Integrin alpha 2 and beta 1 Cross-Communication with mTOR/AKT and the CDK-Cyclin Axis in Hepatocellular Carcinoma Cells

Simple Summary Hepatocellular carcinoma (HCC) progression depends on two major processes, tumor growth and invasion. The present study investigated how these events are linked. A panel of HCC cell lines were stimulated with insulin-like growth factor-1 (IGF1) and the biological behavior was evaluated. IGF1 activated the proliferation and invasion cascade by altering the expression level of integrin alpha subtypes, which were associated with the AKT-mTOR pathway and the CDK-Cyclin axis. We assume that HCC progression is controlled by a fine-tuned network between IGF1 driven integrin signaling, the Akt-mTOR pathway, and the CDK-Cyclin axis. Concerted targeting of these pathways may, therefore, become an innovative option to prevent cancer dissemination. 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 alpha 2, alpha V, and beta 1. Blockade of these integrins led to cell cycle arrest in G2/M and diminished the number of tumor cell clones. Knocking down the integrins alpha 2 or beta 1 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 alpha 2, alpha V, beta 1, activated FAK, and increased tumor cell adhesion and chemotaxis. Blocking the AKT pathway canceled the enhancing effect of IGF on the integrins alpha 2 and beta 1. These findings reveal that HCC growth, proliferation, and invasion are controlled by a fine-tuned network between alpha 2/beta 1-FAK signaling, the AKT-mTOR pathway, and the CDK-Cyclin axis. Concerted blockade of the integrin alpha 2/beta 1 complex along with AKT-mTOR signaling could, therefore, provide an option to prevent progressive dissemination of HCC.