Phosphatidylinositol 4-Kinase III Alpha Governs Cytoskeletal Organization for Invasiveness of Liver Cancer Cells
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
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BibTeX
@article{tran2026phosphatidylinositol,
title = {{Phosphatidylinositol 4-Kinase III Alpha Governs Cytoskeletal Organization for Invasiveness of Liver Cancer Cells}},
author = {Cong Si Tran and Julia Kersten and Jingyi Yan and Marco Breinig and Thorben Huth and Tanja Poth and Ombretta Colasanti and Tobias Riedl and Suzanne Faure‐dupuy and Stefan Diehl and Lieven Verhoye and Teng-Feng Li and Marit Lingemann and Philipp Schult and Gustaf Ahlén and Lars Frelin and Florian Kühnel and Florian W.R. Vondran and Kai Breuhahn and Philip Meuleman and Mathias Heikenwälder and Peter Schirmacher and Ralf Bartenschlager and Vibor Laketa and Stephanie Roessler and Darjus Felix Tschaharganeh and Matti Sällberg and Volker Lohmann},
journal = {Gastroenterology},
year = {2026},
month = sep,
doi = {10.1053/j.gastro.2024.04.009},
url = {https://hal.science/hal-05771072v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Phosphatidylinositol 4-Kinase III Alpha Governs Cytoskeletal Organization for Invasiveness of Liver Cancer Cells
AU - Cong Si Tran
AU - Julia Kersten
AU - Jingyi Yan
AU - Marco Breinig
AU - Thorben Huth
AU - Tanja Poth
AU - Ombretta Colasanti
AU - Tobias Riedl
AU - Suzanne Faure‐dupuy
AU - Stefan Diehl
AU - Lieven Verhoye
AU - Teng-Feng Li
AU - Marit Lingemann
AU - Philipp Schult
AU - Gustaf Ahlén
AU - Lars Frelin
AU - Florian Kühnel
AU - Florian W.R. Vondran
AU - Kai Breuhahn
AU - Philip Meuleman
AU - Mathias Heikenwälder
AU - Peter Schirmacher
AU - Ralf Bartenschlager
AU - Vibor Laketa
AU - Stephanie Roessler
AU - Darjus Felix Tschaharganeh
AU - Matti Sällberg
AU - Volker Lohmann
PY - 2026
DA - 2026/09/30
JO - Gastroenterology
DO - 10.1053/j.gastro.2024.04.009
UR - https://hal.science/hal-05771072v1
AB - 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
SN - 0016-5085
SN - 1528-0012
ER -