2. Academic Validation
  3. Phosphatidylinositol 4-Kinase III Alpha Governs Cytoskeletal Organization for Invasiveness of Liver Cancer Cells

Phosphatidylinositol 4-Kinase III Alpha Governs Cytoskeletal Organization for Invasiveness of Liver Cancer Cells

  • Gastroenterology. 2024 Aug;167(3):522-537. doi: 10.1053/j.gastro.2024.04.009.
Cong Si Tran 1,  Julia Kersten 1,  Jingyi Yan 2,  Marco Breinig 3,  Thorben Huth 4,  Tanja Poth 5,  Ombretta Colasanti 1,  Tobias Riedl 6,  Suzanne Faure-Dupuy 7,  Stefan Diehl 1,  Lieven Verhoye 8,  Teng-Feng Li 1,  Marit Lingemann 1,  Philipp Schult 1,  Gustaf Ahlén 2,  Lars Frelin 2,  Florian Kühnel 9,  Florian W R Vondran 10,  Kai Breuhahn 4,  Philip Meuleman 8,  Mathias Heikenwälder 11,  Peter Schirmacher 4,  Ralf Bartenschlager 12,  Vibor Laketa 13,  Stephanie Roessler 4,  Darjus Felix Tschaharganeh 3,  Matti Sällberg 2,  Volker Lohmann 14
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, Molecular Virology, Section Virus-Host Interactions, Center for Integrative Infectious Disease Research, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany.
  • 2 Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; Clinical Microbiology, Karolinska University Hospital, Huddinge, Sweden.
  • 3 Helmholtz-University Group "Cell Plasticity and Epigenetic Remodeling", German Cancer Research Center (DKFZ) and Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
  • 4 Institute of Pathology, University Hospital Heidelberg, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany.
  • 5 Center for Model System and Comparative Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany.
  • 6 Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany.
  • 7 Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany; Université Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France.
  • 8 Laboratory of Liver Infectious Diseases, Ghent University, Ghent, Belgium.
  • 9 Department of Gastroenterology, Hepatology, Infectiology, and Endocrinology, Hannover Medical School, Hannover, Germany.
  • 10 Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany; German Centre for Infection Research (DZIF), Partner Site Hannover, Hannover, Germany.
  • 11 Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany; The M3 Research Institute, Medical Faculty Tübingen, Tübingen, Germany.
  • 12 DZIF, Partner Site Heidelberg, Heidelberg, Germany; Division of Virus-Associated Carcinogenesis, DKFZ, Heidelberg, Germany; Department of Infectious Diseases, Molecular Virology, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
  • 13 DZIF, Partner Site Heidelberg, Heidelberg, Germany; Department of Infectious Diseases, Virology, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
  • 14 Department of Infectious Diseases, Molecular Virology, Section Virus-Host Interactions, Center for Integrative Infectious Disease Research, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany; DZIF, Partner Site Heidelberg, Heidelberg, Germany. Electronic address: [email protected].
PMID: 38636680 DOI: 10.1053/j.gastro.2024.04.009
Abstract

Background & aims: High expression of phosphatidylinositol 4-kinase III alpha (PI4KIIIα) correlates with poor survival rates in patients with hepatocellular carcinoma. In addition, hepatitis C virus (HCV) infections activate PI4KIIIα and contribute to hepatocellular carcinoma 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 the 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 morphologic 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 phosphatidylinositol 3,4-bisphosphate-enriched, invadopodia-like structures that 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 the progression of liver Cancer and identify promising targets for therapeutic intervention.

Keywords

Akt2; HCV; Hepatocellular Carcinoma; PIK3C2G; Phospholipid.

Figures