bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1107: MicroRNA-182 acts as a chemosensitizer in GBM by repressing Bcl2L12
Authors: Kouri Fotini M. , Wu Yongfei , Chin Lynda , Stegh Alexander H. 
Published: August 2012

Abstract
Glioblastoma Multiforme (GBM) is the most prevalent and aggressive brain tumor, exhibiting high mortality rate and increased resistance to current forms of treatment. GBM development has been linked to deregulation of several signaling cascades involved in cell proliferation and apoptosis. Bcl2-Like 12 (Bcl2L12) is a multi-functional glioma oncoprotein, which is over-expressed in the majority of GBM and regulates tumor progression and resistance to therapy-induced apoptosis. We identified, Bcl2L12 as a potent inhibitor of post-mitochondrial caspases and the p53 tumor suppressor. To dissect the cellular mechanisms that regulate Bcl2L12 expression and function, we interrogated whether Bcl2L12 is under the control of microRNAs (miRs). In silico analysis of 272 primary GBM samples of the TCGA dataset aimed to identify miRs displaying expression levels that anti-correlate with Bcl2L12 mRNA abundance, as such candidates represent potential Bcl2L12-targeting miRs. This approach revealed a significant anti-correlation between Bcl2L12 mRNA and miR-182 expression, preferentially in the proneural subtype, a GBM class with established low Bcl2L12 genomic amplification and mRNA expression and a longer survival compared to patients with mesenchymal, neural or classical tumors. Enforced expression of miR182 in various glioma cell lines confirmed robust downregulation of Bcl2L12 mRNA and protein levels, identified the miR-182 binding site within the 3′UTR of Bcl2L12, and documented that miR-mediated downregulation of Bcl2L12 is highly specific for miR182, but not for other related miRs, such as miR-96 and miR-183. Transfection of pre-miR-182 significantly sensitized cells to various anti-glioma therapeutics, via enhancement of effector caspase activation. Furthermore, it was demonstrated that p53 regulates miR-182 levels. Taken together, our studies confirmed a Bcl2L12- miR-182 axis on genetic and biological levels, and identified miR182 as a potential therapeutic agent to halt GBM progression.
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 1107. doi:1538-7445.AM2012-1107
Abstract 1109: Pleiotropic actions of miR-153 support colorectal cancer progression through enhanced invasion and platinum based chemotherapy resistance
Authors: Mirnezami Alex H. , Zhang Lei , Pickard Karen , Jenei Veronika , Bullock Marc , Strefford John , Mitter Richard , Kelly Gavin , Primrose John N. , Thomas Gareth , Packham Graham 
Published: August 2012

Abstract
Background & Aims MicroRNAs (miRNA) contribute to carcinogenesis, however comparatively less is understood about their role in cancer progression. The aim of this study was to evaluate miRNA expression during progression of colorectal cancer (CRC) and to identify novel miRNA functions. Methods and results Using miRNA microarray profiling of a human cellular model of CRC progression, we have found highly expressed levels of miR-153 in more advanced tumour stages. MiR-153 upregulation was further verified by qRT-PCR. Subsequently, using laser capture microdissected human CRC tumour epithelium and real-time PCR based TaqMan® profiling, we have demonstrated that miR-153 is upregulated in primary human CRC compared with normal colonic epithelium (p&lt;0.0001), and over-expressed in more advanced CRC stages than early stage disease (p&lt;0.005). We show that miR-153 upregulation leads to increased CRC invasiveness using in vitro transwell invasion assays, and to more closely recreate and model in vivo circumstances, we examined the effect of stably transfected GFP-tagged miR-153 over-expression in CRC using a 3-dimensional organotypic co-culture of SW480 cells and human ex-vivo colonic fibroblast cells. Ectopic expression of miR-153 but not control miRNA resulted in increased invasion of CRC into the underlying stroma of organotypic cultures. Further in vitro functional analysis demonstrated that miR-153 over-expression also promotes chemotherapy resistance to Oxaliplatin and Cisplatin. Upregulation of miR-153 but not scrambled miRNA reduced abundance of activated Caspase 3 indicating that miR-153 is functioning as an anti-apoptotic factor in this context. Mechanistic dissection of the above functional effects show that miR-153 induces CRC invasiveness through increased MMP9 production, while resistance to platinum based chemotherapy is mediated through a direct inhibitory effect on the Forkhead box O3 (FOXO3a) transcription factor. Conclusions This is the first demonstration that over-expressed miR-153 has a significant and dual role in CRC progression, promoting both increased invasiveness and chemotherapy resistance. These findings suggest that strategies to suppress miR-153 may prove useful in advanced CRC.
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 1109. doi:1538-7445.AM2012-1109
Abstract 1112: Identification of microRNA-based therapeutic candidates using a unique lentiviral microRNA overexpression library
Authors: van Noort Paula I. , Babae Negar , Poell Jos B. , Bourajjaj Meriem , Vidic Suzana , van Beijnum Judy R. , van Haastert Rick J. , Schultz Iman , de Gunt Thijs , van Hooij Onno , Verhaegh Gerald W. , Gommans Willemijn M. , Cerisoli Francesco , Verheul Mark , Schiffelers Raymond M. , Griffioen Arjan W. , Schalken Jack A. , Berezikov Eugene , Cuppen Edwin , Schaapveld Roel QJ , Prevost Gregoire P. 
Published: August 2012

Abstract
microRNA (miRNA) genes transcribed by RNA polymerase II generate small noncoding miRNAs of 18 to 24 nucleotides after maturation process. The mature miRNAs and their associated isomirs specifically bind to different mRNA transcripts, resulting in down regulation of multiple genes within the cell in a highly multiplexed way. miRNA expression profiles differ between human cell types suggesting cell-specific impacts of each miRNA on the regulation of different biological processes. Comparison of miRNA profiles of tumor samples and adjacent normal tissues showed that some miRNAs are up- or down- regulated and suggested their implication during tumor progression. However, such a miRNA profiling approach is not sufficient to identify the respective role of each miRNA gene during the tumorigenesis. Here, to assess the individual role of each miRNA gene and its different isomirs in a specific cell environment, we have constructed a lentiviral miRNA expression library containing more than 1100 human known and novel miRNA precursors. The arrayed layout of our library allowed high-throughput screens with a large spectrum of functional read-outs using either normal or tumor cells. To exemplify this approach, the results of three different screens will be presented; i.e. identification of miRNAs that inhibit the BRAF pathway, miRNAs that inhibit tumor angiogenesis and miRNAs that stimulate the mesenchymal to epithelial transition. In addition, beyond this hit identification step, we will present detailed characterization of the role of the identified miRNAs in tumor progression by means of molecular and cellular functional assays. Combining our unique miRNA expression library with a functional screening platform has allowed the identification and the further characterization of several miRNAs able to significantly impact on tumor behavior supporting the therapeutic interest of some candidates.
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 1112. doi:1538-7445.AM2012-1112
Abstract 1114: Loss of OPA1 expression results in apoptosis for cells overexpressing c-Myc
Authors: Graves J. Anthony , Cherok Edward P. 
Published: August 2012

Abstract
c-Myc (Myc) is a transcription factor that controls the expression of a vast array of genes that function in many essential cellular pathways, and high levels of Myc have been implicated in the development of many human cancers. One pathway that Myc controls is mitochondrial biogenesis. We have previously shown that Myc does this is in part via the regulation of the expression of proteins involved in mitochondrial fusion, including Opa1, whose levels are increased upon the over-expression of Myc. This results in a highly interconnected mitochondrial network in cells with high levels of Myc. This fused mitochondrial network is present despite the fact that Myc also increases the expression of proteins involved in mitochondrial fission as well. We sought to understand how Myc controls the expression of Opa1 and to determine if the high levels of mitochondrial fusion in Myc over-expressing cells are important in cellular transformation. We hypothesized that the increased mitochondrial fusion driven by the Myc-mediated increase in Opa1 may reduce apoptosis. Rat fibroblasts with inducible Myc expression were transfected with an OPA1-specific shRNA. These cells were characterized by a series of assays that measured different aspects of mitochondrial structure and function. After only 48h of Myc induction, mitochondrial mass increased by approximately two-fold compared to control cells; however, when Opa1 levels were reduced in this background (Myc+/Opa-), mitochondrial mass was decreased four-fold. The cells with decreased Opa1 expression but minimal Myc activity (Myc-/Opa-) had a punctate appearance to the mitochondria, which became even more dramatic in Myc+/Opa- cells. This was likely related to the ability of Myc to increase the proteins involved in fission. There was an approximate 50% decrease in the ability to perform oxidative phosphorylation (OXPHOS) when Myc-/Opa- cells were compared to Myc+/Opa- cells. This was consistent with the four-fold decrease in net ATP levels when Myc-/Opa- cells were compared to Myc+/Opa- cells. Finally, prolonged activation of Myc in cells with decreased expression of OPA1 leads to apoptosis. After 48 hours of Myc induction the Myc+/Opa- cells the cells gradually began to die and cultures were nearly devoid of viable cells within 10 days, whereas Myc-/Opa- cells remained almost completely viable. We believe that the unopposed mitochondrial fission in Myc+/Opa- cells results in an increase susceptibility to an early apoptotic death. The mechanisms involved in this phenomenon are being explored, as is the possibility of exploiting this consequence of Opa1 reduction as a means of selectively eliminating tumor cells that display Myc over-expression.
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 1114. doi:1538-7445.AM2012-1114
Abstract 1115: p32 is a downstream effector of c-Myc induced glutamine addiction
Authors: Fogal Valentina , Chao Ying S. , Pastorino Sandra , Wang Lucia , Jian Pengfei , Mukthavaram Rajesh , Gallagher Matthew , Summitt IlaSri B. , Kesari Santosh 
Published: August 2012

Abstract
Genetic alterations of oncogenes and tumor suppressor genes are the main drivers not only of deregulated cell proliferation but also altered cancer cell metabolism. Compared with normal cells, malignant cells exhibit enhanced utilization of glucose and glutamine. As such, efforts to understand the molecular basis of the addiction to these two nutrients is likely to lead to the identification of new drug targets for the specific killing of cancer cells. A major player in tumor cell addiction to glutamine is the c-Myc oncogene. By stimulating the expression of glutamine transporters and glutaminase, this transcription factor promotes glutamine oxidation through the mitochondria. This rewiring of glutamine metabolism must be sustained by efficient mitochondrial function. The mitochondrial p32 protein was previously demonstrated to be critical in mitochondria metabolism by maintaining oxidative phosphorylation, yet the factors regulating its expression are not clear. Deregulated c-Myc is a frequent feature of gliomas and recent discoveries suggest the importance of metabolic alterations, in particular glutamine addiction, in the pathogenesis of these cancers. Interestingly, medulloblastoma can be clustered into six subgroups based on gene signature and the c-Myc amplified subgroup exhibits high p32 expression. In the present study, we hypothesized that p32 may be a downstream effector of c-Myc induced glutamine addiction. Using a c-Myc and estrogen receptor fusion protein construct in immortalized fibroblast, we demonstrated that p32 expression was up regulated upon c-Myc nuclear translocation. shRNA mediated stable knock-down of p32 in glioma cell lines and patient-derived tumor initiating cells impaired cell proliferation and tumorigenic potential in mouse models. Furthermore, attenuation of p32 expression reduced glioma cells sensitivity to glutamine deprivation and abrogated c-Myc induced glutamine consumption. Additional work is underway to determine whether c-Myc and p32 work in the same or parallel pathways to confer glutamine addiction on glioma cells and to establish the implications of this co-operation on tumor metabolism in vivo.
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 1115. doi:1538-7445.AM2012-1115
Abstract 1127: Bcr-Abl inhibition in leukemia cells creates metabolic addictions
Authors: Alvarez-Calderon Francesca , Zaberezhnyy Vadym , Gemta Lelisa , Gregory Mark A. , DeGregori James V. 
Published: August 2012

Abstract
Bcr-Abl kinase inhibitors are the standard therapy for chronic myelogenous leukemia (CML). While effective in controlling disease in chronic phase, these inhibitors often fail to completely eliminate Bcr-Abl+ CML cells and also fail to achieve durable remissions for advanced CML and Bcr-Abl+ acute lymphoblastic leukemias (ALL). Our lab employed a large-scale synthetic lethal shRNA screen to identify genes involved in CML survival upon treatment with the Bcr-Abl kinase inhibitor imatinib (IM) [Cancer Cell. 2010;18(1):74-87]. This screen identified several genes involved in energy utilization including a component of pyruvate dehydrogenase, dihydrolipoyllysine-residue acetyltransferase. CML proliferation depends on Bcr-Abl-driven glycolysis for energy production. Upon IM treatment, we hypothesized that these cells are forced to rely on other sources of energy including the TCA cycle and the electron transport chain, and that targeting alternative energy production pathways will enhance IM-mediated elimination of CML cells. Thus, we predicted that inhibition of mitochondrial respiration by knockdown or pharmacologic inhibition would cooperate with tyrosine kinase inhibitors (TKI) to eliminate Bcr-Abl+ leukemia. Indeed, our experiments have shown that knocking down pyruvate dehydrogenase in human blast crisis Bcr-Abl+ CML cells (K562) greatly sensitized cells to IM in vitro. Conversely, supplementing the cell culture media with increasing concentrations of methyl-pyruvate protected K562 cells from IM treatment. Moreover, we found that the mitochondrial ATP-synthase inhibitor Oligomycin A (OA) also synergized with IM to kill CML cells in vitro. Interestingly, the doses of OA are far below the IC50 and do not affect the oxygen consumption rates, indicating that mitochondrial respiration is not inhibited. These OA doses alter mitochondrial transmembrane potential and increasing superoxide levels. In addition, OA enhanced elimination of Bcr-Abl+ cells by a Bcr-Abl TKI in vivo and prolonged disease-free survival in a mouse model of Bcr-Abl+ B-ALL. Notably, drug doses of OA used had no apparent adverse effects on these mice. Targeting mitochondrial metabolism as an adjuvant drug therapy may prevent the survival of residual Bcr-Abl+ CML cells upon tyrosine kinase inhibitor treatment. This project is supported by pre-doctoral fellowship number F31CA157166 from the National Cancer Institute, and Leukemia and Lymphoma Society Grant
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 1127. doi:1538-7445.AM2012-1127
Abstract 1146: A functional polymorphism on chromosome 15q25 associated with survival of early stage non-small cell lung cancer
Authors: Choi Yi Young 
Published: August 2012

Abstract
Introduction: The 15q25 region was associated with lung cancer risk and might be associated with prognosis of lung cancer. This study was conducted to determine the impact of a functional polymorphism in the CHRNA3 gene on chromosome 15q25 on the survival of patients with early stage non-small cell lung cancer (NSCLC). Methods: Five hundred eighty-three consecutive patients with surgically-resected NSCLC were enrolled. The rs6495309C&gt;T polymorphism in the promoter of the CHRNA3 gene was investigated. The association between genotype and overall survival and disease-free survival was analyzed. Results: Patients with the rs6495309 CT or TT genotype had a significantly better OS and DFS than the rs6495309 CC genotype (adjusted hazard ratio for overall survival = 0.56, 95% confidence interval = 0.41-0.75, P = 0.0001; and adjusted hazard ratio for disease-free survival = 0.61, 95% confidence interval = 0.48-0.79, P = 0.0001). An association between the rs6495309C&gt;T polymorphism and survival outcome was demonstrated in smokers and never-smokers, and in squamous cell carcinomas and adenocarcinomas. Conclusion: The CHRNA3 rs6495309C&gt;T polymorphism may affect survival in patients with early-stage NSCLC. Analysis of the rs6495309C&gt;T polymorphism can help identify patients at high risk of a poor disease outcome. Key words: CHRNA3, polymorphism, non-small cell lung cancer, survival
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 1146. doi:1538-7445.AM2012-1146
Abstract 115: KIR haplotype polymorphism determines innate susceptibility/resistance to childhood leukemia
Authors: Samarani Suzanne , Nocq Julie , Allam Ossama , Marzouk Rim , Momparler Richard.L , Ahmad Ali 
Published: August 2012

Abstract
Background: The Killer-cell Immunoglobulin-like Receptor (KIR) genes encode receptors that are expressed on the surface of Natural Killer (NK) cells and a subset of T cells. The receptors regulate functional activities of these immune cells in the body. There exist seventeen distinct KIR genes in humans of which nine encode inhibitory, and six encode activating receptors, while two are pseudo genes. KIR haplotypes show extensive variability with respect to their repertoire of activating KIR genes. Humans may have none or up to six different activating KIR genes. The acquisition of these genes is believed to decrease activation threshold of NK cells in humans, and provide resistance to malignancy. Hypothesis: We hypothesized that the acquisition of activating KIR genes by an individual may protect him/her from childhood leukemia. Methods: We used the candidate gene approach. In a case-control study, we determined the presence or absence of different activating KIR genes using gene-specific primer pairs. The frequencies of each gene were compared between cases and controls using Chi2 test and multivariate logistic regression. Results: Our results show for the first time that the inheritance of activating KIR genes is associated with increased resistance to childhood leukemia (both B-ALL and T-ALL; in adjusted analysis p-values being as low as 1.14x10-7). Interestingly, this resistance increased as the number of activating KIR genes increased in the genome of the individual. Furthermore, we found that that this resistance/susceptibility is differentially modulated by co-inheritance of different inhibitory KIR-MHC class I gene pairs. Conclusions: The inheritance of activating KIR gene-containing haplotypes confers innate resistance to childhood leukemia. These receptors may serve as novel target molecules for therapeutic interventions in childhood leukemia. The study was supported by a research grant (≠2010-700554) from the Canadian Cancer Society Research Institute (CCSRI).
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 115. doi:1538-7445.AM2012-115
Abstract 1151: cMYC amplification in colon cancer: A novel association with BRAF V600E and proficient DNA mismatch repair
Authors: French Amy J. , Sargent Daniel , Foster Nathan , Kabat Brian , Blair Hilary , Limburg Paul , Vierkant Robert , Wang Alice , Tillmans Lori , Thibodeau Stephen 
Published: August 2012

Abstract
Background: Colon cancer is categorized by the acquisition of a number of molecular alterations in both oncogenes and in tumor suppressor genes. Although cMYC alterations have been reported in colon cancer cell lines, little other information exists in primary colon tumors. We sought to determine the frequency of cMYC amplification in primary colon cancer and its relationship to other well defined colon tumor alterations. Methods: An initial set of 392 tumors were evaluated. All samples were tested for the BRAF V600E mutation and all were classified as proficient mismatch repair (pMMR) based on both IHC and microsatellite analysis of tumor tissue. A second set of 522 tumors was selected to replicate associations identified in the first set of samples. Similar to the initial cohort, both the BRAF V600E and the mismatch repair status of the tumors were assessed. The second cohort, however, included tumors that were both pMMR and dMMR. In both sets of samples, fluorescent in situ hybridization was used to evaluate cMYC gene amplification. Results: In cohort 1, cMYC amplification was observed in 15 of the 362 (4%) pMMR tumors successfully analyzed (Table 1). cMYC amplification was detected in 10 of 323 (3%) tumors with normal BRAF status vs. 5 of 39 (13%) tumors with altered BRAF status (p=0.015). In the second cohort, cMYC amplification was found in 20 of the 522 (4%) tumors. Only 1 of the 152 (&lt;1%) dMMR tumors had cMYC amplification vs. 19 of the 370 (5%) pMMR tumors (p=0.012). Of the pMMR tumors, cMYC amplification was detected in 13 of 333 (4%) tumors with normal BRAF status vs. 6 of 37 (16%) tumors with altered BRAF status (p=0.007), nearly identical to the first group. Conclusion: cMYC amplification in colon cancer is an infrequent event. However, when present, cMYC amplification occurs almost exclusively in tumors that are pMMR. Additionally, among pMMR tumors, cMYC amplification is associated with the presence of the BRAF V600E mutation.

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 1151. doi:1538-7445.AM2012-1151