic pathways. GO enrichment analysis highlighted the involvement of developmental processes, immune system regulation, and metabolic reprogramming in C. sinensis⁺ HCC. The construction of a ceRNA network revealed key interactions between miRNAs, lncRNAs, and mRNAs in C. sinensis⁺ HCC, suggesting regulatory mechanisms that could be potential therapeutic targets. Additionally, validation through qRT-PCR confirmed these findings, highlighting miRNA dysregulation as a critical factor in C. sinensis⁺ HCC progression.

Conclusions

This study provides novel insights into the role of miRNAs in C. sinensis-infected HCC progression. The findings highlight the critical role of miRNA dysregulation in the progression of C. sinensis-associated HCC, emphasizing the potential for therapeutic interventions targeting these molecular alterations in affected patients.

Graphical Abstract