bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 101: Analysis of GNAQ mutations in subtypes of malignant melanoma
Authors: Puntervoll Hanne E. , Vuhahula Edda , Molven Anders , Akslen Lars A. 
Published: August 2012

Abstract
Background: The MAP kinase pathway has been implicated in the pathogenesis of cutaneous melanoma, and mutations in BRAF and NRAS are commonly found in subtypes of melanomas as well as in benign nevi. Recently, several publications have reported frequent mutations in codon 209 of GNAQ in blue nevi and uveal melanoma, revealing an alternative path to MAP kinase activation. Aim of study: We wanted to investigate the prevalence of GNAQ mutations in codon 209 in a broad spectre of cutaneous melanoma, previously screened for mutations in BRAF, NRAS and EGFR. Methods: 75 benign and malignant tumors of different subgroups were collected at the Department of Pathology, the Gade Institute, Haukeland University Hospital, including: Spitz nevi, superficial spreading melanoma, superficial spreading melanoma in situ, lentigo malignant melanoma, nodular melanoma, metastases from nodular melanoma and uveal melanoma. Additionally, 14 acral African melanomas were collected at the Department of Pathology, Muhimbili University college of Health Sciences, Dar Es Salaam, Tanzania. Tumor tissue was manually dissected from formalin fixated paraffin-embedded sections, before GNAQ exon 5 was screened for mutations in codon 209 by direct Sanger sequencing. Further sample collection and analysis are ongoing. Results: The sequence analysis detected mutations in codon 209 in all five uveal melanomas tested (four harbored a Q209L mutation, and one had a Q209P mutation). However no mutations were found in any of the other subtypes of malignant melanoma. Conclusion: Our study shows that there appears to be a general lack of GNAQ mutations in cutaneous melanoma. This confirms that there may be different routes to MAP kinase activation in malignant melanoma as suggested by other studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 101. doi:1538-7445.AM2012-101
Abstract 1037: Histone lysine methyltransferase EHMT2 is involved in proliferation, apoptosis, and DNA methylation of human neuroblastoma cells
Authors: Lu Ziyan , Salwen Helen R. , Raj J Usha , Yang Qiwei 
Published: August 2012

Abstract
Background: Neuroblastoma (NB), a childhood neoplasm arising from neural crest cells, is characterized by a diversity of clinical behaviors ranging from spontaneous remission to rapid tumor progression and death. In addition to genetic abnormalities, recent studies have indicated that epigenetic aberrations also contribute to NB pathogenesis. However, the epigenetic mechanisms underlying the pathogenesis of NB are largely unknown. Methods: Cell proliferation was measured by cell counting and BrdU incorporation assay in a human NB cell line (LA1-55n). Expression of MYCN was measured by real-time PCR. Caspase 3/7 activity was measured by Caspase-Glo 3/7 assay kit. The level of global DNA methylation was measured by liquid chromatography-mass spectroscopy. Results: BIX-01294, a specific inhibitor of EHMT2 (a key enzyme for histone H3 dimethylation at lysine-9), decreased proliferation of NB LA1-55n cells and induced apoptosis via increasing caspase 3 activity. BIX-01294 at a concentration of 1µg/ml inhibited NB cell proliferation, decreased expression of the MYCN oncogene, and increased global DNA methylation levels. At a concentration of 5 µg/ml and 10 µg/ml, BIX-01294 significantly increased caspase 3/7 activity. Conclusion: Our results demonstrate that histone lysine methylation is involved in cell proliferation, apoptosis, and global DNA methylation in human NB cells. Further understanding of this mechanism may provide insight into the pathogenesis of NB progression and lead to novel treatment strategies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1037. doi:1538-7445.AM2012-1037
Abstract 1048: DNMT1: An emerging target in the treatment of invasive urinary bladder cancer
Authors: Dhawan Deepika , Ramos-Vara José A. , Hahn Noah M. , Zheng Rong , Stewart Jane C. , Knapp Deborah W. 
Published: August 2012

Abstract
Introduction: More than 14,000 people die from invasive transitional cell carcinoma (InvTCC) of the urinary bladder each year in the US, and more effective therapies are needed. Naturally-occurring canine InvTCC very closely resembles the disease in humans and serves as a highly relevant translational model for novel therapy of human InvTCC. Work was undertaken to identify new entry points for anticancer therapy in dogs with the goal of translating successful therapeutic strategies into humans with InvTCC. Methods: Microarray expression analyses were conducted on canine normal bladder from dogs with no urinary tract disease (n=4) and InvTCC tissues (n=4) using Genome Array 1.0 and analyzed by GeneSpring GX 11, with the stringency of p &lt; 0.02 and a ≥2-fold change. The genes thus identified were further analyzed for functional and pathway analysis using PANTHER (Protein ANalysis THrough Evolutionary Relationships) Classification System. In selecting genes for further study, consideration was also given for evidence of a role of the gene in human InvTCC. From these analyses, DNA methyltransferase 1 (DNMT1) was selected for further study. Immunohistochemistry (IHC) of canine normal bladder and InvTCC tissues was performed to confirm the microarray expression analyses. The effects of targeting DNMT1 in vitro was assessed through MTT assay and Western blot of canine InvTCC cells treated with 5-azacitidine (5-azaC) and trichostatin A (TSA). Results: DNMT1 was expressed in 0 of 6 normal canine bladder samples and in 10 of 22 (45%) canine InvTCC samples. The proliferation of canine InvTCC cells was inhibited by 5-azaC (at concentrations &gt; 5µM) and by TSA (at concentrations &gt; 0.1µM). Western blot results were supportive of DNMT1-related effects having a role in the antiproliferative activity. Discussion and Conclusions: Microarray expression analyses on canine tissues identified DNMT1 as a potentially “targetable” gene. Expression of DNMT1 in canine InvTCC was confirmed by IHC, and in vitro studies confirmed that drugs that inhibit DNMT1 have antiproliferative effects. These findings are similar to those recently reported by Wu et al. (Cancer, 2011) in human InvTCC. These findings are also in line with results of a pre-clinical (pre-human) trial of 5-azaC in dogs with naturally-occurring InvTCC, in which remission or cancer control occurred in 72% of dogs. In conclusion, DNMT1 has excellent potential as a target for InvTCC therapy in humans.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1048. doi:1538-7445.AM2012-1048
Abstract 1059: SUV39H1 promotes HCC tumorigenesis and is targeted by tumor suppressive miRNA-125b
Authors: Fan Dorothy Ngo Yin , Tsang Felice Ho Ching , Au Sandy Leung Kuen , Wei Larry Lai , Tam Aegean Hoi Kam , Wong Chun Ming 
Published: August 2012

Abstract
Epigenetic alternation is a common dysregulated event in hepatocellular carcinoma (HCC) development. Through interrogating the expression of 90 major epigenetic regulating genes, we identified SUV39H1, the prototype histone methyltransferase as one of the most frequently up-regulated epigenetic regulators in human HCC (61%, 23/38). SUV39H1 is responsible for H3K9 trimethylation establishment and essentially involves in heterochromatin formation and transcriptional repression. We found that SUV39H1 up-regulation in human HCC was significantly associated with increased Ki67 expression (P &lt; 0.001) and the presence of venous invasion (P = 0.020), suggesting the importance of SUV39H1 in HCC tumor growth and metastasis. To investigate the functions of SUV39H1 in human HCC, both gain- and loss-of-function models were established. Ectopic expression of SUV39H1 remarkably enhanced cell clonogenicity and migratory ability of immortalized hepatocytes. Conversely, stable knockdown of SUV39H1 by shRNA substantially reduced cell proliferation, colony formation and migration of HCC cells. In addition, an elevated lysosomal β-galactosidase activity in SUV39H1 knockdown cells was observed and suggested the senescence-suppressive role of SUV39H1 in cancer progression. Consistent with previous observations, treatment of SUV39H1 inhibitor (Chaetocin) drastically suppressed cell proliferation and induced apoptosis in HCC cells. The oncogenic function of SUV39H1 was further demonstrated by in vivo experiments, knockdown of SUV39H1 significantly inhibited tumorigenicity of HCC cells in both subcutaneous and orthotopic mouse model. Most importantly, SUV39H1 knockdown abolished pulmonary metastasis of HCC cells in orthotopic tumor implantation model. To further investigate the underlying mechanism of SUV39H1 up-regulation in HCC, we explored the potential regulation of SUV39H1 by microRNA. In silico analysis suggested SUV39H1 as a putative target of miR-125b. Ectopic expression of miR-125b precursor in HCC cells significantly inhibited SUV39H1 3′UTR luciferase reporter activity and suppressed endogenous SUV39H1 expression at both mRNA and protein levels. Interestingly, down-regulation of miR-125b was frequently observed in human HCC (70%, 38/54) and was inversely correlated with SUV39H1 expression (P = 0.001). Taken together, we demonstrated that SUV39H1 was frequently up-regulated in human HCC and functioned as an oncogene in promoting HCC progression and metastasis. miR-125b negatively regulated SUV39H1 expression and downregulation of miR-125b may account for SUV39H1 up-regulation in human HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1059. doi:1538-7445.AM2012-1059
Abstract 1065: Growth factor-mediated resistance to BRAF/MEK inhibitors in BRAF mutant melanoma
Authors: Lutterbach Bart , Ware Chris , Davis Lenora , Zhang Qing , Zawel Leigh , Reilly John , Pan Bo-Sheng 
Published: August 2012

Abstract
BRAF and MEK inhibitors induce striking tumor regressions in BRAF V600E melanoma patients. However, relapse occurs in the majority of patients within several months. Reported resistance mechanisms include acquisition of NRAS mutations, PDGFR or IGF1R activation, Cot amplification, or truncated BRAF upregulation. We report here that hepatocyte growth factor (HGF), neuregulin-1 (NRG1), and fibroblast growth factor-2 (FGF2) cause robust resistance in vitro to BRAF or MEK inhibitors in BRAF mutant melanoma cell lines. NRAS mutant lines were similarly resistant to MEK inhibition in the presence of these growth factors. By contrast other mitogenic factors such as PDGF, EGF, NGF, BDNF, MSP, MDK, GRO, and IGF1 did not maintain cell viability or growth. HGF, NRG1 and FGF2 prevented growth arrest and cell death and in some cell lines maintained cells in progressive growth. In addition, HGF and NRG1 could prevent growth arrest after dual treatment with BRAF and MEK inhibitors. Western analysis revealed that HGF and NRG1 reactivated Erk signaling and activated S6RP and AKT phosphorylation. Combined pharmacological inhibition mTor signaling and Akt signaling was required to fully block growth factor-mediated proliferation. In addition, small molecule Met inhibitors and an anti-HGF antibody blocked HGF-mediated resistance, while lapatinib and an anti-NRG1 antibody blocked NRG1-mediated resistance. While combined Akt and mTor inhibition potently inhibited cell line growth independent of BRAF or MEK inhibition, lapatinib and Met inhibitors had minimal effect on growth, suggesting potential for less adverse events with receptor inhibitors. In vitro co-culture experiments revealed that primary cells present in normal skin can cause resistance, and we have identified growth factors produced by these cells that contribute to resistance. We are analyzing receptor activation (Met and Erbb3) and FGF2 expression in wildtype, NRAS, and BRAF mutant primary melanoma samples. In future experiments we plan to test clinical samples from patients treated with BRAF/MEK inhibitors, and we hypothesize that HGF, NRG1, and FGF2 signaling is elevated in patients with poor initial responses or relapse to BRAF or MEK inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1065. doi:1538-7445.AM2012-1065
Abstract 1067: Targeting the fibroblast growth factor receptor axis in malignant pleural mesothelioma
Authors: Hoda Mir Alireza , Schelch Karin , Pirker Christine , Ghanim Bahil , Klikovits Thomas , Laszlo Viktoria , Setinek Ulrike , Filipits Martin , Dome Balazs , Hegedues Balazs , Marian Brigitte , Grasl-Kraupp Bettina , Klepetko Walter , Berger Walter , Grusch Michael 
Published: August 2012

Abstract
Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy characterized by frequent resistance to chemo- and radiotherapy. Fibroblast growth factors (FGF) and their high-affinity receptors (FGFR) contribute to malignant growth in several tumor types including thoracic malignancies while a role in MPM remains widely undefined. Therefore, aim of the present study was to investigate the expression and impact of FGFs and FGFRs in MPM and to evaluate their potential suitability as new therapeutic targets. Material und Methods: Expression of all known FGF and FGFR genes was assessed by expression array analysis and confirmed by qRT PCR in MPM cell lines (n=10) and normal mesothelial cells. Selected FGFs were also investigated by immunohistochemistry on tissue samples. FGFR-specific tyrosine kinase inhibitors and an adenovirus expressing dominant-negative FGFR1 were used to block FGF signal transduction in MPM cell models. MTT and clonogenic assays as well as spheroid formation assays and videomicroscopy were performed to analyze cell growth, survival and migration. The effect on downstream signal transduction was assessed by immunoblotting with phosphorylation site-specific antibodies. Results: FGFR1 as well as the ligands FGF2 and FGF18 were highly expressed in almost all MPM cell lines investigated. Moreover, immunohistochemistry demonstrated high FGF expression also in tissue sections. Stimulation with exogenous FGF2 in contrast, led to a remarkable increase in cell migration and clonogenic growth. In contrast, inhibition of FGFR1 by the specific small molecule kinase inhibitor PD166866 lead to decreased proliferation, survival, migration and spheroid formation in the majority of cell lines tested. Adenoviral expression of dominant-negative FGFR1 further confirmed these results. In addition, concomitant FGFR inhibition increased the efficacy of currently used chemotherapeutic agents such as cisplatin. Also combination of FGFR inhibition and radiation lead to enhanced cytotoxicity. Conclusion: Taken together, these data suggest that FGFR signals contribute to proliferation, survival, migration and chemotherapy resistance of MPM cells and their inhibition should be further evaluated as a potential new treatment strategy in MPM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1067. doi:1538-7445.AM2012-1067
Abstract 1187: Inactivation of p53 in HPV-infected lung cancer is correlated with p53 codon 72 genotypes and HPV 16/18 E6 protein expression but not with HPV 16/18 DNA
Authors: Cheng Ya-Wen , Hsu Nan-Yung 
Published: August 2012

Abstract
Background. A polymorphism at codon 72 of the p53 tumor suppressor gene is a possible determinant for cancer risk, particularly for carcinomas associated with HPV infection. We recently reported that high-risk HPV 16/18 E6 protein was associated with p53 protein degradation in lung cancer. The present study addressed the relationship between the different p53 genotypes and HPV oncoprotein expression with respect to p53 protein degradation in 319 primary lung cancer patients. Methods. The p53 codon 72 polymorphisms, HPV 16/18 infection, HPV 16/18 E6 and p53 protein expression were determined for all patients by PCR-RFLP, nested-PCR and immunohistochemical analysis. Results. The presence of HPV 16/18 DNA and E6 protein was inversely correlated with p53 expression. The frequency of p53 protein degradation in HPV 16/18 E6-positive/Arg/Arg lung cancer tumours was also much higher than in the HPV 16/18 E6-negative/Arg/Arg, HPV 16/18 E6-positive/Arg/pro+pro/pro, and HPV 16/18 E6-negative/Arg/pro+pro/pro groups. After adjusting for polymorphism, HPV 16/18 E6 protein, HPV 16/18 DNA, gender, smoking habit and tumor type, the major contributors to p53 degradation in lung cancer patients were p53 codon72 polymorphism and HPV 16/18 E6 oncoprotein expression. This correlation was not found for HPV 16/18 DNA infection. Conclusion. These results suggested that the involvement of HPV 16/18 E6 protein in the p53 inactivation that contributes to HPV-infected lung tumourigenesis is correlated with the p53 codon 72 genotype.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1187. doi:1538-7445.AM2012-1187
Abstract 1188: Reprimo, a p53-dependent G2 arrest mediator, reduces tumorigenic capacity in human gastric cancer cell lines
Authors: Olivares Wilda , Torres Veronica , Maturana María José , Montecinos Viviana , Aguayo Francisco , Corvalan Alejandro H. 
Published: August 2012

Abstract
Introduction: Gastric cancer (GC) is one of the leading cause of cancer-related deaths worldwide. The progression of GC is related to genetic as well as epigenetic changes, such as DNA methylation, that involves the downregulation of tumor suppressor genes. Recently we have identified Reprimo (RPRM), a p53-dependent G2 arrest mediator candidate as a putative biomarker for early diagnosis of GC (Clin Cancer Res 2008;14:6264-9). However, the role of RPRM in GC is unknown. Methods: The expression and sequence of the promoter and the coding region of RPRM were performed in five GC cell lines (AGS, NCI-N87, KATOIII, MKN28, MKN45). Two expression negative RPRM cell lines were stable transfected with a pCMV6 vector containing the full-length of the coding region of RPRM (pCMV6-RPRM). Cell growth and proliferation were analyzed by MTS, colony formation and soft agar assays. In addition, we analyzed the ability of migration through wound/healing assay. Results: Only two cell lines were negative for RPRM expression (AGS & MKN45). Bisulfite sequence analysis of the promoter region showed a dense CG-rich CpG island suggesting a role for methylation in regulation of gene expression. No mutations in the coding region were found. A significant decreased of cellular proliferation and anchorage independent growth were observed after the transfection with pCMV6-RPRM. The migration ability was also decreased in both cell lines. Conclusion: Our results suggest that RPRM reduces tumorigenic capacity in GC cell lines. Taken together we suggest that downregulation of RPRM is not only a putative biomarker for early diagnosis but also might play a role in the pathogenesis of GC. Grants-in-Aid for Scientific &Technological Research (Fondecyt #1111014 & Fondef #D09I1137) to AH Corvalán from the Government of Chile.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1188. doi:1538-7445.AM2012-1188
Abstract 1192: ZMIZ1 is elevated in epithelial ovarian cancer due to an upregulated alternative promoter and is associated with p53 mutations
Authors: Nadkarni Niyati J. , Rogers Laura , Samuelson Megan , Neff Traci , Bender David P. , Ahmed Amina , Geest Koen De , Button Anna , Dupuy Adam , Goodheart Michael J. 
Published: August 2012

Abstract
Objectives: The ZMIZ1 gene has recently been found to be a possible, candidate oncogene through a transposon mutagenesis screen. It is widely known that one of the most common genetic alterations in epithelial ovarian cancer involves mutations of the p53 tumor suppressor gene. Previous studies have shown that ZMIZ1 appears to transcriptionally regulate the p53 gene. We hypothesize that ZMIZ1 expression is caused by the presence of an alternative promoter and that the interaction between ZMIZ1 and p53 may impart worse survival. Methods: A retrospective chart review was performed to identify 138 patients with epithelial ovarian cancer. Data collected included clinico-pathologic factors, patient follow-up, and mortality. ZMIZ1 staining and p53 sequencing were performed on all patients. For the determination of ZMIZ1 alternative promoter relative gene expression, RT-PCR was performed on 33 tumors after cDNA had been isolated. Statistical analyses included chi-square analysis and the binomial test. The log rank test was used to evaluate survival analysis. Results: Immunostaining for the ZMIZ1 protein was performed with the following results: 55 (40%) tumors stained positive and 83 (60%) were negative. Of those patients that were found to be ZMIZ1 positive, over half were noted to have a p53 gene mutation. The median survival of the ZMIZ1 positive/p53 mutated cohort was approximately 36 months while the median survival for the ZMIZ1 negative/p53 wild type cohort was 84 months (p = 0.012). ZMIZ1 alternative promoter relative gene expression was noted to be elevated in patients with ZMIZ1 positive immunostaining compared to patients with negative staining. Conclusions: ZMIZ1 staining appears to be present in 40% of patients with epithelial ovarian cancer. In tumors that are ZMIZ1 positive, half contain p53 gene mutations; this combination imparts worse survival. ZMIZ1 upregulation may be due to the presence of a newly identified alternative promoter. Additional studies are ongoing to better define the role of this alternative promoter.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1192. doi:1538-7445.AM2012-1192