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Oscar Murcia, Rodrigo Jover, Cecilia M Egoavil, Miriam Juarez, Lucia Perez-Carbonell, Eva Hernández-Illán, Estefanía Rojas, Cristina Alenda, Francesc Balaguer, Montserrat Andreu, Xavier Llor, Antoni Castells, C Richard Boland, Ajay Goel
PURPOSE: A recent study reported that 5-fluorouracil (5FU)-based chemotherapy is less effective in treating advanced colorectal cancer (CRC) patients demonstrating hypermethylation of TFAP2E gene. The aim of our study was to confirm and validate these findings in large, uniformly treated, well-characterized patient cohorts. EXPERIMENTAL DESIGN: Two cohorts of 783 CRC patients: 532 from a population-based, multicenter cohort (EPICOLON I) and 251 patients from a clinic-based trial were used to study the effectiveness of TFAP2E methylation and expression as a predictor of response of CRC patients to 5FU-based chemotherapy...
March 13, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Yi-Dong Hong, Jian Zhang, Ming Zhuang, Wei Li, Puy-Uan Wu, Ru-Tian Li, Nan Hu, Bao-Xiang Bian, Zi-Yan Song, Feng-Lei Wu
Hypermethylation of the transcription factor AP-2 epsilon (TFAP2E) gene affects 5-fluorouridine (5-FU) resistance in gastric cancer (GC) patients. The epigenetic inhibitor 5-Aza-2'-deoxycytidine (DAC), which reverses DNA methylation by targeting DNA methyltransferases (DNMTs), has potential to sensitize GC to 5-FU. Nevertheless, DNA demethylation only DAC transiently occurs since DAC is unstable in aqueous solutions, which limits its potential. Here we developed intelligent nanoparticles (NPs) comprising gelatinase with polyethylene glycol (PEG) and poly-ε-caprolactone) (PCL) to specifically deliver DAC (DAC-TNPs) to tumors...
December 29, 2017: Oncotarget
Jason Tchieu, Bastian Zimmer, Faranak Fattahi, Sadaf Amin, Nadja Zeltner, Shuibing Chen, Lorenz Studer
Directing the fate of human pluripotent stem cells (hPSCs) into different lineages requires variable starting conditions and components with undefined activities, introducing inconsistencies that confound reproducibility and assessment of specific perturbations. Here we introduce a simple, modular protocol for deriving the four main ectodermal lineages from hPSCs. By precisely varying FGF, BMP, WNT, and TGFβ pathway activity in a minimal, chemically defined medium, we show parallel, robust, and reproducible derivation of neuroectoderm, neural crest (NC), cranial placode (CP), and non-neural ectoderm in multiple hPSC lines, on different substrates independently of cell density...
September 7, 2017: Cell Stem Cell
Reina Hoshi, Yosuke Watanabe, Yoshiaki Ishizuka, Takayuki Hirano, Eri Nagasaki-Maeoka, Shinsuke Yoshizawa, Shota Uekusa, Hiroyuki Kawashima, Kensuke Ohashi, Kiminobu Sugito, Noboru Fukuda, Hiroki Nagase, Masayoshi Soma, Toshinori Ozaki, Tsugumichi Koshinaga, Kyoko Fujiwara
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...
April 2017: Oncology Reports
Hannah E Seberg, Eric Van Otterloo, Stacie K Loftus, Huan Liu, Greg Bonde, Ramakrishna Sompallae, Derek E Gildea, Juan F Santana, J Robert Manak, William J Pavan, Trevor Williams, Robert A Cornell
Mutations in the gene encoding transcription factor TFAP2A result in pigmentation anomalies in model organisms and premature hair graying in humans. However, the pleiotropic functions of TFAP2A and its redundantly-acting paralogs have made the precise contribution of TFAP2-type activity to melanocyte differentiation unclear. Defining this contribution may help to explain why TFAP2A expression is reduced in advanced-stage melanoma compared to benign nevi. To identify genes with TFAP2A-dependent expression in melanocytes, we profile zebrafish tissue and mouse melanocytes deficient in Tfap2a, and find that expression of a small subset of genes underlying pigmentation phenotypes is TFAP2A-dependent, including Dct, Mc1r, Mlph, and Pmel...
March 2017: PLoS Genetics
Kaoru S Imai, Hiroki Hikawa, Kenji Kobayashi, Yutaka Satou
Epidermis and neural tissues differentiate from the ectoderm in animal embryos. Although epidermal fate is thought to be induced in vertebrate embryos, embryological evidence has indicated that no intercellular interactions during early stages are required for epidermal fate in ascidian embryos. To test this hypothesis, we determined the gene regulatory circuits for epidermal and neural specification in the ascidian embryo. These circuits started with Tfap2-r.b and Sox1/2/3, which are expressed in the ectodermal lineage immediately after zygotic genome activation...
January 1, 2017: Development
Alena Zolotarenko, Evgeny Chekalin, Alexandre Mesentsev, Ludmila Kiseleva, Elena Gribanova, Rohini Mehta, Ancha Baranova, Tatiana V Tatarinova, Eleonora S Piruzian, Sergey Bruskin
Psoriasis is a common inflammatory skin disease with complex etiology and chronic progression. To provide novel insights into the regulatory molecular mechanisms of the disease, we performed RNA sequencing analysis of 14 pairs of skin samples collected from patients with psoriasis. Subsequent pathway analysis and extraction of the transcriptional regulators governing psoriasis-associated pathways was executed using a combination of the MetaCore Interactome enrichment tool and the cisExpress algorithm, followed by comparison to a set of previously described psoriasis response elements...
November 4, 2016: Experimental & Molecular Medicine
Xiaodong Li, Frédéric Gaillard, Elizabeth A Monckton, Darryl D Glubrecht, Amit R L Persad, Markus Moser, Yves Sauvé, Roseline Godbout
BACKGROUND: AP-2δ is the most divergent member of the Activating Protein-2 (TFAP2) family of transcription factors. AP-2δ is restricted to specific regions of the CNS, including a subset of ganglion cells in the retina. Retinal ganglion cells (RGCs), the only output neurons of the retina, are responsible for transmitting the visual signal to the brain. RESULTS: AP-2δ knockout results in loss of Brn3c (Pou4f3) expression in AP-2δ -positive RGCs. While AP-2δ-/- mice have morphologically normal retinas at birth, there is a significant reduction in retinal ganglion cell numbers by P21, after eye opening...
June 4, 2016: Molecular Brain
K Hardy, F Wu, W Tu, A Zafar, T Boulding, R McCuaig, C R Sutton, A Theodoratos, S Rao
Epithelial-to-mesenchymal transition (EMT) is physiological in embryogenesis and wound healing but also associated with the formation of cancer stem cells (CSCs). Many EMT signaling pathways are implicated in CSC formation, but the precise underlying mechanisms of CSC formation remain elusive. We have previously demonstrated that PKC is critical for EMT induction and CSC formation in inducible breast EMT/CSC models. Here, we used formaldehyde-assisted isolation of regulatory elements-sequencing (FAIRE-seq) to investigate DNA accessibility changes after PKC activation and determine how they influence EMT and CSC formation...
2016: Nucleus
Maria E Baardman, Mathijs V Zwier, Lambertus J Wisse, Adriana C Gittenberger-de Groot, Wilhelmina S Kerstjens-Frederikse, Robert M W Hofstra, Angelika Jurdzinski, Beerend P Hierck, Monique R M Jongbloed, Rolf M F Berger, Torsten Plösch, Marco C DeRuiter
Lipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts ofLrp2knockout (KO) mice have not yet been investigated. We studied the cardiovascular development ofLrp2KO mice between embryonic day 10.5 (E10.5) and E15.5, applying morphometry and immunohistochemistry, using antibodies against Tfap2α (neural crest cells), Nkx2.5 (second heart field), WT1 (epicardium derived cells), tropomyosin (myocardium) and LRP2...
April 2016: Disease Models & Mechanisms
Andrew D Beggs, Mark P Dilworth, Enric Domingo, Rachel Midgley, David Kerr, Ian P M Tomlinson, Gary W Middleton
INTRODUCTION: BRAF mutant colorectal cancer carries a poor prognosis which is thought to be related to poor response to conventional chemotherapy. BRAF mutation is associated with the serrated tumour phenotype. We hypothesised that one of the mechanisms by which BRAF mutant colorectal cancer demonstrate poor outcomes with chemotherapy is abnormal gene methylation. METHODS: The Cancer Genome Atlas (TCGA) methylation data was analysed using a linear regression model with BRAF mutation as an independent variable...
2015: Oncoscience
Stephan Niebler, Thomas Schubert, Ernst B Hunziker, Anja K Bosserhoff
INTRODUCTION: The transcription factor activating enhancer binding protein 2 epsilon (AP-2ε) was recently shown to be expressed during chondrogenesis as well as in articular chondrocytes of humans and mice. Furthermore, expression of AP-2ε was found to be upregulated in affected cartilage of patients with osteoarthritis (OA). Despite these findings, adult mice deficient for AP-2ε (Tfap2e(-/-)) do not exhibit an obviously abnormal cartilaginous phenotype. We therefore analyzed embryogenesis of Tfap2e(-/-) mice to elucidate potential transient abnormalities that provide information on the influence of AP-2ε on skeletal development...
2015: Arthritis Research & Therapy
Jingyue Sun, Nan Du, Jin Li, Jianwei Zhou, Guoquan Tao, Suan Sun, Jingdong He
Chemotherapy is a mainstay of therapy for advanced gastric cancer (GC); however, owing to drug resistances, the effectiveness of chemotherapy is not satisfactory for some patients with GC. Therefore, identification of a marker that predicts treatment response is beneficial to patients. Hypermethylation of transcription factor activating enhancer-binding protein 2∊ (TFAP2E) has been implicated in chemotherapy resistance to fluorouracil-based chemotherapy in patients with colorectal cancer, but its role in GC is still unknown...
April 2016: Technology in Cancer Research & Treatment
Feng-lei Wu, Ru-Tian Li, Mi Yang, Guo-Feng Yue, Hui-yu Wang, Qin Liu, Fang-bo Cui, Pu-yuan Wu, Hui Ding, Li-Xia Yu, Xiao-Ping Qian, Bao-Rui Liu
Aberrant methylation of the transcription factor AP-2 epsilon (TFAP2E) has been attributed to 5-fluorouridine (5-FU) sensitivity. 5-Aza-2'-deoxycytidine (DAC), an epigenetic drug that inhibits DNA methylation, is able to cause reactive expression of TFAP2E by demethylating activity. This property might be useful in enhancing the sensitivity of cancer cells to 5-FU. However, the effect of DAC is transient because of its instability. Here, we report the use of intelligent gelatinases-stimuli nanoparticles (NPs) to coencapsulate and deliver DAC and 5-FU to gastric cancer (GC) cells...
July 10, 2015: Cancer Letters
Elisa Penna, Francesca Orso, Daniela Taverna
MicroRNAs are short regulatory RNAs that are able to post-transcriptionally modulate gene expression and that have crucial roles in the control of physiological and pathological processes including cancer onset, growth, and progression. miR-214, located inside the sequence of the long noncoding Dmn3os transcript, contributes to the regulation of normal and cancer cell biology, even if it operates in a context-dependent and sometimes contradictory manner. miR-214 is deregulated in several human tumors including melanoma, breast, ovarian, gastric, and hepatocellular carcinomas...
April 2015: Journal of Investigative Dermatology
Seong Joon Park, Seung-mi Kim, Yong Sang Hong, Jae-Lyun Lee, Jeong-Eun Kim, Kyu-pyo Kim, Seung-Mo Hong, Dong-Hoon Jin, Chan Wook Kim, Yong Sik Yoon, In Ja Park, Seok-Byung Lim, Chang Sik Yu, Jin Cheon Kim, Tae Won Kim
OBJECTIVES: This study investigates the clinical significance of the gene encoding AP-2ε (TFAP2E) in colorectal cancer (CRC) patients undergoing curative resection. METHODS: A single-institution cohort of 248 patients who underwent curative resection of stage I/II/III CRCs between March and December 2004 was enrolled, and 193 patients whose tumors were available for the determination of the TFAP2E methylation status were included in the analysis. RESULTS: TFAP2E hypermethylation was detected in 112 patients (58%) and was significantly associated with distally located CRCs, low pathologic T stage (T1/T2), and stage I tumors...
2015: Oncology
Zuo-Ming Zhang, Yibaina Wang, Rong Huang, Yu-Peng Liu, Xia Li, Fu-Lan Hu, Lin Zhu, Fan Wang, Bin-Bin Cui, Xin-Shu Dong, Ya-Shuang Zhao
PURPOSE: Hypermethylation of TFAP2E (AP-2E) is associated with the chemotherapy-resistant in patients with colorectal cancer (CRC), but its implications on prognosis directly remain unknown. This study was aimed to investigate the role of AP-2E methylation status and other clinicopathologic parameters as predictors of prognosis. METHODS: We detected the methylation status of AP-2E in tumor and adjacent non-tumor tissues from 311 sporadic CRC patients by methylation-sensitive high-resolution melting analysis...
December 2014: Journal of Cancer Research and Clinical Oncology
Chang-Soo Hong, Arun Devotta, Young-Hoon Lee, Byung-Yong Park, Jean-Pierre Saint-Jeannet
Transcription factors Pax3 and Zic1 are two important regulators of cell fate decision at the neural plate border, where they act synergistically to promote neural crest (NC) formation. To understand the role of these factors in NC development, we performed a microarray analysis to identify downstream targets of Pax3 and Zic1 in Xenopus embryos. Among the genes identified was a member of transcription factor activator protein 2 (Tfap2) family, Tfap2 epsilon (Tfap2e). Tfap2e is first expressed at early neurula stage in NC progenitors and Rohon-Beard sensory neurons, and persists in a subset of migrating cranial NC cells as they populate the pharyngeal arches...
September 2014: Developmental Neurobiology
Binnur Eroglu, Jin-Na Min, Yan Zhang, Edyta Szurek, Demetrius Moskophidis, Ali Eroglu, Nahid F Mivechi
Heat shock factor binding protein 1 (HSBP1) is a 76 amino acid polypeptide that contains two arrays of hydrophobic heptad repeats and was originally identified through its interaction with the oligomerization domain of heat shock factor 1 (Hsf1), suppressing Hsf1's transcriptional activity following stress. To examine the function of HSBP1 in vivo, we generated mice with targeted disruption of the hsbp1 gene and examined zebrafish embryos treated with HSBP1-specific morpholino oligonucleotides. Our results show that hsbp1 is critical for preimplantation embryonic development...
February 15, 2014: Developmental Biology
Kyoko Fujiwara, Srimoyee Ghosh, Ping Liang, Evan Morien, Masayoshi Soma, Hiroki Nagase
Epigenetic alteration of genomic DNA is a common and key process in carcinogenesis. There is considerable evidence indicating that some of the somatic alterations occurring during carcinogenesis in humans also involve the same processes as those observed in mice. Therefore, we analyzed mouse skin cancer tissues induced by the 2-stage carcinogenesis model to identify skin tumor-specific differentially methylated regions (ST-DMRs) during the multistep carcinogenesis process. We have previously identified ST-DMRs using the restriction landmark genomic scanning (RLGS) technique and reported that some of the mouse ST-DMRs were also epigenetically modified in human cancers, such as melanoma, neuroblastoma, and brain tumor...
March 2015: Molecular Carcinogenesis
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