bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3947: Hypoxic regulation of RIO kinase 3 promotes cell migration and invasion
Authors: Singleton Dean C. , Rouhi Pegah , Cao Yihai , Harris Adrian L. 
Published: August 2012

Abstract
RIO kinase 3 (RIOK3) is an atypical serine/threonine protein kinase that is located on a focal amplification at 18q11 observed in several cancer subtypes. Dysregulated expression of RIOK3 has been implicated in migration and invasion of pancreatic cancer cells (Kimmelman et al., 2008). We identified increased RIOK3 expression in microarray analysis of MCF7 cells exposed to severe hypoxia (&lt;0.01% O2) for 24 h. Given the importance of intratumoural hypoxia in promoting cell invasion and metastasis we hypothesised that RIOK3 may contribute to the enhanced migratory phenotype observed in hypoxia. The expression of RIOK3 mRNA was increased 3-9 fold in a panel of cell lines (MCF7, MDA-MB-231, HCT 116 and U-87 MG) following exposure to 0.1% O2 for 48 h. Likewise, RIOK3 protein levels were also increased in each of the cell lines after 24-48 h at 0.1% O2. Knockdown of either HIF-1α or HIF-2α using siRNA reduced the hypoxic up-regulation of RIOK3, suggesting that RIOK3 transcription is mediated by both HIF-1 and HIF-2. To investigate RIOK3 expression in tissue, immunohistochemistry was carried out on tumour spheroids. A modest increase in RIOK3 expression was observed in the hypoxic, pimonidazole-binding area adjacent to the necrotic core. Noticeably, the RIOK3 stain in these hypoxic regions relocalised to the cell membrane, in contrast to the predominantly cytoplasmic localisation in cells located in the oxygenated rim of the spheroid suggesting a role in cytoskeletal organisation. Depletion of RIOK3 using siRNA (siRIOK3) caused MDA-MB-231 cells to become long and spindle-shaped with a reduction of the number of lamellipodia, confirming a role for RIOK3 in cytoskeletal organisation. In the scratch wound assay, siRIOK3 caused a modest reduction in MDA-MB-231 migration in normoxic conditions but strongly inhibited migration in hypoxia. Likewise, MDA-MB-231 invasion through Matrigel was increased approximately 7-fold by 1% O2 and this effect was completely abolished in siRIOK3 cells. To investigate the role of RIOK3 in invasion and metastasis in vivo we utilised a zebrafish tumour model (Rouhi et al., 2010). Following implantation into the perivitelline cavity of developing embryos, metastasis of siRIOK3 cells was significantly reduced compared with control siRNA-transfected MDA-MB-231 cells resulting in 49% less disseminated cells and foci (P &lt; 0.01). In addition to genomic amplification, we have demonstrated that HIF-dependent increased expression of RIOK3 occurs and contributes to cell migration and invasion in hypoxia. References: Kimmelman et al., (2008) PNAS 105(49): 19372-7 Rouhi et al., (2010) Nat Protoc. 5(12): 1911-8
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 3947. doi:1538-7445.AM2012-3947
Abstract 3951: Expression of SIRT1 and p27 during progression of human cervical cancer
Authors: Singh Sapna , Kumar P. Uday , Thakur Suresh , AR Poongothai , Ramakrishna Gayatri 
Published: August 2012

Abstract
Recent studies point to a close connection between cancer and ageing. Cellular senescence when initiated early in cancerous cells results in growth suppression due to permanent growth arrest. Sirtuins, belonging to family of the NAD-dependent deacetylases, play a crucial role in cellular metabolism and organismal ageing/ longevity. However, the role of human Sirtuin isoforms in malignancies and cellular senescence is still not clearly discernible. The present study is therefore designed to evaluate the correlation of SIRT1 expression with proliferation marker Ki-67, and growth arrest/senescence marker p27, during cervical cancer progression. The expression was evaluated by immunohistochemistry in 70 formalin fixed archival human cervical samples: normal/ASCUS (N= 20), squamous intraepithelial lesions (SIL N=20) and invasive squamous cell carcinoma (SCC, N= 30 samples). All the intraepithelial lesions and SCC cases were positive for human papilloma virus as detected by in-situ hybridization. The SIRT1 expression was either absent or feeble in cytoplasm of normal/ASCUS cervical epithelium, while a progressive increase in its expression was noted in 65% of preneoplastic lesions (SIL). Intriguingly, the invasive carcinoma showed heterogeneous pattern for both expression and localization of SIRT1: ranging from negative to strong expression levels and mixed localization pattern in cytoplasm only or both in nucleus and cytoplasm. The growth arrest/senescence marker p27 showed elevated level of expression in SIL cases compared to SCC (75%). Interestingly, the increased nucleo-cytoplasmic expression pattern of SIRT1 correlated well with the increased expression of p27 in the intraepithelial preneoplastic lesion. In conclusion, our results suggest activation of growth suppressive pathways by SIRT1-p27 regulation, atleast in the in preneoplastic lesions of cancer cervix which may help retard its progression to invasive cancer.
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 3951. doi:1538-7445.AM2012-3951
Abstract 3957: Cell death and growth arrest pathways mediating the actions of stilbene 5C in HCT-116 colon cancer cells
Authors: Alotaibi Moureq R. , Beckman Matthew J. , Di Xu , Lee Ray , Gewirtz David A. 
Published: August 2012

Abstract
The stilbene derivative, cis-3, 4′, 5-trimethoxy-3′-aminostilbene (stilbene 5c), is a potentially potent antitumor agent that acts via binding to the colchicine-binding pocket in microtubules. Earlier studies have shown that stilbene 5c induces cell death in ovarian cancer cells and leukemic cells (Lee RM et al, 2008; Lee RM et al, 2008). The present study was designed to investigate the effectiveness of this microtubule poison against the HCT-116 human colon cancer cell line and its mechanisms of action. Time course studies demonstrated that stilbene 5c produces a biphasic decrease in cell viability. The capacity of the cells to proliferate was not restored upon removal of the drug after 6 days of exposure. Consistent with the results of the time course studies, β-galactosidase staining indicated that treatment with stilbene 5c also promotes senescence. In addition to senescence, stilbene 5c-treated HCT-116 cells displayed formation of autophagic vesicles by acridine orange staining, which was supported by fluorescence-activated cell sorting (FACS). Further evidence of autophagy was derived from treatment of HCT116 cells carrying an RFP-LC3 construct with stilbene 5c, in which LC3 puncta formation increased in a time-dependent manner. DAPI staining, TUNEL, and Annexin 5 staining indicated that apoptosis is also occurring in stilbene 5c-treated HCT-116 cells. Cell cycle analysis demonstrated growth arrest at both G1 and G2/M, and an increase in the subG1 population at days 3 and 5, which correspond to senescence and apoptosis respectively. Interestingly, DAPI and Hoechst staining revealed morphological changes in the cell nuclei (binucleated and micronucleated cells), which suggest that mitotic catastrophe may also serve as a mode of cell death after treatment with stilbene 5c. Consistent with previous studies in other experimental cancer models, this work indicates that stilbene 5c could potentially be effective against colon cancer through the promotion of multiple modes of cell death.
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 3957. doi:1538-7445.AM2012-3957
Abstract 3969: A novel statistical method for detecting association of copy number variations in genome-wide association studies of cancers
Authors: Shi Jianxin , Li Peng 
Published: August 2012

Abstract
Copy number variations (CNVs) are one of the major genetic resources in human populations. In large scale genome-wide association studies (GWAS), CNVs are usually detected from intensity data, quantified as Log R Ratio (LRR) and B-allele Frequency (BAF), generated by single nucleotide polymorphism (SNP) genotyping arrays. The standard approach for detecting CNV associations is based on two-step procedures: CNVs are first detected using intensity data and then association is tested based on the detected CNVs. Because the accuracy of CNV calling depends on the number of probes covered in the CNV region, short CNVs are generally detected with low sensitivity. Consequently, the statistical power of detecting short CNVs associated with diseases is low. We develop a novel method, variable thresholding exact statistic (VTES) implemented in a package SegCNV, for identifying genomic regions within which the frequency of CNVs is significantly higher in cases than in controls. VTES optimally summarizes the LRR and BAF of the probes to maximize the power. Extensive simulation studies demonstrated that VTES had a much better power for detecting rare, short CNVs associated with common diseases compared to standard two-step procedures, while maintaining correct type-I error rates. Particularly, the power of VTES is close to the ideal power when CNVs can be called perfectly. VTES is flexible to detect both recurrent CNVs and non-overlapping CNVs associated with diseases. VTES is computationally efficient and can analyze a GWAS of 2000 subjects within 20 hours using a single core. We applied VTES to a GWAS of testicular cancer and lung cancer, and identified regions that show strong evidences of CNV associations. We expect that VTES will prove useful for CNV association analysis in existing large scale GWAS of cancers.
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 3969. doi:1538-7445.AM2012-3969
Abstract 4251: Evaluating novel targeted therapeutic agents in T-cell acute lymphoblastic leukemia using a zebrafish xenotransplantation model
Authors: Corkery Dale , Balci Tugce B. , Berman Jason N. , Dellairee Graham 
Published: August 2012

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy accounting for 25% of adult and 10-15% of pediatric ALL cases. The disease is characterized by infiltration of the bone marrow and peripheral blood with immature lymphoblasts bearing T-lineage markers. Although current multi-agent chemotherapy regimens have dramatically improved cancer outcomes, a significant proportion of T-ALL do not respond to therapy or relapse post therapy. Novel molecular-based treatment strategies are desperately needed to improve outcome and limit toxicity. Mutations that activate the NOTCH and PTEN/PI3K pathways are common in human T-ALL and may drive T-ALL cell proliferation. Gamma secretase inhibiting compounds that block NOTCH signaling have been effective against subtypes of T-ALL with NOTCH mutations but have had limited success in clinical trials due to severe gastrointestinal toxicity, and problems with drug resistance. Recently, inhibition of the PI3K pathway (including the downstream kinase AKT) have shown efficacy in vitro and in pre-clinical animal models. We have recently developed a novel human cancer xenotransplantation (XT) animal model using the zebrafish, which can be used for high throughput pre-clinical testing of human tumour-drug interactions for both leukemia and solid tumours (Corkery et al., 2011 Brit. J. Haemat.). Using the zebrafish XT model we are studying a number of compounds that specifically target the PI3K/AKT kinase pathway for ability to inhibit T-ALL cell proliferation in vivo. Preliminary proof-of-principal studies have shown that we can successfully engraft the PTEN-deficient T-ALL leukemia Jurkat cell line in zebrafish embryos. In agreement with published data, we have shown that treating Jurkat transplanted embryos with the mTOR inhibitor rapamycin inhibits in vivo proliferation of the human leukemia cells line by 60%, while, by contrast, the AKT inhibitor triciribine does not significantly inhibit proliferation. We have also successfully transplanted primary bone marrow from pediatric T-ALL patients which go on to engraft in the zebrafish embryos. The ability to screen novel compounds against a panel of primary patient samples could provide a more accurate means of predicting the efficacy of said compounds across heterogeneous patient populations. We are now employing the zebrafish XT model to study the effects of novel PI3K/AKT kinase inhibition on the proliferation of a panel of human T-ALL cell lines and primary patient samples as a means of rapidly selecting new drug candidates to move forward into the rodent model and Phase I clinical trials.
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 4251. doi:1538-7445.AM2012-4251
Abstract 4253: In vivo activity of small molecule HIF2α inhibitors
Authors: Metelo Ana Marguerita , Xiang Li , Baker Rania , Burger Alexa , Peterson Randall , Iliopoulos Othon 
Published: August 2012

Abstract
Hypoxia-inducible factor (HIF) is a central regulator of the cellular response to hypoxia. Hypoxia promotes HIF activity by increasing its stability, transcriptional activity and translation. HIF target genes involved in several cellular processes including proliferation, angiogenesis, metabolism and promotion of the “stem-cell” phenotype. In normoxic conditions, HIF-α is recognized for degradation by the von Hippel-Lindau tumor suppressor protein (VHL). Loss-of-VHL function leads to constitutive expression of HIF regulatory subunits and consequent over-expression of HIF-target genes. We and others have shown that HIF2a is necessary and sufficient for the development of VHL-related renal cell carcinoma. We have developed small molecules that repress HIF-2α translation, in vitro, by enhancing the binding of Iron-Regulatory Protein 1 (IRP1) to the Iron-Responsive Element (IRE) within the 5′-UTR of HIF-2α mRNA (Zimmer M. et al. Molecular Cell 2008;32: 828-848). We showed that these small molecules down-regulate HIF2a expression in vitro, in all renal cell carcinoma cell lines. To validate these small molecules in vivo, we tested their efficacy on wild-type zebrafish embryos. Treatment of 3 days post fertilization zebrafish embryos with 100microM of the hypoxic mimetic DMOG or hypoxia dramatically upregulated the expression of HIF-target genes, such as Vascular Endothelial Growth Factor (Vegf), erythropoietin (Epo) and prolyl-hydroxylase 3 (Phd3). Pre-treatment of embryos with the small molecule HIF2a inhibitor 76 potently decreased the DMOG-induced upregulation of HIF target genes. The IC50 values of these small molecules were significantly less in vivo than in vitro. We are currently testing the efficacy of HIF2a inhibitors in rescuing the VHL zebrafish phenotype and prolonging survival of VHL mutant zebrafish embryos. In addition, data on the efficacy of these inhibitors on the growth of human renal cell carcinoma cells as tumors in the nude mouse xenograft assay will be presented.
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 4253. doi:1538-7445.AM2012-4253
Abstract 4260: Histone deacetylase 11 (HDAC11) as a novel therapeutic target in the regulation of myeloid-derived suppressor cell (MDSC)
Authors: Sahakian Eva , Powers John , Rock-Klotz Jennifer , Marsilio Adriani , Woan Karune , Merino Oscar , Gill Ajaypal , Deng Susan , Cheng Fengdong , Villagra Alejandro , Luekette Noreen , Seto Edward , Borrello Ivan , Sotomayor Eduardo , Pinilla Javier I. 
Published: August 2012

Abstract
The physiological role of this HDAC11, the newest member of the HDAC family was mainly unknown until the discovery by our group that HDAC11 regulates IL-10 gene expression in myeloid cells in-vitro. To better elucidate the role of HDAC11 in these cells, we have utilized HDAC11 promoter-driven eGFP reporter transgenic mice (TgHDAC11-eGFP) which allow us to “visualize” dynamic changes in HDAC11 gene expression /transcriptional activity in immune cells in vivo. Immature myeloid cells (IMCs) differentiate into macrophages, dendritic cells, and neutrophils and are also considered to be precursors of MDSCs in tumor-bearing hosts. Here, we show for the first time that HDAC11 plays an important role in this process. First, IMCs from the bone marrow and spleen of TgHDAC11-eGFP mice display high expression of eGFP indicative of HDAC11 transcriptional activation in these cells in the steady state. Subcutaneous injection of EL4 tumor cells into these mice resulted in expansion of MDSCs (identified by the expression of CD11b+/GR1+ [Ly6G and Ly6C] with variable expression of CD49d and CD115) in their lymphoid organs which was similar in extent to the expansion observed in tumor-bearing wild type (WT) mice. Of note, flow cytometric analysis revealed that expression of eGFP was significantly decreased in the myeloid compartment of tumor bearing TgHDAC11-eGFP mice, with greatest decrease in the Ly6Chigh population suggesting that the transition of IMC into MDSCs might require a decrease in HDAC11 expression. Reminiscent of our findings in the eGFP mice, studies in nontransgenic mice also demonstrated that tumor derived MDSCs display less HDAC11 mRNA expression compared to splenic MDSCs, with lowest expression of HDAC11 in the Ly6Chigh MDSCs. Additional support for the regulatory role of HDAC11 in MDSC expansion/function has been recently provided by our preliminary functional studies in TgHDAC11-eGFP mice which demonstrates that isolated GR1+/eGFP- cells demonstrate more suppressive phenotype than that of GR1+/eGFP+ cells, in the presence of tumor challenge. Taken together, these results suggest that HDAC11 plays a regulatory role in the expansion and function of MDSCs in vivo. A better understanding of this previously unknown role of HDAC11 in MDSC biology might lead to targeted epigenetic therapies to influence the suppressive abilities of these cells and augment the efficacy of immunotherapeutic approaches against malignancies.
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 4260. doi:1538-7445.AM2012-4260
Abstract 4262: NR2F1 and SOX9 mediate reprogramming of tumor cells into dormancy: Potential role in dormant bone marrow DTCs
Authors: Sosa Maria S. , Estrada Yeriel , Parikh Falguni , Bosch-Gutierrez Almudena , Ekpin Esther , George Ajish , Farias Eduardo F. , Aguirre-Ghiso Julio A. 
Published: August 2012

Abstract
Single disseminated tumor cells (DTCs) found in secondary organs (i.e. bone marrow BM, lung, liver) appear to activate a quiescence program and undergo a dormancy phase triggered by specific tissue microenvironment signals. The timing of this asymptomatic clinical phase may rely on specific signals that convert a previous non-permissive/non-proliferative environment into a permissive one, fueling metastasis development. The mechanisms underlying dormancy and means to maintain this state remain unknown. Here we show that the orphan nuclear receptor NR2F1/COUP-TF1 is silenced in breast and HNSCC tumors, cancer cell lines and MMTV-Neu and -Myc mouse tumor models. Surprisingly, retinoid signaling, stress signaling and microenvironmental cues from target organs (i.e. bone marrow) can induce re-expression of NR2F1 and dormancy of HNSCC cells. Forced NR2F1 re-expression resulted in induction of tumor cell quiescence in vivo and this effect depended on the expression of the transcription factor SOX9 and p27 induction. In contrast, RNAi-mediated silencing of NR2F1 or SOX9 interrupted the quiescence of dormant tumor cells. Further, quiescence induction was associated with p27, p15, p16 and HES-1. Mechanistic analysis revealed that NR2F1 is primarily nuclear and that its expression is activated by MKK6-p38α stress signaling and is negatively regulated by DNA promoter methylation. Lastly, we showed that atRA treatment followed 5-Aza-C treatment reprograms tumorigenic cells into dormancy in an NR2F1-dependent fashion. Our data suggest that re-expression of NR2F1 may promote reprogramming of aggressive tumor cells into dormancy identifying a new target for maintenance therapies for residual disease.
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 4262. doi:1538-7445.AM2012-4262