TGFβ overrides HNF4α tumor suppressing activity through GSK3β inactivation: implication for hepatocellular carcinoma gene therapy. - Archive ouverte HAL Access content directly
Journal Articles Journal of Hepatology Year : 2013

TGFβ overrides HNF4α tumor suppressing activity through GSK3β inactivation: implication for hepatocellular carcinoma gene therapy.

(1) , (2) , (1) , (2) , (2) , (2) , (1) , (1) , (1, 2) , (1)
1
2

Abstract

BACKGROUND & AIMS: The tumor fate derives from cell autonomous properties and niche microenvironmental cues. The transforming growth factor β (TGFβ) is a major microenvironmental factor for hepatocellular carcinoma (HCC) influencing tumor dedifferentiation, induction of epithelial-to-mesenchymal transition (EMT) and acquisition of metastatic properties. The loss of the transcriptional factor HNF4α is a predominant mechanism through which HCCs progress to a more aggressive phenotype; its re-expression, reducing tumor formation and repressing EMT program, has been suggested as a therapeutic tool for HCC gene therapy. We investigated the influence of TGFβ on the anti-EMT and tumor suppressor HNF4α activity. METHODS: Cell motility and invasion were analyzed by wound healing and invasion assays. EMT was evaluated by RT-qPCR and immunofluorescence. ChIP and EMSA assays were utilized for investigation of the HNF4α DNA binding activity. HNF4α post-translational modifications (PTMs) were assessed by 2-DE analysis. GSK3β activity was modulated by chemical inhibition and constitutive active mutant expression. RESULTS: We demonstrated that the presence of TGFβ impairs the efficiency of HNF4α as tumor suppressor. We found that TGFβ induces HNF4α PTMs that correlate with the early loss of HNF4α DNA binding activity on target gene promoters. Furthermore, we identified the GSK3β kinase as one of the TGFβ targets mediating HNF4α functional inactivation: GSK3β chemical inhibition results in HNF4α DNA binding impairment while a constitutively active GSK3β mutant impairs the TGFβ-induced inhibitory effect on HNF4α tumor suppressor activity. CONCLUSIONS: Our data identify in the dominance of TGFβ a limit for the HNF4α-mediated gene therapy of HCC.
Embargoed file
Embargoed file
Ne sera jamais visible

Dates and versions

pasteur-01053512 , version 1 (31-07-2014)

Identifiers

Cite

Angela Maria Cozzolino, Tonino Alonzi, Laura Santangelo, Carmine Mancone, Beatrice Conti, et al.. TGFβ overrides HNF4α tumor suppressing activity through GSK3β inactivation: implication for hepatocellular carcinoma gene therapy.. Journal of Hepatology, 2013, 58 (1), pp.65-72. ⟨10.1016/j.jhep.2012.08.023⟩. ⟨pasteur-01053512⟩

Collections

RIIP RIIP_FCB
34 View
1 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More