Model of a TGF-β1-induced tumor-promoting signaling pathway in HepG2 cells

• Modell eines TGF-β1-induzierten krebsfördernden Signalweges in HepG2-Zellen

Schon, Hans-Theo; Weiskirchen, Ralf (Thesis advisor); Huber, Michael (Thesis advisor); Marquardt, Till (Thesis advisor)

Aachen (2019, 2020)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2019

Abstract

The cytokine transforming growth factor beta-1 (TGF-β1) acts as a tumor suppressor in normal hepatocytes and during early stages of hepatocarcinogenesis, but promotes tumor progression in advanced disease stages. To investigate the tumor-promoting effect of TGF-β1 on cells of the human hepatoma cell line HepG2, high-density oligonucleotide microarrays served as a basis for the identification of differential expression. Furthermore, enrichment analysis was used to determine specific pathways enriched in the gene expression data and differential expression was linked to cellular signaling networks by employing the Expression2Kinases Analysis. Finally, a model of a signaling cascade was extrapolated that depicts the tumor-promoting effect of TGF-β1 in HepG2 cells. Results showed significant enrichment of crucial biological processes in response to TGF-β1 that support defining features of cancer, including continuous proliferative signaling, unresponsiveness to growth-inhibiting signals, avoidance of apoptosis, prolonged angiogenesis, and invasion of tissues and metastasis. The underlying regulatory network responsible for the observed differential expression includes both crucial transcription factors and protein kinases. As TGF-β1 signaling is intact in HepG2 cells, the proposed signaling cascade starts by inducing gene expression of a mitogenic growth factor, followed by autocrine stimulation with its gene product that, via different intermediate kinases, abrogates the cytostatic effect of TGF-β1. Additionally, another branch of the signaling cascade ultimately represses the activity of a cyclin-dependent kinase inhibitor, thereby enhancing proliferation of HepG2 cells. In conclusion, TGF-β1 enhances malignant traits of HepG2 cells and may promote proliferation via autocrine growth factor stimulation.

Institutions

• Chair of Neurobiology [164310]
• Department of Biology [160000]
• [526000-3]