A crucial function of PDGF in TGF-β-mediated cancer progression of hepatocytes

Abstract

Polarized hepatocytes expressing hyperactive Ha-Ras adopt an invasive and metastatic phenotype in cooperation with transforming growth factor (TGF)-b. This dramatic increase in malignancy is displayed by an epithelial to mesenchymal transition (EMT), which mimics the TGFb-mediated progression of human hepatocellular carcinomas. In culture, hepatocellular EMT occurs highly synchronously, facilitating the analysis of molecular events underlying the various stages of this process. Here, we show that in response to TGF-b, phosphorylated Smads rapidly translocated into the nucleus and activated transcription of target genes such as E-cadherin repressors of the Snail superfamily, causing loss of cell adhesion. Within the TGF-b superfamily of cytokines, TGF-b1, -b2 and -b3 were specific for the induction of hepatocellular EMT. Expression profiling of EMT kinetics revealed 78 up-and 235 downregulated genes, which preferentially modulate metabolic activities, extracellular matrix composition, transcriptional activities and cell survival. Independent of the genetic background, platelet-derived growth factor (PDGF)-A ligand and both PDGF receptor subunits were highly elevated, together with autocrine secretion of bioactive PDGF. Interference with PDGF signalling by employing hepatocytes expressing the dominant-negative PDGF-a receptor revealed decreased TGF-b-induced migration in vitro and efficient suppression of tumour growth in vivo. In conclusion, these results provide evidence for a crucial role of PDGF in TGF-bmediated tumour progression of hepatocytes and suggest PDGF as a target for therapeutic intervention in liver cancer.

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

“…It has been observed that STAT3 can also regulate the expression of other angiogenic molecules, such as basic FGF (bFGF) [133] which participates in angiogenesis by inducing the migration, proliferation, and differentiation of endothelial cells and by regulating VEGF expression in tumor cells in an autocrine and paracrine fashion [240]. It is widely believed that the ability of PDGFs to induce liver fibrosis and neoplastic cell transformation is closely associated with the transcriptional induction of TGFβ, an essential mediator of fibrogenesis [241,242]. TGFβ and PDGFs act through activation of STAT3 [75,76] leading to the upregulation of genes promoting cell proliferation, survival, and cell transformation [77].…”

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

“…Important molecular pathway involved in EMT are Wnt/betacatenin signaling [95,96] and through growth factor signalling like PDGF [97] .…”

Reprogramming during epithelial to mesenchymal transition under the control of TGFβ

“…58 In the context of cancer-related EMT, all 3 TGFb isoforms can induce hepatocarcinoma EMT that is mediated by downstream induction and signaling of the platelet derived growth factor (PDGF) A. 59 In EMT and metastatic spreading of breast cancer with oncogenic phosphatidylinositol 3' kinase (PI3K)/Akt pathway activation, TGFb2 activity is required; Akt directly phosphorylates Twist1, causing its stabilization and transcriptional activation, and leading to the enhanced expression of the TGFb2 gene. 60 Finally, EMT and MET cycles are controlled by the reciprocal loop between TGFb and members of the miR-200 family.…”