bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3009: Identification of cancer specific ERG target gene signatures.
Authors: Mohamed Ahmed , Ravindranth Lakshmi , Katta Shilpa , Tan Shyh-Han , Chen Yongmei , Petrovics Gyorgy , Dobi Albert , Srivastava Shiv 
Published: August 2014

Abstract
Introduction and Objective: ETS Related Gene (ERG) is aberrantly expressed in more than two-third of prostate cancers (CaP) due to gene fusions. CaP specific TMPRSS2- ERG fusion is a promising biomarker and potential therapeutic target. Cancer associated expression of ERG have also been described in several cancers. However, the precise molecular mechanisms underlying ERG induced oncogenic process in specific cancers are not clearly understood. Identification and thorough characterization of downstream target genes may aid to design effective therapeutic strategies for ERG expressing cancers. In this study, we have identified cancer specific ERG target gene signature of ERG expressing cancer cells that may be utilized as therapeutic targets for the treatment of ERG expressing CaP patients.
Methods: Illumina BeadChips microarray analysis was performed to profile ERG specific RNA signature from ERG positive tumor cell lines and normal ERG expressing endothelial cells transfected with either ERG specific siRNA or non-targeting siRNA. Functional gene clustering and Venn diagram analysis was employed to show the overlap of the common and unique gene sets regulated by ERG in these cells. Gene expression was analyzed by Western blot, QRT-PCR, and immunofluorescence assays.
Results: Biological function based gene clustering analysis identified two distinct gene signatures (normal and cancer specific) regulated by ERG. Knockdown of ERG in malignant cells resulted in overexpression of differentiation markers such as MSMB, KLK3, SLC45A3, NKX3.1, and NOV4 in prostate cancer (VCaP cells), and APC, DCC, CTNNB1, and NKD1 in colon cancer (COLO320 cells). In contrast, knockdown of ERG in normal endothelial-derived HUVEC cells resulted in the repression of differentiation markers such as CDH5, ANGEL2, and TIE1.
Conclusions: We identified tumor specific ERG target gene signature using normal and various cancer cell lines. This study confirmed the cell context dependent role of ERG in tumor and in normal endothelial cells. These observations have the potential to enhance our understanding of ERG biological functions thereby facilitate the design of suitable therapeutic mechanism.
Citation Format: Ahmed Mohamed, Lakshmi Ravindranth, Shilpa Katta, Shyh-Han Tan, Yongmei Chen, Gyorgy Petrovics, Albert Dobi, Shiv Srivastava. Identification of cancer specific ERG target gene signatures. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3009. doi:10.1158/1538-7445.AM2013-3009
Abstract 3010: Allele-specific loss of OSGIN1 associates with the progression of hepatocellular carcinoma.
Authors: Liu Ming , Li Yan , Chen Leilei , Chan Tim , Guan Xin-Yuan 
Published: August 2014

Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent human malignances worldwide, which causes more than half a million death every year. Most human cancers are characterized by genomic instability. Chromosomal region gains or losses occur during cancer progression and high incidence of allelic imbalance is often observed in cancer patients. The risk alleles were usually overrepresented in cancer cells due to selective retention or amplification. In this report, we found a novel nucleotide variation at the coding region of the gene OSGIN1. Allele imbalance of OSGIN1 was frequently observed in a cohort of HCC patients, and the wild type allele was preferentially lost in the tumor tissue. Functional assays revealed that OSGIN1 has strong tumor suppressive function and associated with chemoresistance of HCC cell lines. The variant allele was less effective in inducing apoptosis than the wild type allele. This functional variation may be due to their different ability to localize to mitochondria. Further more, we found HCC patients carrying the variant allele have poorer prognosis than the wild type carriers. These findings suggested that OSGIN1 might be an important tumor suppressor gene in the progression of HCC and the retention of the variant allele might be a risk factor for HCC.
Citation Format: Ming Liu, Yan Li, Leilei Chen, Tim Chan, Xin-Yuan Guan. Allele-specific loss of OSGIN1 associates with the progression of hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3010. doi:10.1158/1538-7445.AM2013-3010
Abstract 3014: Implication of ΔNp73 isoform in drug resistance.
Authors: Soldevilla Beatriz , Rodríguez Marta , San Millán Coral , Bonilla Félix , Domínguez Gemma 
Published: August 2014

Abstract
Background: Aberrant expression of ▵Np73 has been associated with shorten cancer patient survival. We evaluate here whether this event could be due to the induction of drug resistance mechanisms.
Experimental Design: HCT116 colon cancer cell line transfected with a vector containing ▵Np73 or a mock vector were treated with oxaliplatin and checked for the viability by MTT, Flow-citometry, TUNEL assay and Caspase-3 protein expression levels. Additionally, we determined in 77 colon cancer patients the expression of ΔNp73 and their putative target genes related with drug resistance ABCB1, HMGB1 and CASP1 by quantitative real-time RT-PCR. Disease-free survival (DFS) and overall survival (OS) were examined in each patient.
Results: Ectopic expression of ▵Np73 significantly associated with a higher viability after oxaliplatin exposure. Positive correlations were observed between the expression levels of ▵Np73 variants and HMGB1. A trend was also observed for ABCB1. Overexpression of ΔNp73 isoforms predicted shortened OS (p = 0.05). High levels of ABCB1 and HMGB1 associated with shorter OS (p = 0.04 and p = 0.05, respectively). Multivariate analysis showed that, in addition to the tumor stage, ABCB1 and HMGB1 had independent relationships with OS (p = 0.008).
Conclusions:
The association of the upregulation of ▵Np73 with higher cancer cell viability after oxaliplatin treatment along with the fact that it could trigger HMG1 and ABCB1 in vivo, supports the hyphotesis that the shorten survival observed in those cancer patients showing overexpression of ▵Np73 could be due to the induction of drug resistance processes by this isoform.
Citation Format: Beatriz Soldevilla, Marta Rodríguez, Coral San Millán, Félix Bonilla, Gemma Domínguez. Implication of ΔNp73 isoform in drug resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3014. doi:10.1158/1538-7445.AM2013-3014
Abstract 3021: Mechanistic insight into MIG6 phosphorylation-mediated inhibitory effect on active EGFR.
Authors: Kim Kihong , Zhang Yi , Choi Kyusam , Do Ingu , Meyerson Matthew , Cho Jeonghee 
Published: August 2014

Abstract
Genomic alteration of Epidermal Growth Factor Receptor (EGFR) plays a crucial role in pathogenesis of various types of cancer. By a systematic quantitative phosphoproteomic approach (iTRAQ), we found that tyrosine phosphorylation occurs within segment 2 of MIG6, a negative feedback regulator of EGFR, in the cells transformed by lung-cancer derived EGFR mutants. We further confirmed this MIG6 phosphorylation is directly induced by activated EGFR by in vitro kinase assay with purified proteins followed by immunoblotting with phospho-specific antibody. Importantly, we also found that MIG6 phosphorylation seems to play a crucial role in its inhibitory role of EGFR activation. While wild-type MIG6 was able to completely inhibit the enzymatic activation of oncogenic mutant EGFR and subsequent cellular transformation, phosphorylation defective MIG6 mutants were unable to exert the same effects. Moreover, consistent with its functional role, we found that phosphorylation defective MIG6 failed to interact with mutant EGFR by co-immunoprecipitation assay, suggesting that the phosphorylation on MIG6 is required for interaction between MIG6 and EGFR. Taken together, we propose a working model that phosphorylation on segment 2 of MIG6 is directly induced by active EGFR, promoting tight interaction of MIG6 segment 2 and EGFR active site and subsequently blocking the enzymatic activity of EGFR.
Citation Format: Kihong Kim, Yi Zhang, Kyusam Choi, Ingu Do, Matthew Meyerson, Jeonghee Cho. Mechanistic insight into MIG6 phosphorylation-mediated inhibitory effect on active EGFR. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3021. doi:10.1158/1538-7445.AM2013-3021
Abstract 3030: Regulation of EGFR in pancreatic cancer.
Authors: Halbrook Christopher J. , Takeuchi Kenneth K. , Crawford Howard C. 
Published: August 2014

Abstract
EGFR and EGFR ligand upregulation has been widely seen in both human chronic pancreatitis and pancreatic ductal adenocarcinoma (PDA) for many years; however the role of EGFR in PDA was poorly understood. Recently we and others have shown that genetic ablation of EGFR effectively prevents both spontaneous and cerulein induced tumorigenesis in the pancreas of the LSL-KrasG12D/+;Ptf1aCre/+ (KC) mouse model of pancreatic tumorigenesis. Pockets of EGFR upregulation localized in single acini of KC mice appear to precede pancreatic intraepithelial neoplasia (PanIN) formation in spontaneous tumorigenesis, coupled with a distinct spatially localized immune response. Ubiquitous EGFR upregulation is observed throughout the pancreas upon induction of pancreatitis in wild-type (WT) and KC mice, returning to normal levels in WT mice but continuing to increase along with the widespread tumorigenesis in cerulein treated KC mice. Comparison of cerulein treated KC mice with the EGFRf/f;LSL-KrasG12D/+;Ptf1aCre/+ mice (EKC), which are largely resistant to cerulein induced pancreatitis, offers an opportunity to identify signals in the KC mouse which could be responsible for the upregulation of EGFR and subsequent tumorigenesis.
Citation Format: Christopher J. Halbrook, Kenneth K. Takeuchi, Howard C. Crawford. Regulation of EGFR in pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3030. doi:10.1158/1538-7445.AM2013-3030
Abstract 3037: Mer receptor tyrosine kinase is a novel therapeutic target in melanoma.
Authors: Schlegel Jennifer , Sambade Maria , Sather Susan , Moschos Stergios , Tan Aik-Choon , Winges Amanda , DeRyckere Deborah , Carson Craig C. , Trembath Dimitri G. , Tentler John J. , Eckhardt Gail , Kuan Pei-Fen , Hamilton Ronald L. , Duncan Lyn M. , Miller C. Ryan , Nikolaishvili-Feinberg Nana , Midkiff Bentley R. , Wang Xiaodong , Liu Jing , Zhang Weihe , Yang Chao , Frye Stephen V. , Earp H. Shelton , Shields Janiel , Graham Douglas K. 
Published: August 2014

Abstract
Metastatic melanoma is one of the most aggressive forms of cutaneous cancers. While recent therapeutic advances have prolonged patient survival, prognosis remains dismal. Mer is a receptor tyrosine kinase with oncogenic properties that is often overexpressed or activated in various malignancies. Using both protein immunohistochemistry and microarray analyses, we demonstrate that Mer expression correlates with disease progression. Mer expression was highest in metastatic melanomas followed by primary melanomas whereas the lowest expression was observed in nevi. In addition, over 50% of melanoma cell lines overexpressed Mer compared to normal human melanocytes, however overexpression did not correlate with mutations in BRAF or RAS. Stimulation of melanoma cells with the Mer ligand Gas6 resulted in activation of several downstream signaling pathways including MAPK/ERK, PI3K/Akt, and Jak/STAT. Mer inhibition via shRNA reduced Mer-mediated downstream signaling, reduced colony formation by up to 59% (p&lt;0.05) and diminished tumor volume by 60% (p&lt;0.05) in a human melanoma xenograft murine model. Treatment of melanoma cells with UNC1062, a novel Mer-selective small molecule tyrosine kinase inhibitor, reduced activation of Mer-mediated downstream signaling, induced apoptosis in culture, reduced colony formation in soft agar and inhibited invasion of melanoma cells. In addition, Mer inhibition synergized with mutant BRAF inhibition in signaling and apoptosis assays. This work establishes Mer as a therapeutic target in melanoma and provides rationale for the continued development of Mer-targeted therapies.
Citation Format: Jennifer Schlegel, Maria Sambade, Susan Sather, Stergios Moschos, Aik-Choon Tan, Amanda Winges, Deborah DeRyckere, Craig C. Carson, Dimitri G. Trembath, John J. Tentler, Gail Eckhardt, Pei-Fen Kuan, Ronald L. Hamilton, Lyn M. Duncan, C. Ryan Miller, Nana Nikolaishvili-Feinberg, Bentley R. Midkiff, Xiaodong Wang, Jing Liu, Weihe Zhang, Chao Yang, Stephen V. Frye, H. Shelton Earp, Janiel Shields, Douglas K. Graham. Mer receptor tyrosine kinase is a novel therapeutic target in melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3037. doi:10.1158/1538-7445.AM2013-3037
Abstract 3039: Protein kinase C-δ mediated KIT recycling in colon cancers.
Authors: Park Mi Sun , Kim Won Kyu , Song Meiying , Kim Hoguen 
Published: August 2014

Abstract
Abnormal signals through the receptor tyrosine kinase (RTK) moieties are important in colon cancer both for tumorigenesis and drug targets. Wild type KIT, one of the RTKs, had been reported to be highly expressed in some colon cancers, however little is known about the functional aspects and roles of stem cell factor (SCF) dependent activation in colon cancers. We characterized colorectal cancers with KIT expression and analyzed the biological alterations of KIT after stimulation of SCF and its impact on the downstream signals. We identified wild type KIT is expressed in some colon cancer cell lines, activated by SCF, and subsequently activated AKT and ERK signaling pathways. We also demonstrated that KIT expression was gradually decreased after SCF stimulation due to lysosomal degradation of activated KIT. We found PKC activation rescues KIT by inhibiting ubiquitination of KIT after SCF treatment. Among the various types of PKCs, PKC-δ directly bound to wild type KIT and rescued SCF-KIT complexs. Additionally, we demonstrated that KIT and PKC-δ are concomitantly activated in the colon cancer tissues with wild type KIT expression, and the expression of KIT is correlated with poor survival. Based on these findings we concluded that downstream signal activation after SCF-KIT binding is continuously accomplished by the PKC-δ activation and subsequent KIT recycling. These signal pathways induced by SCF and PKC-δ mediated KIT recycling play important roles in colon cancer progression.
Citation Format: Mi Sun Park, Won Kyu Kim, Meiying Song, Hoguen Kim. Protein kinase C-δ mediated KIT recycling in colon cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3039. doi:10.1158/1538-7445.AM2013-3039
Abstract 3065: The role of miR-18b in MDM2-p53 pathway signaling and melanoma progression.
Authors: Dar Altaf A. , Majid Shahana , de Semir David , Bezrookove Vladimir , Nosrati Mehdi , Kashani-Sabet Mohammed 
Published: August 2014

Abstract
MicroRNAs regulate gene expression and are differentially expressed in various tumors. While p53 is inactivated by point mutations in many tumors, melanomas rarely harbor mutations in the p53 gene. Here we report the biological role of miR-18b in melanoma via targeting the MDM2-p53 pathway. Expression of miR-18b was significantly suppressed in melanoma specimens and cell lines by virtue of hypermethylation, and was re-induced in melanoma cell lines following 5-AZA-deoxycytidine treatment. Lower levels of miR-18b expression in primary melanoma were associated with significantly reduced overall survival. MDM2 was identified as a target of miR-18b action, as miR-18b significantly suppressed the luciferase activity of a reporter plasmid containing the 3’UTR sequence of MDM2 complementary to the miR-18b seed sequence. Induction of miR-18b expression in melanoma cells resulted in reduced MDM2 expression, upregulation of p53 as well as PUMA and p21, and suppression of the anti-apoptotic BCL2 and BCL-XL genes, resulting in significant suppression of melanoma cell proliferation. The effects of miR-18b overexpression on the p53 pathway and on melanoma cell growth were reversed by MDM2 overexpression. Stable overexpression of miR-18b produced potent tumor suppressor activity, as evidenced by suppressed melanoma cell proliferation, induction of apoptosis, and reduced tumor cell growth in vivo. In addition, miR-18b overexpression suppressed melanoma cell migration and invasiveness, and reversed epithelial-to-mesenchymal transition in melanoma cell lines. Our results demonstrate a novel role for miR-18b as a tumor suppressor in melanoma, identify the MDM2-p53 pathway as a target of miR-18b action, and suggest miR-18b overexpression as a novel strategy to reactivate the p53 pathway in human tumors.
Citation Format: Altaf A. Dar, Shahana Majid, David de Semir, Vladimir Bezrookove, Mehdi Nosrati, Mohammed Kashani-Sabet. The role of miR-18b in MDM2-p53 pathway signaling and melanoma progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3065. doi:10.1158/1538-7445.AM2013-3065
Abstract 3066: Comprehensive interactome of embryonic transcription factors, mitogenic stresses and miRNAs involved in breast tumorigenesis.
Authors: Ruiz Emmanuelle , Courtois-Cox Stephanie , Gras Baptiste , Veron Amélie , Ansieau Stephane , Puisieux Alain , MOYRET-LALLE Caroline 
Published: August 2014

Abstract
Epithelial-to-Mesenchymal Transition (EMT) is associated with tumour initiation and progression. EMT is associated with a profound genetic reprogramming including reactivation of embryonic transcription factors (ETFs) and severe changes in miRNA expression. Cross-regulation between EMT-inducers and miRNAs was previously described like the Zeb1-miR-200 feed-back loop. Our goal is to determine whether specific expression networks between ETFs, miRNAs and mitogenic stresses exist in tumors, and represents a driving force towards transformation in breast tumorigenesis.
We performed oncogenic cooperation assays in immortalized human mammary epithelial cells (HMEC-hTert) by using an EMT-inducer expression library in combination with various mitogenic stresses (activated form of beta-catenin, EGFR, shPTEN, shP53). As recently demonstrated in the laboratory, these combinations were efficient in transforming human cells, as assessed by soft-agar colony assay. EMT-inducer expression was next analyzed in a large number of colonies to evaluate a potential specificity of EMT-inducers according to the mitogenic insult.
We found that expression of Slug was specifically enriched in colonies generated when EGFR is highly expressed, whereas Zeb1 expression was selected following PTEN depletion, p53 inactivation and beta-catenin activation. FoxC2 expression was enriched in cells expressing the activated form of beta-catenin. The prediction of specificity of the identified combinations is currently being validated by bioinformatics tools. In parallel, we developed an in silico approach utilizing predictive algorithms to identify novel miRNAs targeting embryonic transcription factors. We have identified two novel miRNAs able to regulate EMT inducers and we have validated their down-regulation in a panel of basal B breast cancer cell lines. We have also found new feedback loops between these two miRNA and some ETFs. The interplay between miRNAs, mitogenic proteins and EMT inducers will be further examined by assessing their expression in a large cohort of Basal B/ Claudin-low human breast tumours, a recently identified subtype displaying a mammary stem cell signature and EMT features.
Citation Format: Emmanuelle Ruiz, Stephanie Courtois-Cox, Baptiste Gras, Amélie Veron, Stephane Ansieau, Alain Puisieux, Caroline MOYRET-LALLE. Comprehensive interactome of embryonic transcription factors, mitogenic stresses and miRNAs involved in breast tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3066. doi:10.1158/1538-7445.AM2013-3066
Abstract 3067: microRNAS implicated in the regulation of NF-κB activity in glioma tumors.
Authors: Haemmig Stefan , Vassella Erik 
Published: August 2014

Abstract
Gliomas are among the most prognostically discouraging neoplasia in human and there is basically no curative option for glioma patients. Nuclear factor κB (NF-κB) is a key effector associated with temozolomide (TMZ) resistance in glioma tumours. This is at least in part due to down-regulation of TNFAIP3, which is a critical negative regulator of NF-κB activity. Downregulation of this gene is strongly associated with resistance to TMZ, but the molecular mechanism of dysregulation is largely unknown. We hypothesize that microRNAs that are implicated in the NF-κB pathway may be important regulators of resistance to alkylating agents in glioma tumours.
TNFAIP3 is a predicted target of brain-enriched microRNAs miR-125a and miR-125b. Consistent with these findings, luciferase activity assays of reporter plasmids containing miR-125a/b target sites revealed that TNFAIP3 is directly regulated by physiological concentrations of miR-125a/b. In addition, overexpression of miR-125a/b resulted in reduced mRNA and protein levels of TNFAIP3 and, as a consequence, also in a significant induction of NF-κB activity. Consistent with these findings, glioblastoma cells overexpressing these miRNAs showed a strong upregulation of the anti-apoptotic proteins Bcl-2 and BIRC3. Interestingly, this was significantly associated with resistance of glioma cells to TNFalpha- and TRAIL-induced apoptosis and also resistance to TMZ. A siRNA directed against TNFAIP3 and miR-125a/b gave rise to similar phenotypes suggesting that TNFAIP3 is a major target of miR-125a/b. In glioblastoma tissues, high level expression of either miRNA was highly correlated with nuclear localisation of NF-κB confirming that miR-125a/b are implicated in NF-κB signalling. Most remarkably, miR-125a/b expression was clearly associated with shorter overall survival of patients treated with TMZ, suggesting that these miRNAs are important predictors of response to therapy. However, we found no correlation between miR-125a/b levels and the MGMT methylation status.
In conclusion, miR-125a/b expression is a predictor of the patient's response to chemotherapy. Since miR-125a/b confers resistance to TMZ, antisense miR-125a/b might potentially be used in adjuvant therapy for the treatment of glioma tumours.
Citation Format: Stefan Haemmig, Erik Vassella. microRNAS implicated in the regulation of NF-κB activity in glioma tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3067. doi:10.1158/1538-7445.AM2013-3067