Characterization of genome-wide TFCP2 targets in hepatocellular carcinoma: implication of targets FN1 and TJP1 in metastasisReportar como inadecuado




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Journal of Experimental and Clinical Cancer Research

, 34:6

First Online: 22 January 2015Received: 05 September 2014Accepted: 04 January 2015DOI: 10.1186-s13046-015-0121-1

Cite this article as: Xu, X., Liu, Z., Zhou, L. et al. J Exp Clin Cancer Res 2015 34: 6. doi:10.1186-s13046-015-0121-1

Abstract

BackgroundTranscription factor CP2 TFCP2 is overexpressed in hepatocellular carcinomaHCC and correlated with the progression of the disease. Here we report the use of an integrated systems biology approach to identify genome-wide scale map of TFCP2 targets as well as the molecular function and pathways regulated by TFCP2 in HCC.

MethodsWe combined Chromatin immunoprecipitation ChIP on chip along with gene expression microarrays to study global transcriptional regulation of TFCP2 in HCC. The biological functions, molecular pathways, and networks associated with TFCP2 were identified using computational approaches. Validation of selected target gene expression and direct binding of TFCP2 to promoters were performed by ChIP -PCR and promoter reporter.

ResultsTFCP2 fostered a highly aggressive and metastatic phenotype in different HCC cells. Transcriptome analysis showed that alteration of TFCP2 in HCC cells led to change of genes in biological functions involved in cancer, cellular growth and proliferation, angiogenesis, cell movement and attachment. Pathways related to cell movement and cancer progression were also enriched. A quest for TFCP2-regulated factors contributing to metastasis, by integration of transcriptome and ChIP on chip assay, identified fibronectin 1 FN1 and tight junction protein 1 TJP1 as targets of TFCP2, and as key mediators of HCC metastasis. Promoter reporter identified the TFCP2-responsive region, and located the motifs of TFCP2-binding sites in the FN1 promoter, which then was confirmed by ChIP-PCR. We further showed that FN1 inhibition blocks the TFCP2-induced increase in HCC cell aggression, and that overexpression of TFCP2 can rescue the effects of FN1 inhibition. Knock down of TJP1 could also rescue, at least in part, the aggressive effect of TFCP2 knockdown in HCC cells.

ConclusionsThe identification of global targets, molecular pathways and networks associated with TFCP2, together with the discovery of the effect of TFCP2 on FN1 and TJP1 that are involved in metastasis, adds to our understanding of the mechanisms that determine a highly aggressive and metastatic phenotype in hepatocarcinogenesis.

KeywordsHepatocellular carcinoma Metastasis Fibronectin 1 Tight junction protein 1 Transcription factor CP2 AbbreviationsTFCP2Transcription factor CP2

FN1Fibronectin 1

TJP1Tight junction protein 1

MMP-9Matrix metalloproteinase-9

TSThymidylate synthase

HBVHepatitis B virus

HCCHepatocellular carcinoma

EMTEpithelial-mesenchymal transition

IPAIngenuity Pathway Analysis

HAHemagglutinin

ChIPChromatin immunoprecipitation

Xiao Xu and Zhikun Liu contributed equally to this work.

Electronic supplementary materialThe online version of this article doi:10.1186-s13046-015-0121-1 contains supplementary material, which is available to authorized users.

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Autor: Xiao Xu - Zhikun Liu - Lin Zhou - Haiyang Xie - Jun Cheng - Qi Ling - Jianguo Wang - Haijun Guo - Xuyong Wei - Shusen Zh

Fuente: https://link.springer.com/







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