Cargando…

Integrin α2 and β1 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 evaluat...

Descripción completa

Detalles Bibliográficos
Autores principales: Juratli, Mazen A., Zhou, He, Oppermann, Elsie, Bechstein, Wolf O., Pascher, Andreas, Chun, Felix K.-H., Juengel, Eva, Rutz, Jochen, Blaheta, Roman A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9139686/
https://www.ncbi.nlm.nih.gov/pubmed/35626034
http://dx.doi.org/10.3390/cancers14102430
_version_ 1784714916695900160
author Juratli, Mazen A.
Zhou, He
Oppermann, Elsie
Bechstein, Wolf O.
Pascher, Andreas
Chun, Felix K.-H.
Juengel, Eva
Rutz, Jochen
Blaheta, Roman A.
author_facet Juratli, Mazen A.
Zhou, He
Oppermann, Elsie
Bechstein, Wolf O.
Pascher, Andreas
Chun, Felix K.-H.
Juengel, Eva
Rutz, Jochen
Blaheta, Roman A.
author_sort Juratli, Mazen A.
collection PubMed
description 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 α 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. ABSTRACT: 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.
format Online
Article
Text
id pubmed-9139686
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-91396862022-05-28 Integrin α2 and β1 Cross-Communication with mTOR/AKT and the CDK-Cyclin Axis in Hepatocellular Carcinoma Cells Juratli, Mazen A. Zhou, He Oppermann, Elsie Bechstein, Wolf O. Pascher, Andreas Chun, Felix K.-H. Juengel, Eva Rutz, Jochen Blaheta, Roman A. Cancers (Basel) Article 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 α 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. ABSTRACT: 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. MDPI 2022-05-14 /pmc/articles/PMC9139686/ /pubmed/35626034 http://dx.doi.org/10.3390/cancers14102430 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Juratli, Mazen A.
Zhou, He
Oppermann, Elsie
Bechstein, Wolf O.
Pascher, Andreas
Chun, Felix K.-H.
Juengel, Eva
Rutz, Jochen
Blaheta, Roman A.
Integrin α2 and β1 Cross-Communication with mTOR/AKT and the CDK-Cyclin Axis in Hepatocellular Carcinoma Cells
title Integrin α2 and β1 Cross-Communication with mTOR/AKT and the CDK-Cyclin Axis in Hepatocellular Carcinoma Cells
title_full Integrin α2 and β1 Cross-Communication with mTOR/AKT and the CDK-Cyclin Axis in Hepatocellular Carcinoma Cells
title_fullStr Integrin α2 and β1 Cross-Communication with mTOR/AKT and the CDK-Cyclin Axis in Hepatocellular Carcinoma Cells
title_full_unstemmed Integrin α2 and β1 Cross-Communication with mTOR/AKT and the CDK-Cyclin Axis in Hepatocellular Carcinoma Cells
title_short Integrin α2 and β1 Cross-Communication with mTOR/AKT and the CDK-Cyclin Axis in Hepatocellular Carcinoma Cells
title_sort integrin α2 and β1 cross-communication with mtor/akt and the cdk-cyclin axis in hepatocellular carcinoma cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9139686/
https://www.ncbi.nlm.nih.gov/pubmed/35626034
http://dx.doi.org/10.3390/cancers14102430
work_keys_str_mv AT juratlimazena integrina2andb1crosscommunicationwithmtoraktandthecdkcyclinaxisinhepatocellularcarcinomacells
AT zhouhe integrina2andb1crosscommunicationwithmtoraktandthecdkcyclinaxisinhepatocellularcarcinomacells
AT oppermannelsie integrina2andb1crosscommunicationwithmtoraktandthecdkcyclinaxisinhepatocellularcarcinomacells
AT bechsteinwolfo integrina2andb1crosscommunicationwithmtoraktandthecdkcyclinaxisinhepatocellularcarcinomacells
AT pascherandreas integrina2andb1crosscommunicationwithmtoraktandthecdkcyclinaxisinhepatocellularcarcinomacells
AT chunfelixkh integrina2andb1crosscommunicationwithmtoraktandthecdkcyclinaxisinhepatocellularcarcinomacells
AT juengeleva integrina2andb1crosscommunicationwithmtoraktandthecdkcyclinaxisinhepatocellularcarcinomacells
AT rutzjochen integrina2andb1crosscommunicationwithmtoraktandthecdkcyclinaxisinhepatocellularcarcinomacells
AT blahetaromana integrina2andb1crosscommunicationwithmtoraktandthecdkcyclinaxisinhepatocellularcarcinomacells