Characterization of genome-wide TFCP2 targets in hepatocellular carcinoma: implication of targets FN1 and TJP1 in metastasis View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-01-22

AUTHORS

Xiao Xu, Zhikun Liu, Lin Zhou, Haiyang Xie, Jun Cheng, Qi Ling, Jianguo Wang, Haijun Guo, Xuyong Wei, Shusen Zheng

ABSTRACT

BackgroundTranscription factor CP2 (TFCP2) is overexpressed in hepatocellular carcinoma(HCC) 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. More... »

PAGES

6

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s13046-015-0121-1

DOI

http://dx.doi.org/10.1186/s13046-015-0121-1

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https://app.dimensions.ai/details/publication/pub.1043479499

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/25609232


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31 schema:description BackgroundTranscription factor CP2 (TFCP2) is overexpressed in hepatocellular carcinoma(HCC) 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.
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37 schema:keywords CP2
38 ChIP assays
39 ChIP-PCR
40 ConclusionsThe identification
41 FN1 promoter
42 HCC
43 HCC cells
44 HCC metastasis
45 Integration of transcriptome
46 MethodsWe
47 TFCP2
48 aggression
49 aggressive effect
50 alterations
51 analysis
52 angiogenesis
53 approach
54 assays
55 attachment
56 binding
57 biological functions
58 biology approach
59 cancer
60 cancer progression
61 carcinoma
62 cell aggression
63 cell movement
64 cells
65 cellular growth
66 changes
67 changes of genes
68 characterization
69 chip
70 chromatin immunoprecipitation
71 computational approach
72 different HCC cells
73 direct binding
74 discovery
75 disease
76 effect
77 expression
78 expression microarrays
79 factors
80 fibronectin 1
81 function
82 gene expression
83 gene expression microarrays
84 genes
85 global targets
86 global transcriptional regulation
87 growth
88 hepatocarcinogenesis
89 hepatocellular carcinoma
90 identification
91 immunoprecipitation
92 implications
93 increase
94 inhibition
95 integrated systems biology approach
96 integration
97 key mediator
98 knockdown
99 maps
100 mechanism
101 mediators
102 metastasis
103 metastatic phenotype
104 microarray
105 molecular functions
106 molecular pathways
107 motif
108 movement
109 network
110 overexpression
111 part
112 pathway
113 phenotype
114 progression
115 proliferation
116 promoter
117 promoter reporter
118 protein 1
119 quest
120 region
121 regulation
122 reporter
123 scale maps
124 sites
125 systems biology approach
126 target
127 target gene expression
128 tight junction protein 1
129 transcriptional regulation
130 transcriptome
131 understanding
132 use
133 validation
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