Integrin α2 and β1 Cross-Communication with mTOR/AKT and the CDK-Cyclin Axis in Hepatocellular Carcinoma Cells

Cancers

He Zhou¹  Elsie Oppermann¹  Mazen A. Juratli¹  Wolf O. Bechstein¹  Andreas Pascher²  Eva Juengel³  Roman A. Blaheta³  Felix K.-H. Chun⁴  Jochen Rutz⁴ 

[1] Department of General and Visceral Surgery, Goethe-University, 60590 Frankfurt am Main, Germany;Department of General, Visceral and Transplant Surgery, Muenster University Hospital, 48149 Muenster, Germany;Department of Urology and Pediatric Urology, University Medicine Mainz, 55131 Mainz, Germany;Department of Urology, Goethe-University, 60590 Frankfurt am Main, Germany;

关键词: hepatocellular carcinoma;    AKT-mTOR pathway;    integrins;    growth;    invasion;   

DOI  :  10.3390/cancers14102430

来源: DOAJ

【 摘 要 】

Integrin receptors contribute to hepatocellular carcinoma (HCC) invasion, while AKT-mTOR signaling controls mitosis. The present study was designed to explore the links between integrins and the AKT-mTOR pathway and the CDK-Cyclin axis. HCC cell lines (HepG2, Huh7, Hep3B) were stimulated with soluble collagen or Matrigel to activate integrins, or with insulin-like growth factor 1 (IGF1) to activate AKT-mTOR. HCC growth, proliferation, adhesion, and chemotaxis were evaluated. AKT/mTOR-related proteins, proteins of the CDK-Cyclin axis, focal adhesion kinase (FAK), and integrin-linked kinase (ILK) were determined following IGF1-stimulation or integrin knockdown. Stimulation with collagen or Matrigel increased tumor cell growth and proliferation. This was associated with significant alteration of the integrins α2, αV, and β1. Blockade of these integrins led to cell cycle arrest in G2/M and diminished the number of tumor cell clones. Knocking down the integrins α2 or β1 suppressed ILK, reduced FAK-phosphorylation and diminished AKT/mTOR, as well as the proteins of the CDK-Cyclin axis. Activating the cells with IGF1 enhanced the expression of the integrins α2, αV, β1, activated FAK, and increased tumor cell adhesion and chemotaxis. Blocking the AKT pathway canceled the enhancing effect of IGF on the integrins α2 and β1. These findings reveal that HCC growth, proliferation, and invasion are controlled by a fine-tuned network between α2/β1-FAK signaling, the AKT-mTOR pathway, and the CDK–Cyclin axis. Concerted blockade of the integrin α2/β1 complex along with AKT-mTOR signaling could, therefore, provide an option to prevent progressive dissemination of HCC.

【 授权许可】

Unknown