c‐Fos accelerates hepatocyte conversion to a fibroblastoid phenotype through ERK‐mediated upregulation of paxillin‐Serine178 phosphorylation

Abstract

Transforming growth factor beta (TGF-beta) exerts an important role in the late steps of carcinogenesis by cooperating with Ras to induce cell motility and tumor invasion. The transcription complex AP-1 has been implicated in the regulation of genes involved in motility and invasion, by mechanisms not yet delineated. We utilized a model of immortalized human hepatocytes (IHH) overexpressing c-Fos (IHH-Fos) or not (IHH-C) to investigate the role of c-Fos on cell motility in response to a prolonged treatment with TGF-beta, EGF or a combination of both. Cotreatment with EGF and TGF-beta, but neither cytokine alone, induced the conversion of hepatocytes to a fibroblastoid phenotype and increased their motility in Boyden chambers. EGF/TGF-beta cotreatment induced a higher effect on ERK phosphorylation compared to TGF-beta treatment alone. It also induced an increase in total and phosphorylated Ser(178) paxillin, a protein previously implicated in cell motility. This response was inhibited by two specific MEK inhibitors, indicating the involvement of the ERK pathway in paxillin activation. Overexpression of c-Fos correlated with increased cell scattering and motility, higher levels of ERK activation and phospho Ser(178) paxillin, increased levels of EGF receptor (EGF-R) mRNA and higher EGF-R phosphorylation levels following EGF/TGF-beta cotreatment. Conversely, siRNA-mediated invalidation of c-Fos delayed the appearance of fibroblastoid cells, decreased EGF-R mRNA and downregulated ERK and Ser(178) paxillin phosphorylations, indicating that c-Fos activates hepatocyte motility through an EGF-R/ERK/paxillin pathway. Since c-Fos is frequently overexpressed in hepatocarcinomas, this newly identified mechanism might be involved in the progression of hepatic tumors in vivo.

Paxillin is positively correlated with the clinicopathological factors of colorectal cancer, and knockdown of Paxillin improves sensitivity to cetuximab in colorectal cancer cells

“…As described in the Introduction, activation of the ERK signaling pathway requires the participation and mediation of PXN in prostate cancer and non-small cell lung cancer (10,17 (11). Several studies have demonstrated that Erk always gives a positive feedback on PXN and plays an important part in the activitation of PXN and interaction between FAK and PXN (11,22,23). Based on these facts, we decided to examine the expression of p-Erk during this experiment.…”

c-Fos mediates α1, 2-fucosyltransferase 1 and Lewis�y expression in response to TGF-β1 in ovarian cancer

“…Previous studies demonstrated that c-Fos was highly expressed in cervical cancer, and almost never expressed in normal tissues and precancerous lesions ( 48 ). c-Fos expression was upregulated following TGF-β1 treatment in immortalized liver cells, which was correlated with cell migration and invasion ( 49 ). Therefore, we proposed that increased TGF-β1 promoted expression of c-Fos and the formation of heterodimers, and upregulated FUT1 transcription.…”

Noncanonical roles of membranous lysyl-tRNA synthetase in transducing cell-substrate signaling for invasive dissemination of colon cancer spheroids in 3D collagen I gels

“…Although paxillin is phosphorylated by active FAK [ 22 ], this study has revealed that paxillin expression is regulated by ERK1/2 and c-Jun activities. Activated ERK1/2 correlates with total paxillin expression and Ser178 phosphorylation but not with Tyr118 phosphorylation during EGF/TGFβ1-mediated hepatocyte migration [ 23 ]. The 3D culture using collagen I gels supplied with 10% FBS-containing culture media in this study efficiently showed laminin expression independent of KRS suppression, suggesting that laminin is available during the experiments in the 3D collagen I gels.…”