{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:13:42Z","timestamp":1790097222978,"version":"4.0.1"},"reference-count":67,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T00:00:00Z","timestamp":1742169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p><jats:italic>Clonorchis sinensis<\/jats:italic> (<jats:italic>Cs<\/jats:italic>)-infected hepatocellular carcinoma (HCC) patients have a poorer prognosis than non-<jats:italic>Cs<\/jats:italic>-infected HCCs. However, the molecular mechanisms of <jats:italic>Cs<\/jats:italic>-infected HCC remain unclear. To address this, this study aims to uncover the tumor microenvironment and molecular features that may contribute to these poor outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The research involved bulk RNA sequencing of paired tumor and adjacent tissue samples from 10 <jats:italic>Cs<\/jats:italic><jats:sup>+<\/jats:sup> HCC and 10 <jats:italic>Cs<\/jats:italic><jats:sup>-<\/jats:sup> HCC patients. Differentially expressed genes were identified, followed by enrichment analyses to reveal functional changes. Survival analysis of the top 10 up- and down-regulated genes in <jats:italic>Cs<\/jats:italic><jats:sup>+<\/jats:sup> HCC tumors was performed using TCGA database. Additionally, clinical data from 1,461 HCC patients were retrospectively analyzed to assess the impact of <jats:italic>Cs<\/jats:italic> infection on microvascular invasion and metastasis rates. <jats:italic>In vitro<\/jats:italic> assays were also conducted using <jats:italic>Cs<\/jats:italic> excretory\/secretory products (<jats:italic>Cs<\/jats:italic>ESPs) to examine their effect on HCC cells and HUVECs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified 785 up-regulated and 675 down-regulated genes in <jats:italic>Cs<\/jats:italic><jats:sup>+<\/jats:sup> HCC tumors compared to <jats:italic>Cs<\/jats:italic><jats:sup>-<\/jats:sup> HCC tumors, enriched in pathways related to extracellular matrix remodeling and immunosuppression. Survival analysis revealed that the top 10 up-regulated genes are associated with HCC poor prognosis. Clinical data from 1,461 HCC patients showed <jats:italic>Cs<\/jats:italic> infection increased microvascular invasion and metastasis rates. <jats:italic>In vitro<\/jats:italic>, <jats:italic>Cs<\/jats:italic>ESPs products enhanced migration and invasion in HCC cells and promoted tube formation in human umbilical vein endothelial cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study provides novel insights into the molecular landscape of <jats:italic>Cs<\/jats:italic>-infected HCC and underscores the <jats:italic>Cs<\/jats:italic> infection\u2019s role in enhancing tumor migration, invasion and angiogenesis. The findings contribute to the understanding of parasitic infections in cancer progression and suggest potential prognostic markers for <jats:italic>Cs<\/jats:italic><jats:sup>+<\/jats:sup> HCC.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1526699","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T07:19:07Z","timestamp":1742195947000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Clonorchis sinensis-infected hepatocellular carcinoma exhibits distinct tumor microenvironment and molecular 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