bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3120: Evidence supporting a role of ETV4 in pancreatic cancer pathogenesis.
Authors: Srivastava Sanjeev K. , Tyagi Nikhil , Kaur Gurpreet , Arora Sumit , Bhardwaj Arun , Grizzle William E. , Singh Ajay P. , Singh Seema 
Published: August 2014

Abstract
The clinical outcome from pancreatic cancer has not improved over the years. This is, in part, due to not well understood disease mechanisms and consequently there is little progress made in developing intervention therapy. Many genetic alterations have been characterized in pancreatic cancer, of which some have been shown to be functionally relevant. ETV4, proto-oncogenic transcription factor, has been shown to be aberrantly expressed in various cancers types and plays important role in disease pathogenesis. The role of ETV4, however, has not been defined in pancreatic cancer so far. In this study, we investigated the pathological involvement of ETV4 in pancreatic cancer. For this, we silenced its expression in two highly tumorigenic and metastatic ETV4 overexpressing pancreatic cancer cell lines (Colo357 and ASPC1) by stable transfection of ETV4-targeted short-hairpin RNA (shRNA)-expression plasmid. Silencing of ETV4 led to a decrease in growth and clonogenicity of ETV4-silenced pancreatic cancer cells (Colo357-shETV4 and ASPC1-shETV4) as compared to their respective controls (Colo357-Scr and ASPC1-Scr). Furthermore, inhibition of ETV4 also caused suppression of pancreatic cancer cell motility and invasiveness. In contrast, ETV4-silenced pancreatic cancer cells exhibited greater cell-cell interaction as compared to their respective control cells. Immunoblot analyses demonstrated a loss of mesenchymal markers, N-cadherin, Vimentin, and twist, and gain of epithelial marker, E-cadherin, in ETV4-silenced Colo357 and ASPC1 cells, indicating a role of ETV4 in epithelial to mesenchymal transition (EMT) of PC cells. Lastly, expression analysis of ETV4 in clinical specimens demonstrated its aberrant expression in malignant pancreatic tissue, while no expression was detected in the normal pancreas. Altogether, these findings provide first experimental evidence for a functional role of ETV4 in pancreatic cancer.
Citation Format: Sanjeev K. Srivastava, Nikhil Tyagi, Gurpreet Kaur, Sumit Arora, Arun Bhardwaj, William E. Grizzle, Ajay P. Singh, Seema Singh. Evidence supporting a role of ETV4 in pancreatic cancer pathogenesis. [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 3120. doi:10.1158/1538-7445.AM2013-3120
Abstract 3290: Modulation of AKT, ERK and Mcl-1 by apigenin sensitizes colon cancer cells to anti-tumor activities of ABT263.
Authors: Shao Huanjie , Jing Kai , Mahmoud Esraa , Fang Xianjun , Yu Chunrong 
Published: August 2014

Abstract
Apigenin is an edible plant-derived flavonoid showing anti-tumor activities in vitro and in vivo.
Pretreatment with apigenin resulted in cell growth arrest and/or apoptosis in various types of tumors via modulating multiple cell signaling pathways. In the present study, we evaluated interactions between apigenin and ABT263 in multiple colon cancer cell lines. We found that apigenin enhanced ABT263-induced apoptosis in colon cancer cells in a time- and dose-dependent manner. ABT263 alone only resulted in limited cell killing in association with upregulation of Mcl-1, a potential mechanism for acquired ABT263 resistance. Apigenin antagonized ABT263-induced Mcl-1 expression and dramatically enhanced ABT263-induced cell death. Apigenin also suppressed AKT and ERK activation. Inactivation of either AKT or ERK pathway by lentivirus-transduced shRNA or specific small molecule inhibitors synergized with ABT263 to induce cell death, reflecting that AKT and ERK pathways are apigenin targets. Moreover, the synergism between ABT263 and apigenin was associated with the upregulation of Bim and subsequent activation of Bax. Xenograft studies with HCT116 cells in SCID mice showed that the combination treatment with apigenin and ABT263 inhibited tumor growth up to 70% without obvious adverse effects, while either agent alone showed only about 30% inhibition. Collectively, our findings demonstrate a novel and effective strategy to treat colon cancer by combination of ABT263 and apigenin. The combined effect is mediated by apigenin downregulation of Mcl-1, Akt and ERK activities.
Citation Format: Huanjie Shao, Kai Jing, Esraa Mahmoud, Xianjun Fang, Chunrong Yu. Modulation of AKT, ERK and Mcl-1 by apigenin sensitizes colon cancer cells to anti-tumor activities of ABT263. [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 3290. doi:10.1158/1538-7445.AM2013-3290
Abstract 3295: Combining GSK3 inhibition and Vitamin D as a differentiation strategy for AML.
Authors: Gupta Kalpana , Stefan Tammy , Wald David N. 
Published: August 2014

Abstract
Vitamin D has widely been considered a promising therapy for cancer, particularly Acute Myeloid Leukemia (AML), due to its ability to terminally differentiate leukemic cells. Despite the promise of Vitamin D in preclinical studies, clinical trials have been disappointing likely due to dose limiting hypercalcemia that occurs at relatively low doses. We have identified that the kinase GSK3 is a major regulator of the Vitamin D receptor (VDR) and that targeting GSK3 can sensitize leukemic cells to low concentrations of Vitamin D that may be achievable clinically.
Utilizing cell and animal based models, we found that GSK3 inhibition can significantly enhance the anti-leukemic effects of Vitamin D. By inhibiting GSK3 with both small molecules and shRNA, we found that targeting GSK3 leads to a significant sensitization in AML cells derived from multiple AML subtypes to Vitamin D-mediated differentiation. Differentiation induction can be seen through immunophenotyping for cell surface markers, functional differentiation as measured by NBT reduction, and changes in morphology. For example, treatment of HL-60 cells with low doses of Vitamin D (5nM) or a GSK3 inhibitor SB415286 (10uM) leads to only moderate differentiation (&lt;50%) while the combination of these agents leads to greater than 95% differentiation as measured by the upregulation of the differentiation associated marker, CD11b. In addition to differentiation induction, GSK3 inhibition also significantly enhanced the ability of Vitamin D to cause irreversible growth inhibition as measured by colony assays and slowed the progression of AML in a mouse model system.
Mechanistic studies have revealed significant insights into how GSK3 modulates Vitamin D signaling. GSK3 was found to bind and phosphorylate VDR which negatively regulates VDR activity as measured by luciferase based reporter assays. The mechanism through which GSK3 appears to regulate VDR activity is through impacting its interactions with co-repressors and co-activators. These co-modulators are known to play a predominant role in regulating VDR activity. Utilizing co-immunoprecipitation and mammalian two hybrid assays, we determined that GSK3 inhibition can impair the interaction of VDR with the co-repressor NcoR, and enhance its interaction with the co-activator, SRC-3. Overall, our studies suggest the potential of Vitamin D and GSK3 inhibition as a strategy to improve the efficacy of AML treatment and provide a mechanistic framework to explain the promising activity of this combination regimen.
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Citation Format: Kalpana Gupta, Tammy Stefan, David N. Wald. Combining GSK3 inhibition and Vitamin D as a differentiation strategy for AML. [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 3295. doi:10.1158/1538-7445.AM2013-3295
Abstract 3416: Genomic alterations of the CDK4-pathway in melanoma and evaluation of the CDK4 Inhibitor PD-0332991.
Authors: Sheppard Karen E. , Foo Allen , Young Richard , Waldeck Kelly , Pearson Richard , McArthur Grant , Christensen James 
Published: August 2014

Abstract
Activation of CDK4 by amplification, increased expression of Cyclin D1 (CCND1) or reduced expression of the CDK inhibitor p16 (CDKN2A) can contribute to melanocyte transformation, indicating that CDK4 can act as an oncogene in melanoma. We have analyzed the frequency of gene copy number variations (CNV) in the CDK4 pathway and looked for associations of these alterations with patient survival to assess if CDK4 is a viable target for the treatment of human melanoma. In addition, we screened a panel of melanoma cells with a highly selective CDK4/6 inhibitor PD-0332991 (PD-991) and performed gene expression and mutation analysis on these cells to explore possible genomic predictors of sensitivity.
Genomic analysis revealed that 75% of primary melanomas had at least one CNV in the CDK4 pathway, with 55% showing a loss of CDKN2A. 28% of melanomas had two or more CNVs and melanomas with two or more CNVs involving CCND1 had worse overall survival (HR 5.56, P=0.02). From the cell line studies low CDKN2A mRNA expression, mutation or loss predicted sensitivity to PD-991 with 23 out of 27 mutant/loss cell lines being sensitive compared to only 3/7 wild type lines (p&lt;0.03). Expression of CDK4, CCND1 or other cyclins or CDK-inhibitors did not predict sensitivity to PD-991. PD-991 induced an increase in both cell size and SA-ß-galactosidase activity that is indicative of a senescent phenotype, and this was associated with cells having wild type p53. In summary, genomic alterations in the CDK4 pathway are frequent in melanoma and are associated with worse survival, particularly when melanomas harbor two or more CNVs involving CCND1. CDK4 inhibition induces a senescent phenotype in melanoma cells that is associated with loss of CDKN2A and wild type TP53. Taken together these data support evaluation of CDK4 inhibitors in melanoma and suggest that CDKN2A and TP53 maybe genomic predictors of sensitivity.
Citation Format: Karen E. Sheppard, Allen Foo, Richard Young, Kelly Waldeck, Richard Pearson, Grant McArthur, James Christensen. Genomic alterations of the CDK4-pathway in melanoma and evaluation of the CDK4 Inhibitor PD-0332991. [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 3416. doi:10.1158/1538-7445.AM2013-3416
Abstract 3592: Roles of miR-199a-5p and COX-2 in arsenic-induced tumor angiogenesis.
Authors: He Jun , Carpenter Richard , Jiang Yue , Xu Qing , Jiang Bing-Hua 
Published: August 2014

Abstract
Arsenic is a well-known human carcinogen which is closely associated with lung cancer. However, the mechanism underlying the arsenic-induced carcinogenesis remains to be elucidated. The alterations of miRNAs profiles in cancers have profound implication in cancer development. However, it remains to be determined whether the alterations of miRNA signature in response to carcinogens such as arsenic may result in cell malignant transformation and tumor growth. In this study, we developed an in vitro model by transforming human lung epithelial BEAS-2B cells through long-term exposure to low concentration of arsenic. The BEAS-2B cells were malignantly transformed validated by cell proliferation, anchorage independent growth and tumor growth assay. By utilizing this model, we found that miR-199a-5p expression level was dramatically repressed in arsenic-transformed cells. Re-expression of miR-199a-5p impaired arsenic-induced tumor angiogenesis through directly targeting hypoxia inducible factor-1α (HIF-1α). Interestingly, we found another proangiogenic factor cyclooxygenase-2 (COX-2) that was also upregulated in arsenic-transformed cells and was predicted as a target of miR-199a-5p. It was confirmed by generating COX-2 3’UTR miRNA luciferase reporters with wild-type or mutant binding sites with miR-199a-5p. Overexpression of miR-199a-5p inhibited COX-2 protein expression. Functional study revealed that knockdown of COX-2 by siRNA in arsenic-transformed cells decreased tumor angiogenesis. We further showed that the COX-2 promoter contains a functional hypoxia response element (HRE). HIF-1α regulated COX-2 expression at the transcriptional level via direct binding to the HRE (-576/-584) located within the COX-2 promoter. Thus, arsenic-induced COX-2 activation is mediated by repression of miR-199a-5p and activation of HIF-1. Moreover, prostaglandin E2 (PGE2), a product of COX-2 regulated HIF-1 expression in a positive-feedback manner. In addition, arsenic-transformed cells have high levels of reactive oxygen species (ROS) for activating COX-2 pathway. Taken together, our results demonstrate that arsenic-induced angiogenesis through miR-199a-5p repression and pro-inflammatory responses induced by ROS. Both pathways lead to activation of HIF-1/COX-2 pathway. These findings establish critical roles of miR-199a-5p and its downstream targets HIF-1/COX-2 in arsenic-induced tumor angiogenesis. As miR-199a-5p is generally downregulated, whereas COX-2 is overexpressed in human lung cancer tissues, they may be used as new therapeutic targets for lung cancer treatment in the future.
Citation Format: Jun He, Richard Carpenter, Yue Jiang, Qing Xu, Bing-Hua Jiang. Roles of miR-199a-5p and COX-2 in arsenic-induced tumor angiogenesis. [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 3592. doi:10.1158/1538-7445.AM2013-3592
Abstract 361: ZNF24 may modulate microvascular endothelial cell invasion by regulating MMP2 transcription.
Authors: Jia Di , Moses Marsha A. 
Published: August 2014

Abstract
ZNF24 is a C2H2 zinc finger transcription factor that regulates angiogenesis by repressing the transcription of vascular endothelial growth factor (VEGF). It has also been implicated in the control of cell proliferation and differentiation in the central nervous system and in hepatocellular carcinoma. In the current study, we have focused on the role of ZNF24 in modulating endothelial cell motility. We have found that silencing of ZNF24 in human microvascular endothelial cells (HMVEC) leads to significantly decreased cell migration and invasion. Consistently, the protein level and proteolytic activity of matrix metalloproteinase-2 (MMP2), but not those of matrix metalloproteinase-9 (MMP9), are significantly downregulated when ZNF24 is silenced in these cells. We have also determined the effect of ZNF24 silencing on the mRNA levels of endogenous inhibitors of MMPs, the tissue inhibitors of metalloproteinases (TIMPs). While TIMP1 and TIMP4 levels are moderately upregulated by ZNF24 silencing, the level of TIMP2, a major regulator of MMP2 proteolytic activity, and that of TIMP3, are significantly decreased. However, ZNF24 siRNA induces only a moderate decrease in the protein level of TIMP2, suggesting that TIMP2 does not play an important role in the regulation of MMP9 activity by ZNF24. Another major regulator of MMP2 proteolytic activity, membrane-type-1 matrix metalloproteinase (MT1-MMP), also does not exhibit significant changes when ZNF24 is silenced, suggesting that MMP2 is regulated by ZNF24 at the transcriptional level. Indeed, the mRNA level of MMP2 is significantly downregulated when cells are transfected with ZNF24 siRNA, indicating that ZNF24 positively regulates the transcription of MMP2. When compared to normal endothelial cells, tumor endothelial cells exhibit higher levels of endogenous ZNF24, suggesting that ZNF24 may function to increase cell invasion in these cells via upregulation of MMP2. Our current studies are focused on determining whether MMP2 is a direct downstream target of ZNF24 as well as on its role(s) in modulating endothelial cell motility in vivo. (Supported by NIH P01 CA045548, the Breast Cancer Research Foundation and the Advanced Medical Research Foundation)
Citation Format: Di Jia, Marsha A. Moses. ZNF24 may modulate microvascular endothelial cell invasion by regulating MMP2 transcription. [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 361. doi:10.1158/1538-7445.AM2013-361
Abstract 3616: Androgen deprivation therapy and second primary lung cancer risk in prostate cancer patients in the US Veterans.
Authors: Kang Hyunseok , Pillai Rathi N. , Brandes Johann C. 
Published: August 2014

Abstract
Background
Previous observational studies have consistently reported decreased risk of lung cancers among prostate cancer patients. Recent literature suggests a role of estrogen receptor (ER) beta and aromatase, which can convert testosterone to estrogen, in development and progression of non small cell lung cancers. Second primary lung cancer risk among breast cancer patients appears to be higher in ER negative patients compared to ER positive patients probably from estrogen receptor blockade. As androgen deprivation therapy (ADT) has been well established for more than 70 years as an effective treatment modality for prostate cancer, we hypothesized the hormone modulation may decrease lung cancer risk and investigated the effect of ADT on second primary lung cancer risk among patients with prostate cancer.
Methods
We identified 62,589 men in VA Central Cancer Registry (VACCR) who were diagnosed with prostate cancer between 1999 and 2008, with follow-up available through 2010. The primary outcome was development of lung cancer, determined by VACCR. Descriptive statistics were used to compare basic characteristics between the groups. Cox proportional hazards model was used to assess the influence of ADT on the lung cancer incidence, adjusted for patient characteristics and prostate cancer stage. All the statistical analyses were performed using STATA 10 (Stata Corp, College Station, TX).
Results
Men who had ADT as part of their treatment for prostate cancer tend to be older (median age 71.3 vs 65.7, p &lt; 0.01) and smoke slightly more (72.5% vs 71.4%, p=0.02). As expected, ADT group tend to have higher stage prostate cancers. There were 766 secondary lung cancers diagnosed in the cohort for the follow-up period. ADT group had significantly decreased secondary lung cancer risk by approximately 20% (HR 0.83, 95%CI=0.70-0.97) when adjusted for age, smoking status and prostate cancer stage at presentation.
Conclusion
Our study suggests that ADT in prostate cancer patients is associated with a decreased risk of second primary lung cancers. Independent validation studies and subgroup analyses to clarify the association is warranted.
This work was supported by Veteran's Health Administration 1IK2BX001283-01 and NCI 5P50CA128613-02.
Citation Format: Hyunseok Kang, Rathi N. Pillai, Johann C. Brandes. Androgen deprivation therapy and second primary lung cancer risk in prostate cancer patients in the US Veterans. [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 3616. doi:10.1158/1538-7445.AM2013-3616
Abstract 363: Activin receptor-like kinase 1 (Alk1) ligands modulate endothelial cell function in vitro and in vivo.
Authors: Davies Gareth C. , Harper James A. , Sainson Richard C. , Brown Lee , Opoku-Ansah Grace , Smith Alison , McCourt Matthew , Legg James W. 
Published: August 2014

Abstract
The TGF-ß type-1 receptor activin receptor-like kinase 1 (Alk1) is predominantly expressed on endothelial cells, regulates vascular morphogenesis, and has been implicated in pathological angiogenesis. Alk1 expression is increased in the vasculature of a broad range of tumours and agents that disrupt of Alk1 signalling in tumour endothelial cells may be potential therapeutics for the treatment of a variety of solid tumours. Alk1 has been described as a receptor for the bone morphogenic proteins, BMP9 and BMP10. In order to study the effects of Alk1 signalling in endothelial cells in vitro and in the vasculature in vivo we used a soluble antagonist Alk1-Fc protein consisting of the extracellular domain of the Alk1 protein fused to the Fc domain of IgG1. In vitro, Alk1-Fc inhibited BMP9-dependent Alk1 signalling via phosphorylation and nuclear translocation of SMAD1/5 in endothelial cells and modulated endothelial cell functions such as an ability to form tube- like structures. In mice, physiological levels of BMP9 could be detected in serum by ELISA, consistent with detectable levels of phosphorylated SMAD1/5 in the lung, a site of high Alk1 vascular expression. In mice, the administration of Alk1-Fc effectively blocked SMAD1/5 phosphorylation in the lung, suggesting that in this tissue Alk1 ligands are the predominant driver of lung SMAD1/5 activation and that signalling is efficiently antagonised by Alk1-Fc. Despite suppression of Alk1 signalling in the lung and expression of Alk1 on the vasculature associated with tumours, Alk1-Fc did not have profound effects on tumour size or microvessel density in mice bearing tumours, however administration of Alk1-Fc in neonatal mice did cause defects in angiogenesis of the retinal vasculature demonstrating that in some contexts Alk1 ligands play an important role in regulating the angiogenic process.
Citation Format: Gareth C. Davies, James A. Harper, Richard C. Sainson, Lee Brown, Grace Opoku-Ansah, Alison Smith, Matthew McCourt, James W. Legg. Activin receptor-like kinase 1 (Alk1) ligands modulate endothelial cell function in vitro and in vivo. [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 363. doi:10.1158/1538-7445.AM2013-363