bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2030: A novel role for the 185delAG BRCA1 mutant protein, BRAT, in ovarian cancer pathology
Authors: Woolery Kamisha T. , Linger Rebecca J. , Kruk Patricia A. 
Published: July 2012

Abstract
Objective: Familial history is the strongest risk factor for developing ovarian cancer (OC) and is associated with BRCA1 truncation mutations, such as the founder mutation 185delAG. Studying these risk-associated mutations may reveal signaling pathways important in OC etiology. Normal human ovarian surface epithelial (HOSE) cells expressing the 185delAG mutant, BRAT, exhibit phenotypic changes due, in part, to up-regulation of maspin, a tumor suppressor important in apoptosis, invasion, and metastasis that exhibits unique up-regulation in some cancer types. In the current study, we determined BRAT's impact on expression of Interleukin-1beta (IL1β), another key player in invasion and metastasis.
Methods: HOSE cells transiently and stably expressing the 185delAG mutation and HOSE cells with endogenous 185delAG were analyzed for differential target gene expression by semi-quantitative, real time PCR, western blot; as well as, IL1β bioactivity. Western blot was used to identify cell signaling targets of BRAT mediated IL1β expression via MAPK pathways. Breast epithelial and breast cancer cells transiently and stably expressing BRAT were evaluated by real time PCR to determine whether BRAT induced IL1β is tissue specific.
Results: BRAT-expressing HOSE cells exhibited enhanced IL1β mRNA expression. Higher levels of pro-IL1β protein were detected by Western blotting of cell lysate and conditioned media. Increased phosphorylation of MAPK pathway constituents were seen in BRAT-expressing HOSE cells as detected by Western blotting of cell lysate. However, expression of BRAT in normal breast and breast cancer cell lines failed to significantly alter IL1β expression levels.
Conclusion: Normal HOSE cells expressing the BRAT mutation exhibit increased expression of IL1β. Further investigation is warranted to elucidate the mechanism of tissue-specific BRAT-mediated IL1β expression since increased IL1β expression may represent an early step of malignant transformation contributing to ovarian cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2030. doi:10.1158/1538-7445.AM2011-2030
Abstract 2032: Regulation of MUC1 expression by activated EGFR and PPARγ in human uterine and pancreatic cancer cell lines
Authors: Dharmaraj Neeraja , Carson Daniel D. 
Published: July 2012

Abstract
Many epithelial tumors including endometrial and pancreatic cancers, overexpress the high molecular weight, transmembrane mucin, MUC1, on their cell surface. Overexpression and aberrant glycosylation of MUC1 makes tumor cells poorly adherent, increases drug resistance and promotes cancer cell metastasis. MUC1 has three distinct domains: an extracellular domain (ECD) composed of a tandem repeat region rich in serine, threonine and proline; a transmembrane domain (TM) and; a short cytoplasmic tail domain (CT) involved in a variety of signal transduction events. Previous studies (Wang et al. 2010. Mol. Endocrinol. 24: 1368-1379) demonstrated that the Peroxisome Proliferator Activated Receptor γ (PPARγ) agonist, rosiglitazone severely inhibits progesterone stimulated MUC1 expression. Two independent approaches were used to determine if rosiglitazone as well as inhibitors of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase activity reduced MUC1 expression in the human uterine epithelial cell line, HES, the uterine adenocarcinoma cell line, HEC-1A, and in the human pancreatic adenocarcinoma cell lines, HPAFII and CAPAN2. EGFR activation by Epidermal Growth Factor (EGF) stimulated (1.5-2 fold) MUC1 protein expression 1.5-2.0 fold in both uterine and pancreatic cancer cells, while treatment with EGFR tyrosine kinase inhibitor, AG1478, reduced both basal and stimulated MUC1 protein expression. Furthermore, the PPARγ agonist, rosiglitatzone, markedly (&gt; 90%) reduced EGFR-driven MUC1 expression detected by antibodies directed against the MUC1 ECD and CT. A combination of biochemical and molecular biological assays have been used to identify the transcriptional and signal transduction pathways activated by EGFR leading to increased MUC1 expression and the impact of AG1478 and rosiglitazone on these events. Understanding the molecular basis of how these agents reduce MUC1 expression may offer novel therapeutic avenues to improve cancer chemotherapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2032. doi:10.1158/1538-7445.AM2011-2032
Abstract 204: p53-induced gene 3 activity is glutathione peroxidase 3 dependent
Authors: Yu Yan P. , Wang Hui , Luo Katherine L. , Luo Jian-Hua 
Published: July 2012

Abstract
The expression of glutathione peroxidase 3 (GPx3) was found widely altered in a variety of human malignancies. Methylation and deletion of GPx3 were reported in several types of human cancers. Recently, GPx3 characterized as a tumor suppressor gene. However, the mechanism of the tumor suppressor activity of GPx3 is not clear. In this report, we demonstrated that GPx3 interacts with p53-induced gene 3 (PIG3) in both prostate cancer cells and immortalized prostate epithelial cells. The PIG3 binding motif is located in amino acid 2-114 of GPx3. Expression of GPx3 resulted in apopotosis and necrotic cell death. Interaction of GPx3 and PIG3 led to dramatic increase of reactive oxygene species (ROS) inside the cells and activation of caspase-3. Knocking down of PIG3 or mutation of PIG3 binding motif in GPx3 abrogated ROS generation activity induced by GPx3. These results suggest that PIG3 activity is GPx3-dependent, and reveal a novel signaling pathway that leads to GPx3 mediated tumor suppression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 204. doi:10.1158/1538-7445.AM2011-204
Abstract 2047: Betulinic acid exerts anti-angiogenic activity via regulation of HIF-1 alpha and STAT3 in PC-3 prostate cancer cells under hypoxia
Authors: Kim Bong I. , Shin Jimin , Jung Deok B. , Park Moon Y. , Ko Hyun Suk , Song Hyo Sook , Koh Wonil , Jung Ji Hoon , Kwon Tae-Rin , Han Ihn , Kim Ji-Hyun , Yun Sun-Mi , Rhee Yun-Hee , Cho Sung Yun , Lee Hyo-Jung , Lee Hyo-Jeong , Jeong Soo-Jin , Lee Eun-Ok , Kim Sung Hoon 
Published: July 2012

Abstract
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor constitutively overexpressed in several human cancer cells and related to various cellular processes such as cell survival, angiogenesis and proliferation. In the present study, we examined whether betulinic acid (BA), a triterpene from the bark of white birch, could inhibit hypoxia-mediated activation of STAT3 and HIF-1 alpha in androgen independent human prostate cancer PC-3 cells. Our results show that BA inhibited the transcriptional activities and nuclear accumulation of both HIF-1 alpha and STAT3 under hypoxia. In addition, BA significantly reduced cellular and secreted levels of hypoxia-induced vascular endothelial growth factor (VEGF), a critical angiogenic factor, in PC-3 cells. BA prevented in vitro capillary tube formation in human umbilical vein endothelial cells (HUVECs) maintained in conditioned medium of hypoxia-induced PC-3 cells. Moreover, silencing HIF 1 alpha and STAT3 by siRNA transfection augmented the suppression of VEGF expression by BA under hypoxia. Mechanistically, BA inhibited the recruitment of HIF-1 alpha and STAT3 on the VEGF promoter. Taken together, these findings suggest that BA may exert angio-prevention via inactivation of hypoxia-induced STAT3 and HIF-1 alpha in PC-3 cells. The in vivo anti-angiogenic and anti-PCa efficacy are being evaluated.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2047. doi:10.1158/1538-7445.AM2011-2047
Abstract 2048: USF2 is HIF2α specific co-transcriptional activator
Authors: Pawlus Matthew , Wang Liyi , Sena Johnny , Hu Cheng-Jun 
Published: July 2012

Abstract
Hypoxia inducible factor HIF1α, and in particular HIF2α have been shown to drive malignant progression by activation of angiogenesis, proliferation, anaerobic metabolism, and other processes that enable tumor cells to survive or to escape their O2-deficient microenvironments. The dominant role of HIF2α in tumor biology is likely due to its selective activation of genes such as cyclin D1, TGFa, PDGFb, and OCT4 that are not regulated by HIF1α. The mechanism through which the highly conserved HIF1 and HIF2 regulate distinct target genes has not been established. We have previously shown that the transcriptional domain, but not the DNA binding domain of HIF determines its target gene specificity, suggesting that HIFs achieve their target gene specificity by interacting with other transcriptional factors or cofactors via their transactivation domains. Here we reported that HIF2α achieves its target gene specificity and enhanced transcriptional activity by interacting with the b/HLH/LZ transcription factor USF2 (upstream stimulatory factor 2) on promoters of HIF2α specific genes. We observed that siRNA-mediated USF2 knockdown significantly inhibited hypoxic induction of HIF2α (but not HIF1α) target genes in Hep3B and RCC4T cells. Additionally, overexpression of a USF2 dominant negative construct in Hep3B cells significantly reduced the levels of HIF2α (but not HIF1α) target genes under hypoxia. These data determined that USF2 is required for HIF2α to activate its target gene under hypoxia. By HIF2 target gene promoter functional analysis, gel-shift, and Chromatin-IP, we found that USF2 enhances HIF2α transcriptional activity by binding to HIF2α specific gene promoters and recruiting co-activator CBP/P300. In summary, we have uncovered a novel function of USF2 in HIF2α target gene regulation and demonstrated that USF2 is required for HIF2, but not HIF1 to activate its target genes. This finding has laid a foundation for the development of specific HIF2α inhibitors for use in solid tumor treatment.
NIH T32-GM08730; RO1 CA134687 NIH/NCI (Hu); Cancer League of Colorado (Hu)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2048. doi:10.1158/1538-7445.AM2011-2048
Abstract 2052: Inhibition of aldose reductase prevents hypoxic stress signaling in human colon cancer cells
Authors: Srivastava Satish K. , Tammali Ravinder , Ramana Kota V. 
Published: July 2012

Abstract
Hypoxia, a hallmark of invasive solid tumors and increased angiogenesis, is strongly associated with the progression of malignant phenotypes, poor prognosis, and resistance to chemo and radiation therapies. In a variety of cancers, hypoxic stress-induces inflammatory signaling which is mediated by specific cytokines, chemokines and growth factors. We have recently shown that inhibition of aldose reductase (AR), an enzyme that catalyzes the reduction of lipid aldehydes and their glutathione conjugates, prevents human colon cancer cell growth in culture as well as in nude mice xenografts by inhibiting the NF-kB-dependent activation of oxidative stress-mediated inflammatory and carcinogenic markers. However, the role of AR in mediating hypoxic stress signals is not known. We therefore investigated the molecular mechanisms by which AR inhibition prevents the hypoxia-induced human colon cancer cells growth and invasion. Our results indicate that AR inhibition by pharmacological inhibitor fidarestat or ablation by AR specific siRNA prevents hypoxia-induced proliferation of HT29 colon cancer cells. Further, hypoxia- induced increase in the level of HIF1a in HT29 cells was significantly decreased by AR inhibition. During hypoxic conditions treatment of HT29 cells with AR inhibitor, fidarestat significantly decreased the expression of VEGF, a down target of HIF1a, at both mRNA and protein levels and also prevented the activation of PI3K/AKT and GSK3b. Further, AR inhibition also prevented hypoxia-induced inflammatory molecules such as Cox-2 and PGE2 and expression of extracellular matrix proteins such as MMP2, vimentin, uPAR and LOX2. In addition, AR inhibition also prevented the hypoxia -induced tube formation (angiogenesis) in vascular endothelial cells. In conclusion, our results indicate that AR mediates hypoxia -induced tumor progression, invasion and angiogenesis which can be prevented by AR inhibition or ablation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2052. doi:10.1158/1538-7445.AM2011-2052
Abstract 2053: Differential regulation of hypoxia-inducible factors 1α and 2α by hypoxia
Authors: Lin Qun , Cong Xiangyu , Yun Zhong 
Published: July 2012

Abstract
The hypoxia-inducible transcription factors (HIF)-1α and -2α are the key transcription factors regulating the expression of hypoxia-induced genes critical for a wide range of tumor cell functions from survival to clonal selection to metastasis. Elevated HIF-α expression correlates with poor patient survival in a large number of cancers. Recent evidence suggests that HIF-2α appears to be preferentially expressed in neuronal tumor cells that exhibit cancer stem cell characteristics. Furthermore, elevated HIF-2α expression is co-localized in vivo with expression of neural crest progenitor markers, suggesting a preferential association of HIF-2α expression with the immature stem cell-like neuroblastoma cells. These observations suggest that expression of HIF-1α and -2α is differentially regulated in the hypoxic tumor microenvironment. However, the underlying mechanisms remain to be fully investigated. In this study, we investigated the transcriptional regulation HIF-1α and -2α under different hypoxic conditions. In addition to conventional hypoxia treatment, we developed an adaptive chronic hypoxia approach by preconditioning tumor cells at 5% O2 before reducing pO2 to hypoxia levels (below 2% O2) to mimic in vivo tumor hypoxia. We found that transcription of HIF-2α was consistently increased by hypoxia in a panel of neuroblastoma cell lines, whereas transcription of HIF-1α showed variable levels of repression. Mechanistically, differential regulation of HIF-α transcription involved hypoxia-induced changes in actetylation of core histones H3 and H4 associated with the proximal promoters of the HIF-1α or HIF-2α gene. We also found that, although highly stable under acute hypoxia, HIF-1α and HIF-2α proteins become destabilized under chronic hypoxia. Our results have thus provided new mechanistic insights into the differential expression and localization of HIF-1α and -2α proteins within the hypoxic tumor microenvironment. These findings further underscore the importance of HIF-2α in the regulation of tumor progression, especially in the regulation of the stem cell-like tumor cell population as observed in neuronal tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2053. doi:10.1158/1538-7445.AM2011-2053
Abstract 2055: Influence of intermittent hypoxia on differentiation in neuroblastoma
Authors: Bhaskara Vasantha Kumar , Mohanam Indra , Rao Jasti S. , Mohanam Sanjeeva 
Published: July 2012

Abstract
Neuroblastomas are the most common extracranial solid tumors in children. Neuroblastomas derive from neural crest stem cells blocked at different stages of the sympathetic nervous system development. Neuroblastomas display a variety of histological features that range from undifferentiated tumors in patients with poor outcome to those containing differentiated cell types which show a better prognosis. Hypoxia has been linked to tumor progression and increased malignancy. Like the most common malignant solid tumors, neuroblastomas contain zones of chronic or acute hypoxia reflecting poor oxygenation. Transient hypoxia and subsequent reoxygenation are common phenomena in solid tumors that greatly influence the outcome of therapies. Differentiation is a key feature in pathologic classification and prognosis of neuroblastomas. The present study focuses on how intermittent hypoxia (IH) modulates the differentiation of neuroblastoma cells. IH-conditioned cells were derived by exposing tumor cells to 10 repeated cycles of hypoxia followed by reoxygenation. We found IH-induced changes in the expression of dedifferentiation markers and genes associated with neural crest-like phenotype in human neuroblastoma cells. The protein levels of HIF-1α, HIF-2α, tyrosine hydroxylase and c-kit were found upregulated in IH-conditioned human neuroblastoma cells as determined by western blotting. Similarly the expression of genes of neuronal crest phenotypic markers Oct-4, Notch-1and angiogenic molecule VEGF was found increased in IH-conditioned neuroblastoma cells. Expression of the cancer stem cell marker CD133 was also found increased in IH-conditioned neuroblastoma cells as evaluated by immunoflorescence analysis. Parallel studies were also performed in neuroblastoma cells exposed to hypoxia for 24h. It has been observed that IH-conditioned neuroblastoma cells exhibit increased expression of the proteins of dedifferentiation markers and genes associated with neural crest-like phenotype compared with neuroblastoma cells exposed to hypoxia for 24h. We cultured neuroblastoma cells, exposed the cells to defined doses of retinoic acid and studied neurite extension. A decrease in the levels of HIF-1α, and neuronal differentiation marker NF-M protein was observed in hypoxic neuroblastoma cells treated with retinoic acid. IH-conditioned neuroblastoma cells showed significantly less neurite extensions when compared with parental cells indicating that IH may suppress the differentiation of neuroblastoma cells. Taken together, our data suggest that IH inhibits differentiation and facilitates stem cell-like characteristics in human neuroblastoma cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2055. doi:10.1158/1538-7445.AM2011-2055
Abstract 2058: The adaptation of small cell lung carcinoma (SCLC) cells to hypoxia is partially hypoxia inducible factor (HIF)-independent
Authors: Persson Matilda Munksgaard , Johansson Martin , Monsef Nastaran , Beckman Siv , Påhlman Sven , Pettersson Helen M. 
Published: July 2012

Abstract
Small cell lung carcinoma (SCLC) is an extremely aggressive tumor that is widely metastasized in early stages of the disease and the 5-year survival rate for these patients is only approximately 9-15%. Here we study the adaptive response of SCLC cells to lower oxygen levels, since tumor hypoxia (∼1% oxygen) is related to aggressive tumor behaviour and poor outcome in several tumor forms. Areas of hypoxia are a common characteristic in solid tumors and in response to hypoxia tumor cells induce expression of several genes involved in a variety of processes. This adaptive response is primarily regulated by the transcription factors hypoxia inducible factor (HIF)-1α and HIF-2α, which become stable at low oxygen levels. Studies using among others lung adenocarcinoma, neuroblastoma and breast carcinoma cells have demonstrated that HIF-1α primarily mediates the acute hypoxic response, whereas HIF-2α dominates during the more chronic phase of hypoxia.
We investigated the viability of SCLC cells cultured at hypoxia and characterized the expression levels of HIF transcription factors in SCLC cells and specimens using quantitative real-time PCR, western blot and immunohistochemistry. Expression levels of well known hypoxia-driven genes were studied and to further characterize the hypoxic adaptive response, a gene expression profile of hypoxic SCLC cells was performed using microarray analyses. In all experiments a panel of non-SCLC cells and neuroblastoma cells were included for comparison.
Our results show that SCLC cells have a high adaptive capacity to hypoxia, even though a modest induction of well known hypoxia-driven genes is observed. Interestingly, the HIF-1α and HIF-2α are differentially regulated in SCLC cells as compared to non-SCLC. In SCLC cells, no HIF-2α protein is detectable whereas HIF-1α protein levels are sustained and increased up to 96 hours. In addition, knock-down of HIF-1α at 0.1% oxygen are not affecting the viability of the SCLC cells and our gene expression profile of hypoxic SCLC cells has identified genes important for SCLC cells survival at hypoxia. Our data suggest that SCLC cells have an adaptive response to hypoxia that is partially HIF-independent.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2058. doi:10.1158/1538-7445.AM2011-2058