Frontiers in immunology · 2026
The metastasis landscape of Clonorchis sinensis-associated hepatocellular carcinoma: an integrated multi-omics and clinical study.
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Zhou Lingling, Sun Lin, Huang Xuhang, Chen Junxian, Huang Taijun, Xu Yulong, Luo Xiaorong, Wei Caibiao, Liu Fengfei, Pan Xiaolan, Dong Madanni, Su Jingyu, Yang Weilong, Fang Min
Аннотация
BACKGROUND: Hepatocellular carcinoma (HCC) patients with Clonorchis sinensis (Cs) infection tend to exhibit a poorer prognosis compared to those without infection. Nevertheless, the molecular mechanisms underlying Cs-associated HCC, particularly those linked to metastatic progression, remain poorly understood. This study therefore seeks to elucidate the role of C. sinensis infection in promoting metastasis.
METHODS: Through a clinical retrospective analysis, we compared overall survival and metastasis incidence between HCC patients with and without Cs infection. To explore the underlying mechanisms, we conducted integrated multi-omics analyses-including RNA-seq, miRNA-seq, ATAC-seq, WGBS-seq, oxWGBS-seq, and ChIP-seq-to profile 369 metastasis-related genes in Cs + and Cs - HCC tumors. The expression of three key metastasis-related genes was further validated by RT-qPCR, and Transwell and wound-healing assays were performed in vitro to confirm the pro-metastatic effect of Cs infection on HCC cells.
RESULTS: In HCC patients, Cs infection was associated with poorer overall survival and an increased metastasis rate. We identified 20 metastasis-related genes, with SPP1, MMP2, and VCAM1 as central hubs, together with 41 interacting miRNAs and 71 accessible promoter regions. Histone modifications-particularly H3K9ac, H3K27ac and H3K4me3-were correlated with chromatin accessibility in the promoters of these genes. Molecular experiments further demonstrated that Cs infection enhances the metastatic potential of HCC.
CONCLUSIONS: Our study reveals that Cs infection promotes HCC metastasis through gene and epigenetic alterations, providing mechanistic insights and identifying potential targets for early intervention.
METHODS: Through a clinical retrospective analysis, we compared overall survival and metastasis incidence between HCC patients with and without Cs infection. To explore the underlying mechanisms, we conducted integrated multi-omics analyses-including RNA-seq, miRNA-seq, ATAC-seq, WGBS-seq, oxWGBS-seq, and ChIP-seq-to profile 369 metastasis-related genes in Cs + and Cs - HCC tumors. The expression of three key metastasis-related genes was further validated by RT-qPCR, and Transwell and wound-healing assays were performed in vitro to confirm the pro-metastatic effect of Cs infection on HCC cells.
RESULTS: In HCC patients, Cs infection was associated with poorer overall survival and an increased metastasis rate. We identified 20 metastasis-related genes, with SPP1, MMP2, and VCAM1 as central hubs, together with 41 interacting miRNAs and 71 accessible promoter regions. Histone modifications-particularly H3K9ac, H3K27ac and H3K4me3-were correlated with chromatin accessibility in the promoters of these genes. Molecular experiments further demonstrated that Cs infection enhances the metastatic potential of HCC.
CONCLUSIONS: Our study reveals that Cs infection promotes HCC metastasis through gene and epigenetic alterations, providing mechanistic insights and identifying potential targets for early intervention.