bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2950: Epigenetic silencing BCL6B inactivates p53 signaling and causes human hepatocellular carcinoma cell resist to 5-FU
Authors: Li Xin , Yu Jie , Brock Malcolm , Tao Qian , Herman James , Liang Ping , Guo Mingzhou 
Published: August 2015

Abstract
BCL6B is a potential tumor suppressor in human gastric cancer, but the regulation and mechanism of BCL6B in human hepatocellular carcinogenesis remain unclear. This study is to explore the epigenetic change and mechanism of BCL6B in human hepatocellular carcinoma (HCC). 14 hepatic cancer cell lines, 8 cases of normal hepatic tissue and 149 cases of HCC were employed. Semi-quantitative RT-PCR, methylation specific PCR (MSP), gene expression array, flow cytometry assay, colony formation, western blot and immunohistochemistry were used. BCL6B is methylated in 100% (14/14) of human HCC cell lines and 86.6% (129/149) of primary cancer samples. Methylation of BCL6B is associated with HBV positive (p&lt;0.05). But no association was found with age, sex, tumor size, differentiation, TNM stage, recurrence and survival. Loss of BCL6B expression was found in 14 of completely methylated HCC cell lines. BCL6B was re-expressed after 5-aza-2′-deoxycytidine (5-AZA) treatment. Restoration of BCL6B expression suppressed cell proliferation, induced apoptosis and G1/S arrest in HCC cells. The expression of EGR1, a key component of p53 signaling, was increased after re-expression BCL6B in HCC cells. Re-expression of BCL6B activated P53 signaling and sensitized HepG2 and SNU449cells to 5-fluorouracil (5-FU). BCL6B is frequently methylated in human HCC and the expression of BCL6B is regulated by promoter region hypermethylation. BCL6B suppresses cell proliferation and induces apoptosis in HCC cells. BCL6B activates P53 signaling by increasing EGR1 expression in HCC. BCL6B sensitizes HCC cells to 5-FU by activating P53 signaling.
Note: This abstract was not presented at the meeting.
Citation Format: Xin Li, Jie Yu, Malcolm Brock, Qian Tao, James Herman, Ping Liang, Mingzhou Guo. Epigenetic silencing BCL6B inactivates p53 signaling and causes human hepatocellular carcinoma cell resist to 5-FU. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2950. doi:10.1158/1538-7445.AM2015-2950
Abstract 2996: Hypoxia pathway activation in HPV-associated OSCC
Authors: Klussmann Jens P. , Knuth JeJennifer , Wagner Steffen 
Published: August 2015

Abstract
Introduction: HIF1A induces hypoxia dependent transcription of its target genes, resulting e.g. in increased glycolysis. However, increased glycolysis is found in a lot of tumors despite presence of oxygen, known as Warburg effect. Under normoxia HIF1A is hydroxylated by prolyl hydroxylases (PHDs) and degraded by the proteasome. According to literature, HIF1A protein level increase in the presence of HPV-oncoproteins. Nevertheless, HPV dependent induction of HIF1A and resulting downstream effects are still ambiguous for cervix carcinoma and even more for OSCC. We propose HPV-associated HIF1A induction in OSCC to be responsible for a Warburg-like effect, to gain nutrient resources for tumor growth and to be related to immune escape and metastasis. We investigated characteristic effects of HPV on the hypoxia signaling cascade and glycolysis for testing these hypotheses.
Experimental Procedure: HPV-positive and -negative cell lines were cultured under normoxic and hypoxic conditions or in the presence or absence of hypoxia mimics. We analyzed components of the hypoxia signaling pathway with molecular- and cell biological methods. Furthermore we analyzed HIF1A and its target gene expression in a cohort of 40 HPV-positive and -negative OSCC by immunohistochemistry.
Data: Immunoblot analysis showed 2.6 times higher HIF1A protein level (normalized relative expression) in normoxia and increased accumulation under hypoxic conditions in HPV-positive compared to HPV-negative (4.5 vs. 1.6 times more) cell lines. HPV-positive and -negative cell lines showed comparable PHD2 expression level under normoxia. Interestingly, PHD2 protein level increased more in HPV-positive than in HPV-negative cell lines (5.5 vs. 1.6 times) under hypoxia. Immunofluorescence also showed increased basal HIF1A expression and higher up-regulation after incubation with deferoxamine in HPV-positive vs. -negative cell lines. Immunohistochemistry of GLUT1 in HPV-associated OSCC showed a distinct “HPV-pattern” with a more evenly distributed expression compared to HPV-negative OSCC.
Conclusion: Our findings suggest a difference between HPV-induced and HPV-unrelated carcinogenesis in OSCC referring to up-regulation of HIF1A and activation of its target genes under normoxia as well as under hypoxia. This was shown for HPV-positive cell lines in vitro and indicated for clinical samples. Current analyzes focus on HPV-oncoprotein interactions with cellular factors related to HIF1A protein degradation and stabilization.
Citation Format: Jens P. Klussmann, JeJennifer Knuth, Steffen Wagner. Hypoxia pathway activation in HPV-associated OSCC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2996. doi:10.1158/1538-7445.AM2015-2996
Abstract 3: Mechanistic rationale for MCL1 inhibition during androgen deprivation therapy
Authors: Santer Frédéric R. , Erb Holger H.H. , Oh Su Jung , Handle Florian , Feiersinger Gertrud E. , Luef Birgit , Bu Huajie , Schäfer Georg , Ploner Christian , Egger Martina , Rane Jayant K. , Maitland Norman J. , Klocker Helmut , Eder Iris E. , Culig Zoran 
Published: August 2015

Abstract
The cellular consequences of androgen deprivation therapy (ADT), a first-line therapy for locally advanced and metastatic prostate cancer (PCa), are induction of apoptosis or G1 cell cycle arrest. Inability of PCa cells to induce apoptosis is the starting point of development of castration resistance. Hence, an improved therapy should target the cell cycle-arrested cells in a combinatorial approach together with currently applied ADT. Here we set out to analyze whether MCL1, a pro-survival member of the BCL2 family and known mediator of chemotherapy resistance regulates the cellular response to androgen withdrawal. Analysis of MCL1 protein and mRNA expression in PCa tissue and primary cell culture specimens of luminal and basal origin, respectively, reveals higher expression in cancerous tissue compared to benign origin. Using PCa cellular models in vitro and in vivo we show that MCL1 expression is regulated through the action of androgens and upregulated in androgen-sensitive PCa cells when grown under steroid-deprived conditions. Analysis of the underlying mechanism suggests that regulation of MCL1 through the AR signaling axis is indirectly mediated via a cell cycle-dependent mechanism. Using constructs downregulating or overexpressing MCL1 we demonstrate that expression of MCL1 prevents induction of apoptosis when androgen-sensitive PCa cells are grown under steroid-deprived conditions. The BH3-mimetic Obatoclax induces apoptosis and decreases MCL1 expression in androgen-sensitive PCa cells, while castration-resistant PCa cells are less sensitive and react with an upregulation of MCL1 expression. Synergistic effects of Obatoclax with androgen receptor inactivation can be observed in androgen-sensitive cells. In addition, Obatoclax efficiently inhibits clonogenicity of primary basal PCa cells. Altogether, our results suggest that MCL1 is a key molecule deciding over the fate of PCa cells upon inactivation of androgen receptor signaling and provide a mechanistic rationale for a clinical assessment of a MCL1-targeting therapy adjuvant to ADT.
Citation Format: Frédéric R. Santer, Holger H.H. Erb, Su Jung Oh, Florian Handle, Gertrud E. Feiersinger, Birgit Luef, Huajie Bu, Georg Schäfer, Christian Ploner, Martina Egger, Jayant K. Rane, Norman J. Maitland, Helmut Klocker, Iris E. Eder, Zoran Culig. Mechanistic rationale for MCL1 inhibition during androgen deprivation therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3. doi:10.1158/1538-7445.AM2015-3
Abstract 30: Medi3622, a monoclonal antibody to ADAM17, inhibits tumor growth by inhibiting EGFR- and non-EGFR-mediated pathways
Authors: Sabol Darrin , RiosDoria Jonathan , Chesebrough Jon , Stewart David , Schifferli Kevin , Rothstein Raymond , Leow Ching Ching , Heidbrink-Thompson Jenny , Cheng Li , Du Qun , Xu Linda , Jin Xiaofang , Tammali Ravinder , Gao Chanshou , Friedman Jay , Wilkinson Brandy , Damschroder Melissa , Pierce Andrew , Patnaik MunMun , Zeng Rong , Wu Yuling , Spitz Susan , Robbie Gabriel , Roskos Lorin , Hollingsworth Robert , Tice David , Michelotti Emil 
Published: August 2015

Abstract
ADAM17 is the primary sheddase for HER pathway ligands. We report the discovery of a potent and specific ADAM17 inhibitory antibody, MEDI3622, which induces tumor regression or stasis in many EGFR-dependent tumor models. The inhibitory activity of MEDI3622 correlated with EGFR activity both in a series of tumor models across several indications as well as in a focused set of head and neck patient derived xenograft models. Cynomolgus monkey and rat PK/PD assays showed MEDI3622 inhibited TNFα shedding. Toxicity observed in cynomolgus monkey and rat was similar to EGFR inhibitor-induced rash. However, the antitumor activity of MEDI3622 was superior to that of EGFR/HER pathway inhibitors in OE21 head and neck and COLO205 colorectal xenograft models suggesting additional activity outside of the EGFR pathway. Combination of MEDI3622 and cetuximab in the OE21 model was additive and eradicated tumors. Proteomics analysis revealed novel ADAM17 substrates which function outside of the HER pathways and may contribute towards the antitumor activity of the monoclonal antibody.
Citation Format: Darrin Sabol, Jonathan RiosDoria, Jon Chesebrough, David Stewart, Kevin Schifferli, Raymond Rothstein, Ching Ching Leow, Jenny Heidbrink-Thompson, Li Cheng, Qun Du, Linda Xu, Xiaofang Jin, Ravinder Tammali, Chanshou Gao, Jay Friedman, Brandy Wilkinson, Melissa Damschroder, Andrew Pierce, MunMun Patnaik, Rong Zeng, Yuling Wu, Susan Spitz, Gabriel Robbie, Lorin Roskos, Robert Hollingsworth, David Tice, Emil Michelotti. Medi3622, a monoclonal antibody to ADAM17, inhibits tumor growth by inhibiting EGFR- and non-EGFR-mediated pathways. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 30. doi:10.1158/1538-7445.AM2015-30
Abstract 3008: CEP55 is a determinant of genomic instability in aneuploid breast cancer cells and facilitates anti-mitotic drugs resistance by interacting directly with HSF1
Authors: Kalimutho Murugan , Waddell Nicola , Jeffry Jessie , Srihari Sriganesh , Khanna Kum Kum 
Published: August 2015

Abstract
Centrosomal proteins have long been known to act as a scaffolds, spindle checkpoint regulators as well as key regulating elements of microtubule organizing centre, hence as an essential component of cell cycle progression. CEP55 is a centrosomal protein originally identified as an indispensable regulator of cytokinesis, the final stage of cell division that divides cytoplasm equally amongst two daughter cells. Failure to faithfully complete cytokinesis due to loss of CEP55 resulted in primary genetic lesion leading to multinucleated cells, thus promotes tumourigenesis and aneuploidy. CEP55 has been to shown elevated in wide range of cancers including breast cancer, however the molecular mechanisms on how CEP55 mediated genomic instability in cancers are still not well understood. To decipher the functional role of CEP55 in regulating genomic instability in breast cancer, through a series of in-vitro and in-vivo experiments we found that high levels of CEP55 is significantly associates with basal-like breast cancer subtype with poor overall survival, relapse free survival and distant-metastasis free survival. Furthermore, we found that depletion of CEP55 decreased cell viability due to induction of apoptosis and hamper primary tumour growth due to clearance of aneuploid cells that are particularly important in oncogenic transformation. In addition, depletion of CEP55 hindered premature exit of mitotic arrested cells and this is partly mediated through CEP55-dependent interaction with HSF1 during mitosis to facilitate development of aneuploidy. Strikingly, we found that CEP55 mediates anti-mitotic drug resistance to docetaxel and PLK1 inhibition. Depletion of CEP55 increased sensitivity to anti-mitotic drugs in particular docetaxel or PLK1 inhibitor, providing a rationale to target CEP55 and its dependent-pathways in aggressive and aneuploid breast cancer.
Citation Format: Murugan Kalimutho, Nicola Waddell, Jessie Jeffry, Sriganesh Srihari, Kum Kum Khanna. CEP55 is a determinant of genomic instability in aneuploid breast cancer cells and facilitates anti-mitotic drugs resistance by interacting directly with HSF1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3008. doi:10.1158/1538-7445.AM2015-3008
Abstract 3010: Meiotic cohesin REC8 associates with chromosome instability in melanoma
Authors: Escandon Julia , Lindsey Scott , Eller Mark S , Grichnik James M 
Published: August 2015

Abstract
Chromosome instability (CIN) is an important component of multiple malignancies. CIN is linked to drug resistance, tumor grade and aggressiveness. Melanoma is a highly chromosome instable tumor and CIN is a differentiating feature between melanoma and benign nevi. Meiotic proteins are present in melanoma and previous work in our lab suggests a role for these proteins in CIN and that melanoma cell replication has attributes as chromosome pairing and DNA bridging that can be explained by the presence of meiosis proteins. REC8 is a meiotic cohesin which holds sister chromatids together during the first meiotic division, therefore we sought to study the potential role for REC8 in CIN in Melanoma. A model of chromosome instability developed in melanocytic cell lines showed association of REC8 as CIN progressed strengthening the hypothesis that REC8 may be involved in CIN. We overexpressed REC8 in melanoma lines and in E6E7 melanocytes with a TET-inducible system and examined the change in the polyploid population by flow cytometry, cell count and FISH. Results suggest that overexpression of REC8 alone is not sufficient to drive polyploidy in these cell lines. Nevertheless, the association of REC8 with CIN is intriguing and further research in the role of meiosis proteins in melanoma is warranted. Future work will aim at dissecting coexisting meiotic proteins; specially the proteins of the cohesin ring and its regulatory proteins that are also present at high levels in melanoma and could be responsible of chromosome number abnormalities.
Citation Format: Julia Escandon, Scott Lindsey, Mark S Eller, James M Grichnik. Meiotic cohesin REC8 associates with chromosome instability in melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3010. doi:10.1158/1538-7445.AM2015-3010
Abstract 3013: RNF126 promotes homologous recombination via regulating E2F1-mediated BRCA1 expression
Authors: Wang Ying , Deng Ou , Feng Zhihui , Du Zhanwen , Xiong Xiahui , Chen Ceshi , Ma Zhefu , Zhang Junran 
Published: August 2015

Abstract
Abstract: Homologous recombination (HR)-mediated DNA double-strand break repair is important for cell proliferation, cancer prevention and cancer therapy resistance. HR protein BRCA1 is one of the most important breast/ovarian cancer suppressor genes. Lower expression of BRCA1 has been frequently observed in a broad spectrum of human cancers, particularly sporadic breast/ovarian cancers. However, the mechanisms governing BRCA1 expression is elusive. RNF126 is an E3 ubiquitin ligase and is mapped to chromosome 19 p13.3 which is a commonly deleted region in ovarian cancers. In addition, high-resolution 19p13.2-13.3 allelotyping of breast carcinomas demonstrates frequent loss of heterozygosity. The Cancer Genome Atlas (TCGA) data suggested that RNF126 depletion present in a broad spectrum of human tumors, particularly ovarian cancers. Although a recent study suggested that RNF126 promote cell growth, the function of RNF126 remains largely unknown. Here, we demonstrate that RNF126 facilitates HR by promoting the expression of BRCA1, in a manner independent of its E3 ligase activity but depending on E2F1, a well-known transcription factor of BRCA1 promoter. In support of this result, RNF126 promotes transactivation of BRCA1 promoter by directly binding to E2F1. Most importantly, an RNF126 mutant lacking 10 amino acids that is responsible for the interaction with E2F1 has a dominant-negative effect on BRCA1 expression by suppressing E2F1-mediated transactivation of BRCA1 promoter and blocking the enrichment of E2F1 on BRCA1 promoter. Last, RNF126 depletion leads to the increased sensitivity to ionizing radiation (IR) and poly (ADP-ribose) polymerase (PARP) inhibitor. Collectively, our results suggest a novel role of RNF126 in promoting HR-mediated repair through the positive regulation on BRCA1 expression by binding to E2F1. This study not only offers novel insights into our current understanding of the biological functions of RNF126 but also provides a potential therapeutic target for the cancer treatment.
Key words: Homologous recombination, RNF126, E2F1, BRCA1
Citation Format: Ying Wang, Ou Deng, Zhihui Feng, Zhanwen Du, Xiahui Xiong, Ceshi Chen, Zhefu Ma, Junran Zhang. RNF126 promotes homologous recombination via regulating E2F1-mediated BRCA1 expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3013. doi:10.1158/1538-7445.AM2015-3013
Abstract 3031: Replication stress and DNA damage promote genomic instability in near-tetraploid colorectal cancer cells
Authors: Quintanilla Isabel , Wangsa Darawalee , Brown Markus , Ercilla Amaia , Klus Greg , Vila Maria , Lozano Juan José , Szallsi Zoltan , Agell Neus , Castells Antoni , Ried Thomas , Camps Jordi 
Published: August 2015

Abstract
Aneuploidy represents a hallmark of most solid tumours, and potentially has a causal role in carcinogenesis. Also, cancer cells exhibit high rates of chromosome missegregation, which leads to chromosomal instability (CIN). However, a large amount of tumours present near-triploid karyotypes likely to go through a tetraploid transient stage. Here, by using DLD-1 isogenic diploid and tetraploid cell lines generated by single cell FACS-sorting, we aimed at exploring how polyploidization affects cellular functions and whether tetraploid per se generates CIN in a genomically stable background. First, gene expression and subsequent gene set enrichment analysis revealed that genes involved in the machinery of the DNA synthesis and replication, such as MCM2 and RRM2, and genes involved in cell cycle, were significantly upregulated in near-tetraploid cells compared to their diploid counterparts. Functionally, polyploidy cells exhibited replication stress, as indicated by higher levels of pCHK1, RPA and 53BP1 foci, which resulted in increased DNA damage in S- and M-phase. In addition, tetraploid cells displayed impaired proliferative capabilities as a consequence of a cell cycle delay confirmed by BrdU pulse and flow cytometry. Furthermore, near-tetraploid clones showed a higher amount of intracellular karyotypic heterogeneity due to the higher frequency of micronuclei formation compared to their diploid counterparts. In fact, polyploid cells displayed an increased tendency of abnormal anaphase events, including lagging chromosomes and acentric fragments. Interestingly, these heterogeneous cellular populations showed strengthen migratory capabilities and preliminary experiments suggested an increment in tumor invasiveness too. Taken together, our data suggest that near-tetraploid cells systematically undergo replication stress, which can be responsible for the increased levels of genomic instability.
Citation Format: Isabel Quintanilla, Darawalee Wangsa, Markus Brown, Amaia Ercilla, Greg Klus, Maria Vila, Juan José Lozano, Zoltan Szallsi, Neus Agell, Antoni Castells, Thomas Ried, Jordi Camps. Replication stress and DNA damage promote genomic instability in near-tetraploid colorectal cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3031. doi:10.1158/1538-7445.AM2015-3031
Abstract 3040: NANOG metabolically reprograms tumor-initiating stem-like cells in oxidative phosphorylation and fatty acid metabolism
Authors: Chen Chia-Lin , Uthaya Kumar Dinesh Babu , Punj Vasu , Xu Jun , Sher Linda , Hess Sonja , Machida Keigo 
Published: August 2015

Abstract
Stem cell markers such as NANOG have been implicated in various cancers; however, the functional contribution of pluripotency transcription factor NANOG to cancer pathogenesis has remained unclear. Gene profiling, proteomics and metabolomics approaches were combined to identify the pathway(s) altered in tumors. Here, we show that Toll-like receptor 4 (TLR4) signaling phosphorylates E2F1 to transactivate NANOG via TAK1/TBK1. CD133+/CD49f+ TICs isolated from human HCC have tumorigenic activities dependent on TLR4 and NANOG. Down-regulation of Nanog significantly reduces tumor development in obesity-associated HCC mouse model. In the search for the NANOG-dependent mechanisms underlying growth of tumor-initiating stem-like cells (TICs), NANOG ChIP-seq identifies the genes associated with mitochondrial metabolic pathways. The specific pathways, which were examined: oxidative phosphorylation (OXPHOS) and fatty acid oxidation were identified as novel NANOG-mediated oncogenic pathways by NANOG ChIP-seq analysis and metabolomics. The causal roles of NANOG in mitochondrial metabolic reprogramming occurs through the inhibition of oxidative phosphorylation (OXPHOS) and levels of mitochondrial ROS and activation of fatty acid oxidation (FAO), which are required for both the self-renewal of TICs and their drug resistance. PPARδ physically interacts with NANOG. Restoration of OXPHOS and inhibition of FAO rendered TICs susceptible to drug. Our data showed that NANOG reprogramming of mitochondrial metabolism was responsible for human TIC oncogenicity and chemo-resistance. Together, NANOG-mediated metabolic reprogramming through dysregulation of mitochondrial functions generates TICs and drives tumorigenesis, providing insight into mechanisms of NANOG-mediated metabolic reprogramming and its roles in TIC oncogenic activity and chemo-resistance. NANOG suppresses OXPHOS and activates FAO, thus inhibiting OCR and ROS production, conferring a tumor chemoresistant state. These novel pathways are potential drug targets for the highly malignant TICs found in cancer patients. Reversal of NANOG-dependent effects on OXPHOS and FAO gene may offer a noteworthy strategy of countering therapeutic drug resistance associated with NANOG activation.
Citation Format: Chia-Lin Chen, Dinesh Babu Uthaya Kumar, Vasu Punj, Jun Xu, Linda Sher, Sonja Hess, Keigo Machida. NANOG metabolically reprograms tumor-initiating stem-like cells in oxidative phosphorylation and fatty acid metabolism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3040. doi:10.1158/1538-7445.AM2015-3040