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Phosphatidylinositol 4-kinase III alpha governs cytoskeletal organization for invasiveness of liver cancer cells. 2024

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
Heidelberg University, Medical Faculty Heidelberg, Department of Infectious Diseases, Molecular Virology, Section Virus-Host-Interactions, Center for Integrative Infectious Disease Research, Heidelberg, Germany.

OBJECTIVE 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.

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