bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1369: miR-645 inhibits apoptosis of AGEJ
Authors: Feng Xiaoshan , Wang Ying , Ma Zhikun , Yang Ruina , Zhang Mengxi , Liang Shuo , Li Shuoguo , Liu Gang , Dai Fanming , Gao Shegan 
Published: May 2015

Abstract
Background: An increasing body of evidence indicates that miRNAs have a critical role in carcinogenesis and cancer progression; however, the role of miRNAs in the tumorigenesis of adencarcinoma of gastric esophageal junction(AGEJ) remains largely unclear.Methods: The SGC7901 and BGC-823 gastric cancer cell lines were used. The expressions of miR-645 and IFIT2 were examined by qRT-PCR. The expressions of IFIT2 was examined by western blotting and immunohistochemistry assay. The cell apoptosis was determined by FACS. MiR-645 inhibitor, mimics and plasmid-IFIT2 transfections were performed to study the loss- and gain-function. Caspase-3/7 activity was examined by caspase-3/7 assay. Results: In the present study, we have reported an increased expression of miR-645 in AGEJ clinical specimens compared with paired non-cancerous tissues. We also observed a significant miR-645 up-regulation in two gastric cancer ( GC ) cell lines, SGC7901 and BGC-823, which were used as cell models because there was no available AGEJ cell lines established to date. We found that inhibition of miR-645 could sensitize dramatically SGC7901 and BGC-823 cells to both serum starvation- and chemotherapeutic drug-induced apoptosis by up-regulating IFIT2, a mediator of apoptosis via a mitochondrial pathway, with a potential binding site for miR-645 in its mRNA's 3′UTR. Further investigation exhibited that IFIT2 expression decreases in SGC7901 and BGC-823 cells and AGEJ tissues. IFIT2 ectopic expression leads to promotion of cell apoptosis, indicating that IFIT2 may function as a suppressor in the development of AGEJ. Furthermore, inhibition of miR-645 induces up-regulation of IFIT2 and increased caspase-3/7 activity compared with control groups. Conclusions: Our data suggest that miR-645 functions as an oncogene in human AGEJ by, at least partially through, targeting IFIT2. &lt;!–EndFragment–&gt;
Note: This abstract was not presented at the meeting.
Citation Format: Xiaoshan Feng, Ying Wang, Zhikun Ma, Ruina Yang, Mengxi Zhang, Shuo Liang, Shuoguo Li, Gang Liu, Fanming Dai, Shegan Gao. miR-645 inhibits apoptosis of AGEJ. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1369. doi:10.1158/1538-7445.AM2014-1369
Abstract 1372: The methylome of ER-negative tumors is predominantly hypermethylated
Authors: Worsham Maria J. , Chitale Dhananjay , Chen Kang Mei , Divine George 
Published: May 2015

Abstract
The biological significance of DNA methylation in the regulation of gene expression and its role in cancer is increasingly recognized. The underlying hypothesis of this study is that strategic global approaches will identify aberrantly methylated genes that underlie the pathogenesis of ER-negative (ER-) breast cancer (BC).
We used the Infinium HumanMethylation450 BeadChip to profile the methylome of ER- breast cancers to determine differentially methylated genes. The 450K array includes 485,577 cytosine positions of the human genome. Whole genomic DNA from 40 primary ER-, 40 ER positive (ER+), and 40 normal breast tissue samples were assayed for genome-wide methylation. Data were analyzed by GenomeStudio software (Illumina). Degree of methylation was calculated as a β-value (ranging from 0 to 1) and M-values [log (β/ (1- β)] were used for significance tests. With 30 sets of paired tumor/normal tissue, GEE was performed to account for their correlation. To identify methylated genes associated with ER- subtypes and distinct from ER+, a 3-tiered approach to call out genes in which methylation changed dramatically between ER+ and ER- subtypes was used. Tier 1: computed adjusted FDR values for all CpGs/ (or their averages for each gene) to be 0.05 or lower. Tier 2: the CpGs/genes to include genes with a 2-fold change (ratio &gt;= 2.0 or ratio &lt;= 0.5). Tier 3: CpGs/genes to include genes with an absolute difference between the mean β of =&gt;0.2.
Differentially methylated genes (DMGs) at tier 3 for the different comparison groups were as follows: all BC (n=80) vs normal (n=40): 1070 DMGs: 1001: hypermethylated, 69: hypemethylated; ER+ vs normal: 1720: 1518 hyper, 202 hypo; ER- vs normal: 1170, 1085 hyper, 85 hypo; ER- vs ER+ vs: 289, 191 hyper, 97 hypomethylated.
Overall, ER- BC tumors were more hypermethylated than hypomethylated when compared to normal breast tissue and ER+ BC. Estrogen receptor-negative BC is a more aggressive form than ER positive BC with approximately double the incidence in African Americans than in Caucasian Americans. The emerging differential methylation pattern would further help stratify them into distinct subgroups. Promotor methylation being potentially reversible, methylated genes may serve as future molecular targets for demethylating therapies.
Support: Komen Foundation: KG110218
Citation Format: Maria J. Worsham, Dhananjay Chitale, Kang Mei Chen, George Divine. The methylome of ER-negative tumors is predominantly hypermethylated. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1372. doi:10.1158/1538-7445.AM2014-1372
Abstract 1374: Identification of a transcription factor driving BET dependency in SCLC
Authors: Wee Susan , Wong Tai ,   BMS
Published: May 2015

Abstract
The regulation, and subsequent recognition, of covalent chromatin modifications by an array of cellular proteins are key determinants of gene expression. For instance, the binding of bromodomain and extra terminal domain (BET) proteins to acetylated histone tails has been shown to regulate c-MYC transcription in some cell types. Consequently, pharmacological inhibition of BET proteins leads to an anti-proliferative activity in cancers dependent on c-MYC activity such as multiple myeloma and acute myelogenous leukemia. Since c-MYC has been implicated as a driver of cell proliferation in many cancer types, we investigated if BET inhibitors may have anti-proliferative activity in solid tumor cancer cell lines as well. Strikingly, in a panel of over 100 mixed histology lung cancer cell lines we identified selective growth inhibition of lines derived from small cell lung cancer (SCLC) histology. To better understand the mechanism of this dependency we performed 12-point dose response microarray analyses using the BET inhibitor, JQ1, in order to identify genes that are regulated by BET proteins in SCLC. In contrast to what has been observed in myeloma and leukemia, BET inhibition is not always accompanied by inhibition of c-MYC expression in the SCLC cell lines. From this analysis a lineage-specific transcription factor was found to be highly regulated in a dose-dependent manner. Previous studies have reported this transcription factor to be essential in maintaining the differentiated neuroendocrine phenotype characteristic of human SCLC. It has also been shown that loss of this transcription factor results in growth inhibition in SCLC tumor models. We have confirmed the growth dependency of SCLC to BET via dysregulation of this transcription factor using RNAi and a small molecule inhibitor. Furthermore, chromatin immunoprecipitation followed by deep-sequencing confirmed binding of BRD4, a BET family member, and RNA polymerase II, a marker of active gene transcription, to the enhancer region of this target gene in two sensitive SCLC cell lines. This binding is disrupted in the presence of BET compound treatment. SCLC is a disease with high unmet medical need, and the results of our studies have identified BET inhibition as a potential novel therapeutic opportunity for this subtype of lung cancer. Our results have also provided a mechanistic basis for the sensitivity of SCLC to BET inhibition, and a rationale for the clinical development of BET inhibitors beyond hematologic cancers.
Citation Format: Susan Wee, Tai Wong, BMS. Identification of a transcription factor driving BET dependency in SCLC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1374. doi:10.1158/1538-7445.AM2014-1374
Abstract 1377: Transcriptional silencing of MST1/Hippo by a coordinated MYC and EZH2 signaling in prostate cancer
Authors: Abali Gamze Kuser , Alptekin Ahmet , Cinar Bekir 
Published: May 2015

Abstract
Prostate cancer is a major cause of cancer-related death in western countries because of the poorly understood disease mechanisms. Hippo-like MST1 protein kinase regulates cell growth, stem cell self-renewal and carcinogenesis. The loss of Mst1 expression is implicated in the etiology several types of cancers with poor prognosis, including prostate cancer. However, the underlying mechanism of Mst1 transcriptional downregulation in prostate cancer is unknown. Here, we report that MYC and EZH2 function as epigenetic suppressors of MST1 in human prostate cancer cells. We showed that decline in MST1 expression correlated with EZH2 and MYC upregulation as demonstrated by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) and western blot. Using methylation sensitive PCR and bisulfite genomic DNA sequencing, we showed that Mst1 promoter DNA was methylated at CpG sites that led to a reduction in MST1 expression. Our pharmacologic or RNAi experiments revealed that EZH2 contributed to MST1 silencing by inducing MST1 promoter DNA methylation and H3K27me3 modification that was accompanied by a reduced H3K4me3 mark and RNA polymerase II occupancy on MST1 promoter and thereby reducing its promoter activity and expression. On the other hand, overexpression of MYC stimulated EZH2 and conversely reduced MST1 promoter activation and its mRNA levels. Potent EZH2 inhibitors reversed the MYC effects on MST1, indicating that MYC attenuates MST1 through EZH2. Moreover, MST1 knockdown caused cell resistance to androgen deficiency and to EZH2, or MYC inhibitor-induced growth retardation. These findings indicate that MYC cooperates with EZH2 to epigenetically silence MST1 and suggest that the loss of MST1/Hippo is critical for MYC- and EZH2-driven cancer cell survival.
Citation Format: Gamze Kuser Abali, Ahmet Alptekin, Bekir Cinar. Transcriptional silencing of MST1/Hippo by a coordinated MYC and EZH2 signaling in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1377. doi:10.1158/1538-7445.AM2014-1377
Abstract 1378: The histone methyltransferase adaptor WDR5 is a novel cofactor in neuroblastoma
Authors: Sun Yuting , Liu Pei Yan , Carter Daniel , Sokolowski Nicolas , MacKenzie Karen L. , Marshall Glenn M. , Liu Tao 
Published: May 2015

Abstract
Introduction: Neuroblastoma is the most common extracranial solid malignancy in early childhood. WDR5 is an essential component of the MLL and SET1/COMPASS histone H3 lysine 4 (H3K4) methyltransferase complex and plays a key role in the trimethylation of H3K4. However, there is no previous study establishing the role of WDR5 in neuroblastoma.
Results: Affymetrix gene array studies showed that knocking-down WDR5 expression with siRNAs reduced the expression of the cell cycle genes cyclin E1. Consistently, RT-PCR and immunoblot confirmed that WDR5 siRNAs reduced cyclin E1 mRNA and protein expression, ChIP assays showed that WDR5 siRNAs reduced histone H3K4 tri-methylation at the cyclin E1 gene promoter, and Alamar blue assays demonstrated that WDR5 induced neuroblastoma cell proliferation. Additionally, high levels of WDR5 gene expression in human neuroblastoma tissues predict poor patient survival independent of patient age and disease stage.
Conclusions: Our data demonstrate WDR5 as a novel co-factor in neuroblastoma oncogenesis, and provide critical evidence to support the application of WDR5 inhibitors for the therapy of neuroblastoma patients.
Citation Format: Yuting Sun, Pei Yan Liu, Daniel Carter, Nicolas Sokolowski, Karen L. MacKenzie, Glenn M. Marshall, Tao Liu. The histone methyltransferase adaptor WDR5 is a novel cofactor in neuroblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1378. doi:10.1158/1538-7445.AM2014-1378
Abstract 1379: Identification of global DNA methylation signatures in glioblastoma-derived cancer stem cells
Authors: Lee Eun Joon , Rath Prakash , Liu Jimei , Ryu Dungsheng , Free Alan , Pei Lirong , Anthony Douglas C , Sharma Suash , Kirk Mark D , Laterra John J. , Ryu Duck Hwan , Choi Jeong-Hyeon , Shi Huidong , Miller Douglas C. , Litofsky N. Scott , Feng Qi 
Published: May 2015

Abstract
Glioblastoma (GBM) is the most common and most aggressive brain tumor in adults. Its frequent recurrence after resection and dismal prognosis are thought to be due to a small population of stem-like tumor cells that efficiently propagate tumors and resist cytotoxic therapy. In this study, we performed an in depth analysis of the DNA methylation landscape in GBM-derived cancer stem cells (GSCs). Parallel comparisons of primary GBM tumors and GSC lines derived from these tumors with normal controls (a neural stem cell (NSC) line and normal brain tissue) identified two groups hyper- and hypomethylated of genes that display a trend of either increasing or decreasing methylation levels in the order of controls, primary GBMs, and their counterpart GSC lines, respectively. Interestingly, concurrent promoter hypermethylation and gene body hypomethylation were observed in a subset of genes including MGMT, AJAP1 and PTPRN2. These unique DNA methylation signatures were also be found in primary GBM-derived xenograft tumors suggesting that they were not tissue culture-related epigenetic changes. Integration of GSC-specific epigenetic signatures with gene expression analysis further identified candidate tumor suppressor genes that are frequently down regulated in GBMs such as SPINT2, NEFM, and PENK. The comparison between the NSC line and the normal brain tissue sample leads to the identification of a group of NSC-specific differentially methylated regions (nsDMRs). Cluster analysis using nsDMRs revealed the presence of stem cell-specific DNA methylation signatures in both primary GBM and GSC lines. Higher expression of genes associated with stem cell-specific DNA methylation signatures such as DNMT3A, STAT5A, CSTB, PMEPA1 and G6PD in GBM patients was found to be associated with poor patient survival. The results from this study demonstrate the utility of using cancer stem cell models for advancing understanding of the pathobiology of gliomas.
Citation Format: Eun Joon Lee, Prakash Rath, Jimei Liu, Dungsheng Ryu, Alan Free, Lirong Pei, Douglas C Anthony, Suash Sharma, Mark D Kirk, John J. Laterra, Duck Hwan Ryu, Jeong-Hyeon Choi, Huidong Shi, Douglas C. Miller, N. Scott Litofsky, Qi Feng. Identification of global DNA methylation signatures in glioblastoma-derived cancer stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1379. doi:10.1158/1538-7445.AM2014-1379
Abstract 1382: Developmental exposure to BPA increases the prostate cancer susceptibility via reprogramming of androgen-responsive genes via increased H3K4me3 methylation
Authors: Wang Quan , Wong Rebecca Lee Yean , Kusewitt Donna F. , Bosland Maarten C. , Chen Jing , Medvedovic Mario , Prins Gail S. , Kannan Kurunthachalam , Ho Shuk-Mei , Walker Cheryl Lyn 
Published: May 2015

Abstract
Background:
Early life exposure to endocrine disrupting compounds (EDCs) during critical developmental periods increases susceptibility to cancer and other diseases in adulthood. Because EDC exposures cause life-long changes in gene expression of target tissues, identification of gene targets for developmental reprogramming holds promise for both understanding the etiology of environmental causes of cancer and development of biomarkers of EDC exposure.
Aim:
Our goal was to identify targets for developmental reprogramming in the prostate using a rat model for development of hormone-dependent early prostate (PIN) lesions induced by the EDC bisphenol A (BPA).
Methods:
Rats were exposed neonatally to vehicle or BPA and assessed at 12 months for development of hormone-dependent prostate lesions. Epigenetic status and gene expression were profiled in the at-risk (d70) adult prostate using CHIP- and RNA-seq, with qRT-PCR and ChIP used to confirm changes in gene expression and histone methylation (respectively).
Results:
As expected, BPA exposure significantly increased PIN lesions and the dysplasia score in 12 mo rats. CHIP-seq in adult rats (day 70) prior to lesion development showed a significant increase in histone H3, lysine 4 trimethylation (H3K4me3) levels in prostate cancer-associated KEGG pathway genes of rats exposed to BPA neonatally. Changes reflective of both increased basal, as well as hormone-induced, KEGG pathway gene expression were observed in BPA exposed animals at increased risk for development of PIN lesions.
Conclusion:
Neonatal BPA exposure reprograms the developing prostate to alter gene expression in adulthood and increase incidence and severity of prostatic dysplasia. Several KEGG-pathway prostate cancer pathway genes were identified as targets for epigenetic reprogramming, providing new tools for future studies to understand gene-environment interactions as determinants of prostate cancer risk.
Citation Format: Quan Wang, Rebecca Lee Yean Wong, Donna F. Kusewitt, Maarten C. Bosland, Jing Chen, Mario Medvedovic, Gail S. Prins, Kurunthachalam Kannan, Shuk-Mei Ho, Cheryl Lyn Walker. Developmental exposure to BPA increases the prostate cancer susceptibility via reprogramming of androgen-responsive genes via increased H3K4me3 methylation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1382. doi:10.1158/1538-7445.AM2014-1382
Abstract 1386: Enhanced expression of HMGA1 and THY1 in human hepatocellular carcinoma correlates with poor prognosis
Authors: Andreozzi Mariacarla , Quagliata Luca , Benz David , Trapani Francesca , Eppenberger-Castori Serenella , Ruiz Christian , Pallante Pierlorenzo , Heim Markus , Tornillo Luigi , Fusco Alfredo , Piscuoglio Salvatore , Terracciano Luigi Maria 
Published: May 2015

Abstract
Background and aim: Mounting evidence suggest that hepatocellular carcinoma (HCC) contains a subset of cells possessing some functional properties similar to normal tissue stem cells, usually referred as cancer stem cells (CSCs). THY1 (aka CD90) is involved in tumor-genesis and is commonly acknowledged as a maker of CSC in HCC. HMGA1, an HMG (high mobility group) chromatin-remodelling protein, has been recently highlighted as a key player in stem cell biology. HMGA1 overexpression induces malignant transformation in vitro and is deregulated in many cancer entities. This study aims to address the interrelated role of HMGA1 and THY1 in HCC.
Methods: Using a global transcriptomic profiling (Affymetrix), validated by RT-qPCR, we analysed HMGA1 and THY1 expression levels in a cohort of HCC needle biopsy matched with corresponding non-neoplastic liver (total n=118) and normal liver (n=5). Using tissue microarray (TMA) technology, we evaluated by immunohistochemical staining HMGA1 and THY1 protein levels in a large collective of liver specimens (n=434, of which n=216 were HCCs).
Results: We observed that both HMGA1 and THY1 expression is significantly up regulated in a subset of HCC specimens, correlating with metastatic disease and histological grading. Additionally, we demonstrate that high HMGA1 protein levels along with THY1 positivity in HCC samples results in unfavorable patients' outcome and disease progression.
Conclusion: With this work we provide new evidence for HMGA1 and THY1 involvement in HCC progression and disease outcome and set the basis for further studies aiming to address their role in CSC biology of HCC.
Citation Format: Mariacarla Andreozzi, Luca Quagliata, David Benz, Francesca Trapani, Serenella Eppenberger-Castori, Christian Ruiz, Pierlorenzo Pallante, Markus Heim, Luigi Tornillo, Alfredo Fusco, Salvatore Piscuoglio, Luigi Maria Terracciano. Enhanced expression of HMGA1 and THY1 in human hepatocellular carcinoma correlates with poor prognosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1386. doi:10.1158/1538-7445.AM2014-1386
Abstract 1392: The Pursuit of p73 Regulation: interaction partners tell many different stories
Authors: Satija Yatendra K. , Das Sanjeev 
Published: May 2015

Abstract
p73 is a member of the p53 tumor suppressor family, which can trigger cell cycle arrest and apoptosis through its ability to bind p53 DNA target sites, thereby it acts as a negative regulator of tumorigenesis. Similar to p53, at normal state p73 is maintained at very low level but it rapidly gets induced upon genotoxic stress. Accumulating evidences demonstrated that p73 is mainly regulated at the protein level but its significance is still not clearly understood. It is believed that it is a consequence of post-translational modifications (PTMs) of p73 upon DNA damage. Emerging reports suggested that other than PTMs, various co-factors are responsible for regulating its level and activity. But all these reports remained inadequate to explain the molecular mechanisms behind regulation and activity of p73 under non-stressed and stressed conditions. The aim of our study is to find out novel interactors of p73 which distinctively affect its stability and activity in normal state and upon DNA damage.
We employed a proteomic approach to identify differential interactors of p73 under unstressed and genotoxic stress conditions. We prepared adenovirus system to ectopically overexpress dual-tagged p73 into cells. Our tandem affinity purification screening lead us to identification of many p73-associated proteins. Among the novel interactors, TRIM28, a RING-type E3 ligase, was of particular interest because it interacts with p73 under unstressed condition but no visible interaction was detected after DNA damage. We show here that TRIM28 ubiquitylates and targets p73 for proteasome-mediated degradation in unstressed conditions. Upon genotoxic stress, p73 gets phosphorylated at tyrosine 99 position in c-Abl-dependent manner leading to abrogation of its interaction with TRIM28 which subsequently leads to p73 stabilization. Another protein, MED15 was of particular interest because it interacts with p73 in phosphorylation-dependent manner and it serves as a coactivator of p73. Interestingly, we found that phosphorylation of p73 is a prerequisite for its interaction with MED15. Furthermore, loss of MED15 leads to decline in p73-mediated transactivation of its downstream target genes under DNA damaging conditions. Therefore, we propose a model in which DNA damage-induced phosphorylation of p73 affects its interaction with its negative regulator and leads to its preferential association with its coactivator.
Citation Format: Yatendra K. Satija, Sanjeev Das. The Pursuit of p73 Regulation: interaction partners tell many different stories. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1392. doi:10.1158/1538-7445.AM2014-1392