TY  - JOUR
AU  - Tran, Cong Si
AU  - Kersten, Julia
AU  - Yan, Jingyi
AU  - Breinig, Marco
AU  - Huth, Thorben
AU  - Poth, Tanja
AU  - Colasanti, Ombretta
AU  - Riedl, Tobias
AU  - Faure-Dupuy, Suzanne
AU  - Diehl, Stefan
AU  - Verhoye, Lieven
AU  - Li, Teng-Feng
AU  - Lingemann, Marit
AU  - Schult, Philipp
AU  - Ahlén, Gustaf
AU  - Frelin, Lars
AU  - Kühnel, Florian
AU  - Vondran, Florian W R
AU  - Breuhahn, Kai
AU  - Meuleman, Philip
AU  - Heikenwälder, Mathias
AU  - Schirmacher, Peter
AU  - Bartenschlager, Ralf
AU  - Laketa, Vibor
AU  - Roessler, Stephanie
AU  - Tschaharganeh, Darjus Felix
AU  - Sällberg, Matti
AU  - Lohmann, Volker
TI  - Phosphatidylinositol 4-kinase III alpha governs cytoskeletal organization for invasiveness of liver cancer cells.
JO  - Gastroenterology
VL  - 167
IS  - 3
SN  - 0016-5085
CY  - Philadelphia, Pa. [u.a.]
PB  - Saunders
M1  - DKFZ-2024-00830
SP  - 522-537
PY  - 2024
N1  - 2024 Aug;167(3):522-537
AB  - 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.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.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.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.
KW  - Akt2 (Other)
KW  - HCV (Other)
KW  - PIK3C2G (Other)
KW  - hepatocellular carcinoma (Other)
KW  - phospholipid (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:38636680
DO  - DOI:10.1053/j.gastro.2024.04.009
UR  - https://inrepo02.dkfz.de/record/289597
ER  -