C/EBPα Regulates FOXC1 to Modulate Tumor Growth by Interacting with PPARγ in Hepatocellular Carcinoma

Author(s): Zhuo Xu, Shao-Hua Meng, Jian-Guo Bai, Chao Sun*, Li-Li Zhao*, Rui-Feng Tang, Zhao-Lin Yin, Jun-Wei Ji, Wei Yang, Guang-Jun Ma

Journal Name: Current Cancer Drug Targets

Volume 20 , Issue 1 , 2020

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Graphical Abstract:


Background: Forkhead box C1 (FOXC1) is an important cancer-associated gene in tumor. PPAR-γ and C/EBPα are both transcriptional regulators involved in tumor development.

Objective: We aimed to clarify the function of PPAR-γ, C/EBPα in hepatocellular carcinoma (HCC) and the relationship of PPAR-γ, C/EBPα and FOXC1 in HCC.

Methods: Western blotting, immunofluorescent staining, and immunohistochemistry were used to evaluate protein expression. qRT-PCR was used to assess mRNA expression. Co-IP was performed to detect the protein interaction. And ChIP and fluorescent reporter detection were used to determine the binding between protein and FOXC1 promoter.

Results: C/EBPα could bind to FOXC1 promoter and PPAR-γ could strengthen C/EBPα’s function. Expressions of C/EBPα and PPAR-γ were both negatively related to FOXC1 in human HCC tissue. Confocal displayed that C/EBPα was co-located with FOXC1 in HepG2 cells. C/EBPα could bind to FOXC1 promoter by ChIP. Luciferase activity detection exhibited that C/EBPα could inhibit FOXC1 promoter activity, especially FOXC1 promoter from -600 to -300 was the critical binding site. Only PPAR-γ could not influence luciferase activity but strengthen inhibited effect of C/EBPα. Further, the Co-IP displayed that PPAR-γ could bind to C/EBPα. When C/EBPα and PPAR-γ were both high expressed, cell proliferation, migration, invasion, and colony information were inhibited enormously. C/EBPα plasmid combined with or without PPAR-γ agonist MDG548 treatment exhibited a strong tumor inhibition and FOXC1 suppression in mice.

Conclusion: Our data establish C/EBPα targeting FOXC1 as a potential determinant in the HCC, which supplies a new pathway to treat HCC. However, PPAR-γ has no effect on FOXC1 expression.

Keywords: HCC, FOXC1, PPAR-γ, C/EBPα, proliferation, hepatocellular carcinoma.

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Year: 2020
Published on: 27 January, 2020
Page: [59 - 66]
Pages: 8
DOI: 10.2174/1568009619666190912161003
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