Gene Summary

Gene:TFAP2C; transcription factor AP-2 gamma
Aliases: ERF1, TFAP2G, hAP-2g, AP2-GAMMA
Summary:The protein encoded by this gene is a sequence-specific DNA-binding transcription factor involved in the activation of several developmental genes. The encoded protein can act as either a homodimer or heterodimer with other family members and is induced during retinoic acid-mediated differentiation. It plays a role in the development of the eyes, face, body wall, limbs, and neural tube. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcription factor AP-2 gamma
Source:NCBIAccessed: 29 August, 2019


What does this gene/protein do?
Show (25)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 29 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Biomarkers, Tumor
  • Up-Regulation
  • Cell Differentiation
  • Neoplastic Cell Transformation
  • Binding Sites
  • TFAP2C
  • Chromosome 20
  • Signal Transduction
  • Core Binding Factor beta Subunit
  • Sp1 Transcription Factor
  • Gene Expression
  • Neoplasm Proteins
  • TFAP2A
  • Chromosome Inversion
  • Down-Regulation
  • Messenger RNA
  • fas Receptor
  • Apoptosis
  • Myeloid Leukemia
  • DNA-Binding Proteins
  • DNA Methylation
  • Zinc Fingers
  • Protein Binding
  • Proto-Oncogene Proteins
  • Leukaemia
  • Acute Myeloid Leukaemia
  • Molecular Sequence Data
  • Amino Acid Sequence
  • Cloning, Molecular
  • Base Sequence
  • Melanoma
  • Breast Cancer
  • Gene Expression Profiling
  • Chromosome 16
  • Promoter Regions
  • Upstream Stimulatory Factors
  • Cancer Gene Expression Regulation
  • siRNA
  • Cell Proliferation
  • Core Binding Factor Alpha 2 Subunit
  • Recombinant Fusion Proteins
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TFAP2C (cancer-related)

Zhou B, Guo H, Tang J
Long Non-Coding RNA TFAP2A-AS1 Inhibits Cell Proliferation and Invasion in Breast Cancer via miR-933/SMAD2.
Med Sci Monit. 2019; 25:1242-1253 [PubMed] Free Access to Full Article Related Publications
BACKGROUND It is well documented that long non-coding RNAs (lncRNAs) are involved in the progression of multiple human tumors by sponging microRNAs (miRNAs). However, whether lncRNA TFAP2A-AS1 plays a role in the tumorigenesis of breast cancer (BC) remains undetermined. MATERIAL AND METHODS Real-time PCR (qRT-PCR) assay was performed to detect the relative mRNA expression of TFAP2A-AS1 and miR-933. Flow cytometry analysis, CCK-8 assay, and Transwell assay were applied to detect the effects of TFAP2A-AS1 overexpression on cell cycle, apoptosis, viability, and invasion of BC cells. In vivo proliferation assay was performed to evaluate the effects of TFAP2A-AS1 overexpression on tumor growth. Bioinformatics methods, dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays were used to predict and validate the interaction between TFAP2A-AS1 and miR-933, as well as SMAD2 and miR-933. Western blot assay was performed to examine the protein expression of SMAD2 in treated BC cells. RESULTS TFAP2A-AS1 expression was significantly lower in BC tissues and cell lines, and patients with high TFAP2A-AS1 expression exhibited a better prognosis than those with low TFAP2A-AS1 expression. Overexpression of TFAP2A-AS1 in BC cells caused cell cycle arrest, promoted cell apoptosis, suppressed cell ability, and attenuated cell invasion in vitro, and inhibited tumor growth in vivo. TFAP2A-AS1 was revealed to act as a miRNA sponge for miR-933 and then regulated the expression of Smad2. CONCLUSIONS Results from the present study suggest that TFAP2A-AS1 acts as a tumor suppressor in BC via the miR-933/SMAD2 axis.

Lv J, Guo L, Wang JH, et al.
Biomarker identification and trans-regulatory network analyses in esophageal adenocarcinoma and Barrett's esophagus.
World J Gastroenterol. 2019; 25(2):233-244 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Esophageal adenocarcinoma (EAC) is an aggressive disease with high mortality and an overall 5-year survival rate of less than 20%. Barrett's esophagus (BE) is the only known precursor of EAC, and patients with BE have a persistent and excessive risk of EAC over time. Individuals with BE are up to 30-125 times more likely to develop EAC than the general population. Thus, early detection of EAC and BE could significantly improve the 5-year survival rate of EAC. Due to the limitations of endoscopic surveillance and the lack of clinical risk stratification strategies, molecular biomarkers should be considered and thoroughly investigated.
AIM: To explore the transcriptome changes in the progression from normal esophagus (NE) to BE and EAC.
METHODS: Two datasets from the Gene Expression Omnibus (GEO) in NCBI Database ( were retrieved and used as a training and a test dataset separately, since NE, BE, and EAC samples were included and the sample sizes were adequate. This study identified differentially expressed genes (DEGs) using the R/Bioconductor project and constructed trans-regulatory networks based on the Transcriptional Regulatory Element Database and Cytoscape software. Enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) terms was identified using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics Resources. The diagnostic potential of certain DEGs was assessed in both datasets.
RESULTS: In the GSE1420 dataset, the number of up-regulated DEGs was larger than that of down-regulated DEGs when comparing EAC
CONCLUSION: After the construction and analyses of the trans-regulatory networks in EAC and BE, the results indicate that COL1A1 and MMP1 could be potential biomarkers for EAC and BE, respectively.

Nag JK, Bar-Shavit R
Transcriptional Landscape of PARs in Epithelial Malignancies.
Int J Mol Sci. 2018; 19(11) [PubMed] Free Access to Full Article Related Publications
G protein-coupled receptors (GPCRs), the largest family of cell receptors, act as important regulators of diverse signaling pathways. Our understanding of the impact of GPCRs in tumors is emerging, yet there is no therapeutic platform based on GPCR driver genes. As cancer progresses, it disrupts normal epithelial organization and maintains the cells outside their normal niche. The dynamic and flexible microenvironment of a tumor contains both soluble and matrix-immobilized proteases that contribute to the process of cancer advancement. An example is the activation of cell surface protease-activated receptors (PARs). Mammalian PARs are a subgroup of GPCRs that form a family of four members, PAR

Wei L, He F, Zhang W, et al.
Bioinformatics analysis of microarray data to reveal the pathogenesis of diffuse intrinsic pontine glioma.
Biol Res. 2018; 51(1):26 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is the main cause of pediatric brain tumor death. This study was designed to identify key genes associated with DIPG.
METHODS: The gene expression profile GSE50021, which consisted of 35 pediatric DIPG samples and 10 normal brain samples, was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified by limma package. Functional and pathway enrichment analyses were performed by the DAVID tool. Protein-protein interaction (PPI) network, and transcription factor (TF)-microRNA (miRNA)-target gene network were constructed using Cytoscape. Moreover, the expression levels of several genes were validated in human glioma cell line U251 and normal glia HEB cells through real-time polymerase chain reaction (PCR).
RESULTS: A total of 378 DEGs were screened (74 up-regulated and 304 down-regulated genes). In the PPI network, GRM1, HTR2A, GRM7 and GRM2 had higher degrees. Besides, GRM1 and HTR2A were significantly enriched in the neuroactive ligand-receptor interaction pathway, and calcium signaling pathway. In addition, TFAP2C was a significant down-regulated functional gene and hsa-miR-26b-5p had a higher degree in the TF-miRNA-target gene network. PCR analysis revealed that GRM7 and HTR2A were significantly downregulated while TFAP2C was upregulated in U251 cells compared with that in HEB cells (p < 0.001). GRM2 was not detected in cells.
CONCLUSIONS: GRM1 and HTR2A might function in DIPG through the neuroactive ligand-receptor interaction pathway and the calcium signaling pathway. Furthermore, the TFAP2C and hsa-miR-26b-5p might play important roles in the development and progression mechanisms of DIPG.

Yuan J, Zhang N, Zheng Y, et al.
LncRNA GAS5 Indel Genetic Polymorphism Contributes to Glioma Risk Through Interfering Binding of Transcriptional Factor TFAP2A.
DNA Cell Biol. 2018; 37(9):750-757 [PubMed] Related Publications
Long noncoding RNA (lncRNA) growth arrest-specific 5 (GAS5) accumulates in growth-arrested cells and plays a crucial role in progression of multiple cancers, including glioma. There is a functional GAS5 rs145204276 indel genetic polymorphism in the promoter region. However, it is still largely unknown how the GAS5 indel genetic polymorphism is involved in etiology of glioma. We evaluated the association between the GAS5 indel genetic polymorphism and glioma development in a Chinese population. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression adjusted by age and sex. We found that carriers of the GAS5 del allele was significantly associated with elevated risk of glioma (OR = 1.71, 95% CI = 1.34-2.18, p = 1.7 × 10

Hu J, Tan SK, Lim MGL, et al.
Identification of a Wells-Dawson polyoxometalate-based AP-2γ inhibitor with pro-apoptotic activity.
Biochem J. 2018; 475(11):1965-1977 [PubMed] Related Publications
AP-2 gamma (AP-2γ) is a transcription factor that plays pivotal roles in breast cancer biology. To search for small molecule inhibitors of AP-2γ, we performed a high-throughput fluorescence anisotropy screen and identified a polyoxometalate compound with Wells-Dawson structure K

Takahashi C, Miyatake K, Kusakabe M, Nishida E
The atypical mitogen-activated protein kinase ERK3 is essential for establishment of epithelial architecture.
J Biol Chem. 2018; 293(22):8342-8361 [PubMed] Free Access to Full Article Related Publications
Epithelia contribute to physical barriers that protect internal tissues from the external environment and also support organ structure. Accordingly, establishment and maintenance of epithelial architecture are essential for both embryonic development and adult physiology. Here, using gene knockout and knockdown techniques along with gene profiling, we show that extracellular signal-regulated kinase 3 (ERK3), a poorly characterized atypical mitogen-activated protein kinase (MAPK), regulates the epithelial architecture in vertebrates. We found that in

Xiong G, Huang H, Feng M, et al.
MiR-10a-5p targets TFAP2C to promote gemcitabine resistance in pancreatic ductal adenocarcinoma.
J Exp Clin Cancer Res. 2018; 37(1):76 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: By regulating target genes, microRNAs play essential roles in carcinogenesis and drug resistance in human pancreatic ductal adenocarcinoma (PDAC). Previous studies have shown that microRNA-10a-5p (miR-10a-5p) is overexpressed in PDAC and acts as an oncogene to promote the metastatic behavior of PDAC cells. However, the role of miR-10a-5p in PDAC chemoresistance remains unclear.
METHODS: The effects of miR-10a-5p on biological behaviors were analyzed. MiR-10a-5p and TFAP2C levels in tissues were detected, and the clinical value was evaluated.
RESULTS: We found that miR-10a-5p is up-regulated in gemcitabine-resistant PDAC cells and enhances PDAC cell gemcitabine resistance in vitro and vivo. Meanwhile, we also determined that miR-10a-5p promotes the migratory and invasive ability of PDAC cells. Next, we confirmed that transcription factor activating protein 2 gamma (TFAP2C) is a target of miR-10a-5p, and TFAP2C overexpression resensitizes PDAC cells to gemcitabine, which is initiated by miR-10a-5p. Further studies revealed that TFAP2C also decreased PDAC cell migration and invasion capability. Finally, survival analysis demonstrated that high miR-10a-5p expression levels and low TFAP2C expression levels were both independent adverse prognostic factors in patients with PDAC.
CONCLUSION: Together, these results indicate that miR-10a-5p/TFAP2C may be new therapeutic target and prognostic marker in PDAC.

Cao L, Wang S, Zhang Y, et al.
Zinc-finger protein 471 suppresses gastric cancer through transcriptionally repressing downstream oncogenic PLS3 and TFAP2A.
Oncogene. 2018; 37(26):3601-3616 [PubMed] Free Access to Full Article Related Publications
Zinc-finger protein 471 (ZNF471) was preferentially methylated in gastric cancer using promoter methylation array. The role of ZNF471 in human cancer is unclear. Here we elucidated the functional significance, molecular mechanisms and clinical impact of ZNF471 in gastric cancer. ZNF471 mRNA was silenced in 15 out of 16 gastric cancer cell lines due to promoter hypermethylation. Significantly higher ZNF471 promoter methylation was also observed in primary gastric cancers compared to their adjacent normal tissues (P < 0.001). ZNF471 promoter CpG-site hypermethylation correlated with poor survival of gastric cancer patients (n = 120, P = 0.001). Ectopic expression of ZNF471 in gastric cancer cell lines (AGS, BGC823, and MKN74) significantly suppressed cell proliferation, migration, and invasion, while it induced apoptosis in vitro and inhibited xenograft tumorigenesis in nude mice. Transcription factor AP-2 Alpha (TFAP2A) and plastin3 (PLS3) were two crucial downstream targets of ZNF471 demonstrated by bioinformatics modeling and ChIP-PCR assays. ZNF471 directly bound to the promoter of TFAP2A and PLS3 and transcriptionally inhibited their expression. TFAP2A and PLS3 showed oncogenic functions in gastric cancer cell lines. Moreover, ZNF471 recruited KAP1 to the promoter of the target genes, thereby inducing H3K9me3 enrichment for transcriptional repression and inhibition of oncogenic TFAP2A and PLS3. In conclusion, ZNF471 acts as a tumor suppressor in gastric cancer by transcriptionally inhibiting downstream targets TFAP2A and PLS3. KAP1 is a co-repressor of ZNF471 at the promoter of the target genes. The promoter CpG-site methylation is an independent prognostic factor for overall survival of gastric cancer patients.

Wu H, Zhang J
Decreased expression of TFAP2B in endometrial cancer predicts poor prognosis: A study based on TCGA data.
Gynecol Oncol. 2018; 149(3):592-597 [PubMed] Related Publications
BACKGROUND: Transcription factor activator protein-2β (TFAP-2β) was previously reported to constituted promoter activity in endometrial carcinoma (EC). We evaluated the role of TFAP2B in ECs using publicly available data from The Cancer Genome Atlas (TCGA).
METHODS: The relationship between clinical pathologic features and TFAP2B were analyzed with the Wilcoxon signed-rank test and logistic regression. Clinicopathologic characteristics associated with overall survival in TCGA patients using Cox regression and the Kaplan-Meier method. Gene Set Enrichment Analysis (GSEA) was performed using TCGA data set.
RESULTS: Reduced TFAP2B expression in EC was significantly associated with high grade (OR=2.2 for well, moderate vs. poor), stage (OR=2.5 for I vs. IV), histology (OR=1.8 for serous vs. endometrioid), distant metastasis (OR=2.4 for positive vs. negative) (all p-values<0.05). Kaplan-Meier survival analysis showed that EC with TFAP2B-low had a worse prognosis than that with TFAP2B-high (p=0.013). The univariate analysis revealed that TFAP2B-low correlated significantly with a poor overall survival (OS) (HR: 2.35; 95% confidence interval [CI]: 1.17-4.73; p=0.016). The multivariate analysis revealed that TFAP2B remained independently associated with overall survival, with a HR of 4.42 (CI: 1.25-12.64; p=0.021). GSEA show that p53/hypoxia pathway, androgen response, notch signaling, fatty acid metabolism, glycolysis and estrogen response late are differentially enriched in TFAP2B high expression phenotype.
CONCLUSIONS: TFAP2B expression may be a potential prognostic molecular marker of poor survival in endometrial cancer, Moreover, the p53/hypoxia, androgen response and notch signaling pathway may be the key pathway regulated by TFAP2B in EC.

Meng Q, Wu S, Wang Y, et al.
Cancer Res. 2018; 78(10):2760-2769 [PubMed] Free Access to Full Article Related Publications
Myeloperoxidase (

Wang X, Sun D, Tai J, et al.
TFAP2C promotes stemness and chemotherapeutic resistance in colorectal cancer via inactivating hippo signaling pathway.
J Exp Clin Cancer Res. 2018; 37(1):27 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Aberrant expression of transcription Factor AP-2 Gamma (TFAP2C) has been reported to be implicated in malignant process of many cancers. The purpose of this study is to investigate the clinical significance and biological roles of TFAP2C in colorectal cancer (CRC).
METHODS: TFAP2C expression was evaluated by real-time PCR, Western blot and immunohistochemistry (IHC) respectively in clinical CRC tissues. Statistical analysis was performed to explore the correlation between TFAP2C expression and clinicopathological features, and overall and progression-free survival in CRC patients. In vitro and in vivo assays were performed to assess the biological roles of TFAP2C in CRC cells. Western blot, luciferase and Chromatin immunoprecipitation (ChIP) assays were used to identify the underlying pathway mediating the biological roles of TFAP2C in CRC.
RESULTS: TFAP2C is robustly upregulated in CRC tissues and cells, and high expression of TFAP2C correlates with advanced clinicopathological features, poor prognosis and disease progression in CRC patients. Furthermore, upregulating TFAP2C enhances spheroids formation ability, the fraction of SP cells, expression of stem cell factors and the mitochondrial potential, and reduces the apoptosis induced by 5-fluorouracil in colorectal cancer cells in vitro, and promotes stemness and chemoresistance of CRC cells in vivo; while silencing TFAP2C yields an opposite effect. Importantly, downregulation of TFAP2C dramatically restores chemotherapeutic sensitivity of CRC cells to 5-FU in vivo. Our results further demonstrate that TFAP2C promotes stemness and chemoresistance of CRC cells to 5-FU by inhibiting Hippo signaling via transcriptionally upregulating ROCK1 and ROCK2 in CRC cells.
CONCLUSION: Our findings indicate that TFAP2C may serve as a novel prognostic factor in CRC patients, and a therapeutic target for the treatment of CRC, suggesting that silencing TFAP2C in combination with 5-FU may be an effective therapeutic strategy to improve survival in CRC patients.

Yamashita S, Kishino T, Takahashi T, et al.
Genetic and epigenetic alterations in normal tissues have differential impacts on cancer risk among tissues.
Proc Natl Acad Sci U S A. 2018; 115(6):1328-1333 [PubMed] Free Access to Full Article Related Publications
Genetic and epigenetic alterations are both involved in carcinogenesis, and their low-level accumulation in normal tissues constitutes cancer risk. However, their relative importance has never been examined, as measurement of low-level mutations has been difficult. Here, we measured low-level accumulations of genetic and epigenetic alterations in normal tissues with low, intermediate, and high cancer risk and analyzed their relative effects on cancer risk in the esophagus and stomach. Accumulation of genetic alterations, estimated as a frequency of rare base substitution mutations, significantly increased according to cancer risk in esophageal mucosae, but not in gastric mucosae. The mutation patterns reflected the exposure to lifestyle risk factors. In contrast, the accumulation of epigenetic alterations, measured as DNA methylation levels of marker genes, significantly increased according to cancer risk in both tissues. Patients with cancer (high-risk individuals) were precisely discriminated from healthy individuals with exposure to risk factors (intermediate-risk individuals) by a combination of alterations in the esophagus (odds ratio, 18.2; 95% confidence interval, 3.69-89.9) and by only epigenetic alterations in the stomach (odds ratio, 7.67; 95% confidence interval, 2.52-23.3). The relative importance of epigenetic alterations upon genetic alterations was 1.04 in the esophagus and 2.31 in the stomach. The differential impacts among tissues will be critically important for effective cancer prevention and precision cancer risk diagnosis.

Yang L, Wu D, Chen J, et al.
A functional CNVR_3425.1 damping lincRNA FENDRR increases lifetime risk of lung cancer and COPD in Chinese.
Carcinogenesis. 2018; 39(3):347-359 [PubMed] Related Publications
Genomic imbalance referring to somatic variation in chromosome copies represents the most frequent event in tumorigenesis. Germline copy number variations (gCNVs) overlapping regions of genomic imbalance harbor similar structural characteristics and thus influence tumor susceptibility. We aimed to test effects of such gCNVs on the risk of lung cancer and chronic obstructive pulmonary disease (COPD). Genomic imbalance of lung cancer was determined by the array comparative genomic hybridization (aCGH), and common gCNVs at these imbalance regions were genotyped in lung cancer-based and COPD-based retrospective studies. Functional assays were conducted to assess function of promising CNVs. A total of 115 genomic imbalances were discovered occurring at a frequency of more than 25%. The CNVR_3425.1, overlapping the chr16q24.1 with genomic imbalance, was significantly associated with increased risks of lung cancer (OR = 1.76; 95% CI = 1.46-2.11) and COPD (OR = 1.98; 95% CI = 1.57-2.51). The increase copy of CNVR_3425.1 forms a new additional truncated FOXF1 adjacent non-coding developmental regulatory RNA (FENDRR) sequences comparing the gene promoter and perturbs the transcriptional factors (TFs) binding to the original FENDRR promoter and further downregulates FENDRR, a long intergenic non-coding RNA (lincRNA) that functions to inhibit lung cancer by affecting expressions of an abundant number of genes, including the tumor suppressor FOXF1. FENDRR can upregulate FOXF1 by competitively binding to miR-424. The TFs early growth response 1 (EGR1) and transcription factor AP-2 alpha (TFAP2A) were further found to involve the CNVR_3425.1-mediated FENDRR dysregulation. These findings suggested the CNVR_3425.1 to be a possibly predictive biomarker for the risk of lung cancer and COPD, and targeted molecular therapy pertaining to FENDRR upregulation may be a valuable pathway to fight two diseases.

Liu Y, Yang Y, Wang T, et al.
Long non-coding RNA CCAL promotes hepatocellular carcinoma progression by regulating AP-2α and Wnt/β-catenin pathway.
Int J Biol Macromol. 2018; 109:424-434 [PubMed] Related Publications
OBJECTIVE: Long non-coding RNAs are emerging as key molecules in cancer progression. LncRNA-CCAL has shown to be highly expressed and important in regulating CRC and osteosarcoma development. Nevertheless, the expression and mechanism of CCAL in HCC is still not well understood.
METHODS: qRT-PCR and ISH were used to evaluate CCAL expression in HCC tissues and cell lines. Histone H3 methylation and acetylation levels across CCAL promoter region were examined by chromatin immunoprecipitation assays. Transfection of Lv-CCAL-shRNAs into HCC cell lines was used to evaluate cellular invasion and proliferation. The influence of CCAL depletion on AP-2α expression and Wnt/β-catenin pathway was analyzed by qRT-PCR, western blot and immunofluorescence.
RESULTS: Higher expression of CCAL was found in HCC tumor tissues compared with normal tissues, and was associated with tumor metastasis and TNM stage. Furthermore, the decreased histone H3 methylation and increased histone H3 acetylation across CCAL promoter region contributed to the upregulation of CCAL in HCC. Moreover, the depletion of CCAL inhibited HCC cellular invasion and proliferation, and promoted cell apoptosis. In addition, CCAL depletion up-regulated AP-2α expression and inhibited Wnt/β-catenin pathway activation.
CONCLUSIONS: CCAL has an important role in hepatic carcinogenesis and may serve as a new target for HCC diagnosis and treatment.

Zhang D, Li H, Jiang X, et al.
Role of AP-2α and MAPK7 in the regulation of autocrine TGF-β/miR-200b signals to maintain epithelial-mesenchymal transition in cholangiocarcinoma.
J Hematol Oncol. 2017; 10(1):170 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cholangiocarcinoma (CCA) is characterized by early lymphatic, metastasis, and low survival rate. Epithelial-mesenchymal transition (EMT) is able to induce tumor metastasis. Although the TGF-β/miR-200 signals promote EMT in various types of cancer, the regulatory mechanism in CCA is still unclear.
METHODS: Expression of miR-200b, TGF-β, and EMT markers were measured in tumor samples and cell lines by qRT-PCR and western blot. CCK8 assay was performed to measure the cell viability. Transwell assay was used to evaluate migration and invasion. The target genes of miR-200b and transcription factor of TGF-β were analyzed using dual-luciferase reporter system.
RESULTS: We have demonstrated that CCA exhibited remarkable EMT phenotype and miR-200b was reduced in CCA patients (n = 20) and negatively correlated to TGF-β. Moreover, two CCA cells, HCCC, and RBE, with epithelial appearances treated with TGF-β, showed fibroblastic-like cell morphology with downregulated miR-200b expression. Forced expression of miR-200b abrogated TGF-β-induced EMT initiation, with decreased cell proliferation, migration, and invasion in vitro. Also, TFAP2A (encode AP-2α) and MAPK7 were found to be targeted by miR-200b to downregulate EMT and AP-2α inhibited miR-200b by directly promoting transcription of TGFB1. Overexpression of MAPK7 significantly reversed miR-200b-induced inhibition of EMT, migration, and proliferation by increasing the expression of TGF-β, cyclin D1, and Cdk2. Further, the administration of miR-200b induced a remarkably tumor regression in vivo and reduced the effect of TGF-β-related EMT in AP-2α and MAPK7-dependent manner.
CONCLUSIONS: Our study highlights that miR-200b-based gene therapy is effective in the treatment of CCA.

Vastrad B, Vastrad C, Tengli A, Iliger S
Identification of differentially expressed genes regulated by molecular signature in breast cancer-associated fibroblasts by bioinformatics analysis.
Arch Gynecol Obstet. 2018; 297(1):161-183 [PubMed] Related Publications
OBJECTIVE: Breast cancer is a severe risk to public health and has adequately convoluted pathogenesis. Therefore, the description of key molecular markers and pathways is of much importance for clarifying the molecular mechanism of breast cancer-associated fibroblasts initiation and progression. Breast cancer-associated fibroblasts gene expression dataset was downloaded from Gene Expression Omnibus database.
METHODS: A total of nine samples, including three normal fibroblasts, three granulin-stimulated fibroblasts and three cancer-associated fibroblasts samples, were used to identify differentially expressed genes (DEGs) between normal fibroblasts, granulin-stimulated fibroblasts and cancer-associated fibroblasts samples. The gene ontology (GO) and pathway enrichment analysis was performed, and protein-protein interaction (PPI) network of the DEGs was constructed by NetworkAnalyst software.
RESULTS: Totally, 190 DEGs were identified, including 66 up-regulated and 124 down-regulated genes. GO analysis results showed that up-regulated DEGs were significantly enriched in biological processes (BP), including cell-cell signalling and negative regulation of cell proliferation; molecular function (MF), including insulin-like growth factor II binding and insulin-like growth factor I binding; cellular component (CC), including insulin-like growth factor binding protein complex and integral component of plasma membrane; the down-regulated DEGs were significantly enriched in BP, including cell adhesion and extracellular matrix organization; MF, including N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase activity and calcium ion binding; CC, including extracellular space and extracellular matrix. WIKIPATHWAYS analysis showed the up-regulated DEGs were enriched in myometrial relaxation and contraction pathways. WIKIPATHWAYS, REACTOME, PID_NCI and KEGG pathway analysis showed the down-regulated DEGs were enriched endochondral ossification, TGF beta signalling pathway, integrin cell surface interactions, beta1 integrin cell surface interactions, malaria and glycosaminoglycan biosynthesis-chondroitin sulfate/dermatan sulphate. The top 5 up-regulated hub genes, CDKN2A, MME, PBX1, IGFBP3, and TFAP2C and top 5 down-regulated hub genes VCAM1, KRT18, TGM2, ACTA2, and STAMBP were identified from the PPI network, and subnetworks revealed these genes were involved in significant pathways, including myometrial relaxation and contraction pathways, integrin cell surface interactions, beta1 integrin cell surface interaction. Besides, the target hsa-mirs for DEGs were identified. hsa-mir-759, hsa-mir-4446-5p, hsa-mir-219a-1-3p and hsa-mir-26a-5p were important miRNAs in this study.
CONCLUSIONS: We pinpoint important key genes and pathways closely related with breast cancer-associated fibroblasts initiation and progression by a series of bioinformatics analysis on DEGs. These screened genes and pathways provided for a more detailed molecular mechanism underlying breast cancer-associated fibroblasts occurrence and progression, holding promise for acting as molecular markers and probable therapeutic targets.

Wang G, Zeng Y, Chen S, et al.
Localization of TFPI-2 in the nucleus modulates MMP-2 gene expression in breast cancer cells.
Sci Rep. 2017; 7(1):13575 [PubMed] Free Access to Full Article Related Publications
TFPI-2 has recently been recognized as a tumor suppressor, which not only plays a fundamental role in modulation of ECM integrity, but also involves the regulation of many oncogenes. In this study, we investigated the potential mechanism of TFPI-2 in the suppression of breast cancer growth and invasion. We showed that, with either over-expression of TFPI-2 or after treatment with exogenous rTFPI-2, breast cancer cells exhibited reduced proliferation and invasion. We demonstrated that in addition to being secreted, TFPI-2 was also distributed throughout the cytoplasm and nucleus. Nuclear localization of TFPI-2 contributed to inhibition of MMP-2 mRNA expression, which could be reversed after the nuclear localization signal was deleted. In the nucleus, interaction of TFPI-2 with Ap-2α attenuated the binding of AP-2α to the MMP-2 promoter, therefore reducing the transcriptional activity of the gene. Our results suggest that one of the mechanisms by which TFPI-2 inhibits breast cancer cell invasion could be via the regulation of MMP-2 gene transcription.

Liu Q, Kulak MV, Borcherding N, et al.
A novel HER2 gene body enhancer contributes to HER2 expression.
Oncogene. 2018; 37(5):687-694 [PubMed] Free Access to Full Article Related Publications
The transcriptional regulation of the human epidermal growth factor receptor-2 (HER2) contributes to an enhanced HER2 expression in HER2-positive breast cancers with HER2 gene amplification and HER2-low or HER2-negative breast cancers following radiotherapy or endocrine therapy, and this drives tumorigenesis and the resistance to therapy. Epigenetic mechanisms are critical for transcription regulation, however, such mechanisms in the transcription regulation of HER2 are limited to the involvement of tri-methylated histone 3 lysine 4 (H3K4me3) and acetylated histone 3 lysine 9 (H3K9ac) at the HER2 promoter region. Here, we report the identification of a novel enhancer in the HER2 3' gene body, which we have termed HER2 gene body enhancer (HGE). The HGE starts from the 3' end of intron 19 and extends into intron 22, possesses enhancer histone modification marks in specific cells and enhances the transcriptional activity of the HER2 promoters. We also found that TFAP2C, a known regulator of HER2, binds to HGE and is required for its enhancer function and that DNA methylation in the HGE region inhibits the histone modifications characterizing enhancer and is inversely correlated with HER2 expression in breast cancer samples. The identification of this novel enhancer sheds a light on the roles of epigenetic mechanisms in HER2 transcription, in both HER2-positive breast cancer samples and individuals with HER2-low or HER2-negative breast cancers undergoing radiotherapy or endocrine therapy.

Raap M, Gronewold M, Christgen H, et al.
Lobular carcinoma in situ and invasive lobular breast cancer are characterized by enhanced expression of transcription factor AP-2β.
Lab Invest. 2018; 98(1):117-129 [PubMed] Related Publications
Transcription factor AP-2β (TFAP2B) regulates embryonic organ development and is overexpressed in alveolar rhabdomyosarcoma, a rare childhood malignancy. Gene expression profiling has implicated AP-2β in breast cancer (BC). This study characterizes AP-2β expression in the mammary gland and in BC. AP-2β protein expression was assessed in the normal mammary gland epithelium, in various reactive, metaplastic and pre-invasive neoplastic lesions and in two clinical BC cohorts comprising >2000 patients. BCs from various genetically engineered mouse (GEM) models were also evaluated. Human BC cell lines served as functional models to study siRNA-mediated inhibition of AP-2β. The normal mammary gland epithelium showed scattered AP-2β-positive cells in the luminal cell layer. Various reactive and pre-invasive neoplastic lesions, including apocrine metaplasia, usual ductal hyperplasia and lobular carcinoma in situ (LCIS) showed enhanced AP-2β expression. Cases of ductal carcinoma in situ (DCIS) were more often AP-2β-negative (P<0.001). In invasive BC cohorts, AP-2β-positivity was associated with the lobular BC subtype (P<0.001), loss of E-cadherin (P<0.001), a positive estrogen receptor (ER) status (P<0.001), low Ki67 (P<0.001), low/intermediate Oncotype DX recurrence scores (P<0.001), and prolonged event-free survival (P=0.003). BCs from GEM models were all AP-2β-negative. In human BC cell lines, AP-2β expression was independent from ER-signaling. SiRNA-mediated inhibition of AP-2β diminished proliferation of lobular BC cell lines in vitro. In summary, AP-2β is a new mammary epithelial differentiation marker. Its expression is preferentially retained and enhanced in LCIS and invasive lobular BC and has prognostic implications. Our findings indicate that AP-2β controls tumor cell proliferation in this slow-growing BC subtype.

Pu M, Li C, Qi X, et al.
MiR-1254 suppresses HO-1 expression through seed region-dependent silencing and non-seed interaction with TFAP2A transcript to attenuate NSCLC growth.
PLoS Genet. 2017; 13(7):e1006896 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) are a class of small non-coding RNAs, which direct post-transcriptional gene silencing (PTGS) and function in a vast range of biological events including cancer development. Most miRNAs pair to the target sites through seed region near the 5' end, leading to mRNA cleavage and/or translation repression. Here, we demonstrated a miRNA-induced dual regulation of heme oxygenase-1 (HO-1) via seed region and non-seed region, consequently inhibited tumor growth of NSCLC. We identified miR-1254 as a negative regulator inhibiting HO-1 translation by directly targeting HO-1 3'UTR via its seed region, and suppressing HO-1 transcription via non-seed region-dependent inhibition of transcriptional factor AP-2 alpha (TFAP2A), a transcriptional activator of HO-1. MiR-1254 induced cell apoptosis and cell cycle arrest in human non-small cell lung carcinoma (NSCLC) cells by inhibiting the expression of HO-1, consequently suppressed NSCLC cell growth. Consistently with the in vitro studies, mouse xenograft studies validated that miR-1254 suppressed NSCLC tumor growth in vivo. Moreover, we found that HO-1 expression was inversely correlated with miR-1254 level in human NSCLC tumor samples and cell lines. Overall, these findings identify the dual inhibition of HO-1 by miR-1254 as a novel functional mechanism of miRNA, which results in a more effective inhibition of oncogenic mRNA, and leads to a tumor suppressive effect.

Chang TH, Tsai MF, Gow CH, et al.
Upregulation of microRNA-137 expression by Slug promotes tumor invasion and metastasis of non-small cell lung cancer cells through suppression of TFAP2C.
Cancer Lett. 2017; 402:190-202 [PubMed] Related Publications
The epithelial-mesenchymal transition (EMT) regulator, Slug, plays multifaceted roles in controlling lung cancer progression, but its downstream targets and mechanisms in promoting lung cancer progression have not been well defined. In particular, the miRNAs downstream of Slug in non-small cell lung cancer (NSCLC) remain undetermined. Here, we report that miR-137 is downstream of the EMT regulator, Slug, in lung cancer cells. Slug binds directly to the E-box of the miR-137 promoter and up-regulates its expression in lung cancer cells. Knockdown of miR-137 abolished Slug-induced cancer invasion and migration, whereas upregulation of miR-137 was found to trigger lung cancer cell invasion and progression by direct suppressing TFAP2C (transcription factor AP-2 gamma). Clinical data showed that lung adenocarcinoma patients with low-level expression of Slug and miR-137 but high-level expression of TFAP2C experienced significantly better survival. miR-137 is a Slug-induced miRNA that relays the pro-metastatic effects of Slug by targeting TFAP2C. Our findings add new components to the Slug-mediated regulatory network in lung cancer, and suggest that Slug, miR-137, and TFAP2C may be useful prognostic markers in lung adenocarcinoma.

Lian W, Zhang L, Yang L, Chen W
AP-2α reverses vincristine-induced multidrug resistance of SGC7901 gastric cancer cells by inhibiting the Notch pathway.
Apoptosis. 2017; 22(7):933-941 [PubMed] Related Publications
Multidrug resistance (MDR) remains a major clinical obstacle in the treatment of gastric cancer (GC) since it causes tumor recurrence and metastasis. The transcription factor activator protein-2α (AP-2α) has been implicated in drug-resistance in breast cancer; however, its effects on MDR of gastric cancer are far from understood. In this study, we aimed to explore the effects of AP-2α on the MDR in gastric cancer cells selected by vincristine (VCR). Decreased AP-2α levels were markedly detected by RT-PCR and Western blot in gastric cancer cell lines (BGC-823, SGC-7901, AGS, MKN-45) compared with that in the gastric epithelial cell line (GES-1). Furthermore, we found that the expression of AP-2α in SGC7901/VCR or SGC7901/adriamycin (ADR) cells was lower than in SGC7901 cells. Thus, a vector overexpressing AP-2α was constructed and used to perform AP-2α gain-of-function studies in SGC7901/VCR cells. The decreased IC50 values of the anti-cancer drugs in sensitive and resistant cells after transfect with pcDNA3.1/AP-2α were determined in SGC7901/VCR cells by MTT assay. Moreover, flow cytometry analysis indicated that overexpressed AP-2α induced cell cycle arrest in the G0/G1 phase and promoted cell apoptosis of VCR-selected SGC7901/VCR cells. RT-PCR and Western blot demonstrated that overexpressed AP-2α can significantly induce the down-regulation of Notch1, Hes-1, P-gp and MRP1 in SGC7901/VCR cells. Similar effects can be observed when Numb (Notch inhibitor) was introduced. In addition, the intracellular ADR accumulation was markedly detected in AP-2α overexpressed or Numb cells. In conclusion, our results indicate that AP-2α can reverse the MDR of gastric cancer cells, which may be realized by inhibiting the Notch signaling pathway.

Wang F, Huang W, Hu X, et al.
Transcription factor AP-2β suppresses cervical cancer cell proliferation by promoting the degradation of its interaction partner β-catenin.
Mol Carcinog. 2017; 56(8):1909-1923 [PubMed] Related Publications
Transcription factor AP-2β mediates the transcription of a number of genes implicated in mammalian development, cell proliferation, and carcinogenesis. Although the expression pattern of AP-2β has been analyzed in cervical cancer cell lines, the functions and molecular mechanism of AP-2β are unknown. Here, we found that AP-2β significantly inhibits TCF/LEF reporter activity. Moreover, AP-2β and β-catenin interact both in vitro through GST pull-down assays and in vivo by co-immunoprecipitation. We further identified the interaction regions to the DNA-binding domain of AP-2β and the 1-9 Armadillo repeats of β-catenin. Moreover, AP-2β binds with β-TrCP and promotes the degradation of endogenous β-catenin via the proteasomal degradation pathway. Immunohistochemistry analysis revealed a negative correlation between the two proteins in cervical cancer tissues and cell lines. Finally, functional analysis showed that AP-2β suppresses cervical cancer cell growth in vitro and in vivo by inhibiting the expression of Wnt downstream genes. Taken together, these findings demonstrated that AP-2β functions as a novel inhibitor of the Wnt/β-catenin signaling pathway in cervical cancer.

Hoshi R, Watanabe Y, Ishizuka Y, et al.
Depletion of TFAP2E attenuates adriamycin-mediated apoptosis in human neuroblastoma cells.
Oncol Rep. 2017; 37(4):2459-2464 [PubMed] Related Publications
Neuroblastoma is a childhood malignancy originating from the sympathetic nervous system and accounts for approximately 15% of all pediatric cancer-related deaths. To newly identify gene(s) implicated in the progression of neuroblastoma, we investigated aberrantly methylated genomic regions in mouse skin tumors. Previously, we reported that TFAP2E, a member of activator protein-2 transcription factor family, is highly methylated within its intron and its expression is strongly suppressed in mouse skin tumors compared with the normal skin. In the present study, we analyzed public data of neuroblastoma patients and found that lower expression levels of TFAP2E are significantly associated with a shorter survival. The data indicate that TFAP2E acts as a tumor suppressor of neuroblastoma. Consistent with this notion, TFAP2E-depleted neuroblastoma NB1 and NB9 cells displayed a substantial resistance to DNA damage arising from adriamycin (ADR), cisplatin (CDDP) and ionizing radiation (IR). Silencing of TFAP2E caused a reduced ADR-induced proteolytic cleavage of caspase-3 and PARP. Of note, compared with the untransfected control cells, ADR-mediated stimulation of CDK inhibitor p21WAF1 was markedly upregulated in TFAP2E‑knocked down cells. Therefore, our present findings strongly suggest that TFAP2E has a pivotal role in the regulation of DNA damage response in NB cells through the induction of p21WAF1.

Ren KW, Li YH, Wu G, et al.
Quercetin nanoparticles display antitumor activity via proliferation inhibition and apoptosis induction in liver cancer cells.
Int J Oncol. 2017; 50(4):1299-1311 [PubMed] Related Publications
Quercetin is a potent cancer therapeutic agent and dietary antioxidant present in fruit and vegetables. Quercetin prevents tumor proliferation by inducing cell cycle arrest and is a well known cancer therapeutic agent and autophagy mediator. Recent studies showed that drug delivery by nanoparticles have enhanced efficacy with reduced side effects. In this regard, gold-quercetin into poly(DL-lactide-co-glycolide) nanoparticles was examined. In this study, we explored the role and possible underlying mechanisms of quercetin nanoparticle in regulation of antitumor activity in liver cancer cells. Treatment with quercetin nanoparticle effectively inhibited the liver cancer cell proliferation, cell migration and colony formation, thus suppressing liver cancer progression. Quercetin nanoparticle also upregulated apoptosis markedly. Further study suggested that quercetin nanoparticle accelerated the cleavage of caspase-9, caspase-3, and induced the up-releasing of cytochrome c (Cyto-c), contributing to apoptosis in liver cancer cells. Quercetin nanoparticles also promoted telomerase reverse transcriptase (hTERT) inhibition through reducing AP-2β expression and decreasing its binding to hTERT promoter. In addition, quercetin nanoparticle had an inhibitory role in cyclooxygenase 2 (COX-2) via suppressing the NF-κB nuclear translocation and its binding to COX-2 promoter. Quercetin nanoparticle also inactivated Akt and ERK1/2 signaling pathway. Taken together, our results suggested that quercetin nanoparticle had an antitumor effect by inactivating caspase/Cyto-c pathway, suppressing AP-2β/hTERT, inhibiting NF-κB/COX-2 and impeding Akt/ERK1/2 signaling pathways. Our results provided new mechanistic basis for further investigation of quercetin nanoparticles to find potential therapeutic strategies and possible targets for liver cancer inhibition.

Kim W, Kim E, Lee S, et al.
TFAP2C-mediated upregulation of TGFBR1 promotes lung tumorigenesis and epithelial-mesenchymal transition.
Exp Mol Med. 2016; 48(11):e273 [PubMed] Free Access to Full Article Related Publications
TFAP2C (transcription factor-activating enhancer-binding protein 2C) expression has been positively correlated with poor prognosis in patients with certain types of cancer, but the mechanisms underlying TFAP2C-mediated tumorigenesis in non-small-cell lung cancer (NSCLC) are still unknown. We previously performed a microarray analysis to identify TFAP2C regulation genes, and TGFBR1 (transforming growth factor-β receptor type 1) was found to be upregulated by TFAP2C. We observed that TFAP2C or TGFBR1 overexpression led to oncogenic properties, such as cell viability, proliferation and cell cycle progression. TGFBR1 upregulation induced by TFAP2C also promoted cell motility and migration, leading to malignant development. We also found that PAK1 (p21 protein (Cdc42/Rac)-activated kinase 1) signaling was involved in TFAP2C/TGFBR1-induced tumorigenesis. These results were confirmed by an in vivo xenograft model and patient tissue samples. This study shows that TFAP2C promoted tumor progression by upregulation of TGFBR1 and consequent activation of PAK1 signaling.

Jeselsohn R, Barry WT, Migliaccio I, et al.
TransCONFIRM: Identification of a Genetic Signature of Response to Fulvestrant in Advanced Hormone Receptor-Positive Breast Cancer.
Clin Cancer Res. 2016; 22(23):5755-5764 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Fulvestrant is an estrogen receptor (ER) antagonist and an approved treatment for metastatic estrogen receptor-positive (ER
EXPERIMENTAL DESIGN: Primary tumor samples from 134 patients enrolled in the phase III CONFIRM study of patients with metastatic ER
RESULTS: Pathway analysis demonstrated that increased EGF pathway and FOXA1 transcriptional signaling is associated with decreased response to fulvestrant. Using a multivariate Cox model, we identified a novel set of 37 genes with an expression that is independently associated with progression-free survival (PFS). TFAP2C, a known regulator of ER activity, was ranked second in this gene set, and high expression was associated with a decreased response to fulvestrant. The negative predictive value of TFAP2C expression at the protein level was confirmed by IHC.
CONCLUSIONS: We identified biologic pathways and a novel gene signature in primary ER

Hao H, Xiao D, Pan J, et al.
Sentinel Lymph Node Genes to Predict Prognosis in Node-Positive Melanoma Patients.
Ann Surg Oncol. 2017; 24(1):108-116 [PubMed] Related Publications
PURPOSE: Melanoma patients with a single microscopically-positive sentinel lymph node (SLN) are classified as stage III and are often advised to undergo expensive and substantially toxic adjuvant therapy. However, the 5-year survival rate for these patients, with or without adjuvant therapy, varies from 14 to 85 %, representing a heterogeneous biological population with a variable prognosis. We aimed to identify an SLN gene signature to aid in risk stratification of patients with tumor-positive SLNs.
METHODS: Microarray experiments were performed to screen SLN genes in recurrence (N = 39) versus non-recurrence (N = 58) groups in the training dataset. Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) assay was applied to confirm the expression of selected SLN genes, which were further verified using an independent validation cohort (N = 30). Area under the receiver operating characteristic curve (AUC) was calculated to evaluate prognostic accuracy of the selected SLN gene panel, and the prognostic value of our SLN gene signature was also compared with the current American Joint Committee on Cancer (AJCC) staging system.
RESULTS: We identified two SLN genes (PIGR and TFAP2A) that provided high prognostic accuracy in SLN-positive melanoma patients (AUC = 0.864). These two SLN genes, along with clinicopathological features, can differentiate the high- and low-risk groups in node-positive melanoma patients in this cohort.
CONCLUSION: The two SLN genes, when combined with clinicopathological features, may offer a new tool for personalized patient risk assessment.

Kang J, Kim W, Lee S, et al.
TFAP2C promotes lung tumorigenesis and aggressiveness through miR-183- and miR-33a-mediated cell cycle regulation.
Oncogene. 2017; 36(11):1585-1596 [PubMed] Related Publications
Non-small cell lung cancer (NSCLC) remains one of the leading causes of death worldwide, and thus new molecular targets need to be identified to improve treatment efficacy. Although epidermal growth factor receptor (EGFR)/KRAS mutation-driven lung tumorigenesis is well understood, the mechanism of EGFR/KRAS-independent signal activation remains elusive. Enhanced TFAP2C (transcription factor activating enhancer-binding protein 2C) expression is associated with poor prognosis in some types of cancer patients, but little is known of its relation with the pathogenesis of lung cancer. In the present study, we found that TFAP2C overexpression was associated with cell cycle activation and NSCLC cell tumorigenesis. Interestingly, TFAP2C blocked AKAP12-mediated cyclin D1 inhibition by inducing the overexpression of oncogenic microRNA (miRNA)-183 and simultaneously activated cyclin-dependent kinase 6-mediated cell cycle progression by downregulating tumor-suppressive miRNA-33a. In a mouse xenograft model, TFAP2C promoted lung tumorigenesis and disease aggressiveness via the miR-183 and miR-33a pathways. The study provides a mechanism of mitogenic and oncogenic signaling via two functionally opposed miRNAs and suggests that TFAP2C-induced cell cycle hyperactivation contributes to lung tumorigenesis.

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