{
  "abstract": "Background and Aims High expression of phosphatidylinositol 4-kinase III alpha (PI4KIIIα) correlates with poor survival rates in patients with hepatocellular carcinoma (HCC). In addition, Hepatitis C virus (HCV) infections activate PI4KIIIα and contribute to HCC progression. We aimed at mechanistically understanding the impact of PI4KIIIα on the progression of liver cancer and the potential contribution of HCV in this process. Methods Several hepatic cell culture and mouse models were used to study functional importance of PI4KIIIα on liver pathogenesis. Antibody arrays, gene silencing and PI4KIIIα specific inhibitor were applied to identify the involved signaling pathways. The contribution of HCV was examined by using HCV infection or overexpression of its nonstructural protein. Results High PI4KIIIα expression and/or activity induced cytoskeletal rearrangements via increased-phosphorylation of paxillin and cofilin. This led to morphological alterations and higher migratory and invasive properties of liver cancer cells. We further identified the liver specific lipid kinase phosphatidylinositol 3-kinase C2 domain-containing subunit gamma (PIK3C2γ) working downstream of PI4KIIIα in regulation of the cytoskeleton. PIK3C2γ generates plasma membrane (PM) phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2]- enriched, invadopodia-like structures which regulate cytoskeletal reorganization by promoting Akt2 phosphorylation. Conclusions PI4KIIIα regulates cytoskeleton organization via PIK3C2γ/Akt2/paxillin-cofilin to favor migration and invasion of liver cancer cells. These findings provide mechanistic insight into the contribution of PI4KIIIα and HCV to progression of liver cancer and identify promising targets for therapeutic intervention. IMPACT AND IMPLICATIONS Understanding mechanistically how high PI4KIIIα expression are associated with poor clinical outcomes of liver cancer is important to develop pharmaceutical interventions. Our study sheds light on the importance of the two lipid kinases PI4KIIIα and PIK3C2γ as well as the contribution of HCV on liver cancer progression, unraveling the signaling pathway governing this process. This preclinical study contributes to better understanding the complex connection of phospholipids, cytoskeleton and liver cancer and suggests strategies to improve therapeutic outcomes by targeting important signaling molecules. Graphical abstract",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 28,
  "authors": [
    {
      "name": "Cong Si Tran"
    },
    {
      "name": "Julia Kersten"
    },
    {
      "name": "Jingyi Yan"
    },
    {
      "name": "Marco Breinig"
    },
    {
      "name": "Thorben Huth"
    },
    {
      "name": "Tanja Poth"
    },
    {
      "name": "Ombretta Colasanti"
    },
    {
      "name": "Tobias Riedl"
    },
    {
      "name": "Suzanne Faure‐dupuy"
    },
    {
      "name": "Stefan Diehl"
    },
    {
      "name": "Lieven Verhoye"
    },
    {
      "name": "Teng-Feng Li"
    },
    {
      "name": "Marit Lingemann"
    },
    {
      "name": "Philipp Schult"
    },
    {
      "name": "Gustaf Ahlén"
    },
    {
      "name": "Lars Frelin"
    },
    {
      "name": "Florian Kühnel"
    },
    {
      "name": "Florian W.R. Vondran"
    },
    {
      "name": "Kai Breuhahn"
    },
    {
      "name": "Philip Meuleman"
    },
    {
      "name": "Mathias Heikenwälder"
    },
    {
      "name": "Peter Schirmacher"
    },
    {
      "name": "Ralf Bartenschlager"
    },
    {
      "name": "Vibor Laketa"
    },
    {
      "name": "Stephanie Roessler"
    },
    {
      "name": "Darjus Felix Tschaharganeh"
    },
    {
      "name": "Matti Sällberg"
    },
    {
      "name": "Volker Lohmann"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2rh90j3vz82ad.bib",
  "cited_by": 11,
  "doi": "10.1053/j.gastro.2024.04.009",
  "fulltext_url": null,
  "id": "2rh90j3vz82ad",
  "issns": [
    "0016-5085",
    "1528-0012"
  ],
  "landing_url": "https://hal.science/hal-05771072v1",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "hal",
      "0.sdv"
    ],
    [
      "openalex",
      "1306|Cancer, Lipids, and Metabolism"
    ]
  ],
  "openalex": "W4394840225",
  "pdf_url": "http://www.gastrojournal.org/article/S0016508524004244/pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-30",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/2rh90j3vz82ad.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:44Z",
      "native_id": "hal-05771072",
      "source": "hal",
      "url": "https://hal.science/hal-05771072v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:1306|Cancer, Lipids, and Metabolism",
      "subfield": "oncology"
    }
  ],
  "title": "Phosphatidylinositol 4-Kinase III Alpha Governs Cytoskeletal Organization for Invasiveness of Liver Cancer Cells",
  "title_text": "Phosphatidylinositol 4-Kinase III Alpha Governs Cytoskeletal Organization for Invasiveness of Liver Cancer Cells",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:44Z",
  "url": "https://research.draconitic.com/paper/2rh90j3vz82ad",
  "venue": "Gastroenterology",
  "versions": []
}