bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1113: TGFβ pathway activation limits hematopoietic recovery from chemotherapy
Authors: Brenet Fabienne , Scandura Joseph M. 
Published: June 2012

Abstract
Hematopoietic stem cells (HSCs) are capable of self-renewal and govern the long-term repopulation of all cell types of the blooding forming system. During normal hematopoiesis, there is a tight balance maintained between HSC self-renewal and differentiation. This balance is partially regulated through cell cycle regulators such as cyclin-dependent-kinases (CDKs) and CDK inhibitors (CKDIs); crucial positive and negative regulators of cell-cycle progression. We previously identified the CDKI p57Kip2 (Cdkn1c, p57) as an early transcriptional target of the tumor suppressor TGFβ that is required for TGFβ-induced cytostasis of human CD34+ hematopoietic progenitor/stem cells; functions that provide a mechanistic basis for its expression being silenced in many aggressive human myeloid and lymphoid malignancies. P57 is essential during late embryogenesis, functioning in tissue-specific developmental programs to coordinate proliferation, differentiation and apoptosis. We, and others, have found that p57 is highly expressed in deeply quiescent HSCs yet no role for p57 in hematopoiesis has been assigned. Utilizing a murine p57 knockout (KO) model, we studied the function of p57 in steady-state and stress hematopoiesis. Using limiting-dilution and competitive repopulation HSC assays, we found fewer long-term HSCs in the fetal liver of p57-KO animals demonstrating a role for p57 in HSCs development. In adult hematopoiesis, we found that p57 restrains the hematopoietic response to stresses imposed by serial-HSCs transplantation, hemolysis or myelotoxic chemotherapy. As a consequence, animal with p57-KO hematopoiesis tolerate higher doses of chemotherapeutics due to their more robust recovery from chemotherapy-induced myelosuppression. Using phospho-specific SMAD2 antibodies we found that the TGFβ pathway is activated in immature hematopoietic cells, in vivo, following chemotherapy-induced hematopoietic stress. Normally this promotes p57-induced cytostasis but p57-KO HSCs escape this restraint. We used 9-color flow cytometry to investigate how p57 affects hematopoietic recovery in long-term HSCs (LKSCD34- Flk2-), short-term HSCs (LKSCD34+ Flk2-), multipotent progenitors (LKSCD34+ Flk2+), common myeloid progenitors (LKSca-CD34+ FcRlo), granulocyte-monocyte progenitors (LKSca- CD34+ FcR+) and megakaryocyte erythroid progenitors (LKSca- CD34- FcR-). These results show that the most deeply quiescent HSCs undergo more robust self-renewal during stress in the absence of p57. Our results suggest that myelotoxic chemotherapy blockade of TGFβ-induced cytostasis, normally mediated by p57, could be used to limit chemotherapy-induced myelosuppression.
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 1113. doi:10.1158/1538-7445.AM2011-1113
Abstract 1124: IGFBP-4 activates the Wnt/beta-catenin signaling pathway and induces M-CAM expression in human renal cell carcinoma
Authors: Ueno Koji , Hirata Hiroshi , Tabatabai Z. Laura , Hinoda Yuji , Dahiya Rajvir 
Published: June 2012

Abstract
Introduction and Objective : The Wnt/beta-catenin signaling pathway is inactivated by Wnt antagonists in most cancers. IGFBP-4 is an antagonist of the Wnt/beta-catenin signaling pathway, however its function is not currently understood in renal cell carcinoma (RCC).
Methods : The expression levels of IGFBP-4 protein in kidney tissue microarray were examined by immunostaining using antibody to IGFBP-4. The IGFBP-4 mRNA expression level was analyzed in a normal kidney cell line (HK-2), primary renal cancer cell lines (A498, 769-P) and metastatic renal cancer cell lines (ACHN, Hs891.T). To examine the function of IGFBP4, MTS, matrigel invasion, colony formation and wound healing assays were performed using 769-P mock and stable IGFBP-4 transfected cells. To screen for metastatic related genes in IGFBP-4 stable cells, cDNA PCR array was performed with a Human RT2 Profiler PCR Array. We investigated mRNA expression of the MMP family and measured Tcf transcriptional activity to monitor the Wnt/beta-catenin dependent pathway in 769-P mock and IGFBP-4 stable transfected cells. To analyze the role of IGFBP-4 in metastatic RCC cell lines, IGFBP-4 mRNA was knocked down using a siRNA technique.
Results : We found that the expression of IGFBP-4 was significantly lower in primary RCC and higher in metastatic RCC compared to normal human kidney tissues. To assess the function of IGFBP4, we established IGFBP4 transfectants (primary renal cancer cell line) and performed functional analyses including Tcf reporter assays, cell viability, invasive capability, mortality, and in vivo tumor growth. Interestingly IGFBP-4 transfectants promoted cell growth (in vitro and in vivo), invasion, and motility in 769-P cancer cells. Tcf transcriptional activity was significantly increased in IGFBP-4 transfectants compared to mock cells and beta-catenin expression was increased. Also the beta-catenin downstream effector, MT1-MMP showed increased expression in IGFBP4 transfectants. Additionally IGFBP4 induced the expression of M-CAM, a marker of tumor progression. In order to assess the role of IGFBP4 in metastatic renal cancer, IGFBP-4 mRNA in a metastatic renal cancer cell line (ACHN) was knocked-down using a siRNA technique. Cell growth and motility was decreased in si-IGFBP4 transfected ACHN cells compared to cells transfected with control siRNA.
Conclusions : This is the first report documenting that IGFBP-4 expression in RCC activates cell growth, metastasis, Wnt/beta-catenin signaling and may be involved in RCC metastasis.
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 1124. doi:10.1158/1538-7445.AM2011-1124
Abstract 1129: Function of mutant EGFR in maintaining glioblastoma growth and heterogeneity
Authors: Inda Maria Del Mar , Bonavia Rudy , Vandenberg Scott , Cavenee Webster , Furnari Frank 
Published: June 2012

Abstract
Glioblastoma Multiforme (GBM) exhibits intratumoral heterogeneity on the morphological and molecular levels, a hallmark feature which may contribute to its poor response to targeted therapy. A powerful oncogenic event in GBM is amplification and rearrangement of the epidermal growth factor receptor (EGFRvIII variant, deleted for exons 2-7, hereafter ΔEGFR), strikingly, despite its greater biological activity than wildtype EGFR (wtEGFR), only a minority of cancer cells in the primary tumor possess the hallmark ΔEGFR lesion, while the remainder of cancer cells express wtEGFR. We observed that the tumorigenicy of wtEGFR-expressing cells can be significantly enhanced by the presence of ΔEGFR-expressing cells within the tumor, suggesting that soluble factors produced by the latter cells might mediate this potent tumor enhancement. Using a combination of mixed tumor engraftments and biochemical analysis of paracrine factors and signaling pathways activation, we determined that human glioma tissues, glioma cell lines, glioma stem cells and primary mouse astrocytes, that express ΔEGFR each secrete IL-6 and/or LIF cytokines. This then prompts a novel interaction between the receptor that is common to these cytokines, gp130, and wtEGFR in neighboring cells that express amplified levels of EGFR, resulting in co-receptor activation and tumor growth enhancement. Ablating IL-6, LIF or gp130 uncouples this cellular cross-talk and potently attenuates tumor growth enhancement. In addition, over-expression of both receptors in the same cell potently enhances tumorigenicity in vivo and colony formation in vitro through the activation of wtEGFR, as well as Akt and STAT3 pathways, suggesting that the secretion of IL-6/LIF cytokines can act not only in a paracrine fashion, but also in an autrocrine fashion when the cell express both receptors. These findings demonstrate that the heterogeneity which characterizes GBM, and perhaps other tumors with this feature, does not occur stochastically, but instead can be an actively maintained feature and illuminates a heterotypic cancer cell interaction of potential therapeutic significance.
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 1129. doi:10.1158/1538-7445.AM2011-1129
Abstract 1132: Oncogenic role of EAPII/TTRAP in lung cancer development and its activation of MAPK-ERK pathway
Authors: Li Chunyang , Fan Songqing , Owonikoko Taofeek K. , Khuri Fadlo R. , Sun Shi-yong , Li Runzhao 
Published: June 2012

Abstract
Cancer progression involves multiple complex and interdependent steps including progressive proliferation, angiogenesis and metastases. The complexity of these processes requires a comprehensive elucidation of the integrated signaling networks for better understanding. EAPII/TTRAP interacts with multiple cancer-related proteins, but its biological significance in cancer development remains unknown. In this report we identified the elevated level of EAPII/TTRAP protein in non-small cell lung carcinoma (NSCLC) patients and NSCLC cell lines in culture. The oncogenic role of EAPII in lung cancer development was demonstrated using NSCLC cells with genetic manipulations that influence EAPII expression: EAPII overexpression increases proliferation of NSCLC cells with an accelerated transition of cell cycle and facilitates xenograft tumor growth in vivo; EAPII knockdown results in apoptosis of NSCLC cells and reduces xenograft tumor formation. To further explore the mechanism of EAPII's oncogenic role in lung cancer development and to elucidate the potential signaling pathway(s) that EAPII may impact, we employed antibody array to investigate the alternation of the major signaling pathways in NSCLC cells with altered EAPII level. We found that EAPII overexpression significantly activated Raf-1 and ERK1/2, but not JNK and p38 pathways. Consistently, the protein and mRNA levels of MYC and cyclin D1, which are targets of the mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK-ERK) pathway, are significantly increased by EAPII overexpression. Taken together, we demonstrated that EAPII is an oncogenic factor and the activation of MAPK-ERK signaling pathway by EAPII may contribute to lung cancer development.
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 1132. doi:10.1158/1538-7445.AM2011-1132
Abstract 1146: Multiple HDAC inhibitors (HDACi) reduce the expression of the oncogenic miR-17∼92 cluster; a pan HDACi class effect
Authors: Talbert Dominique R. , Peng Xiaodong , Shell Scott A. , Bacus Sarah 
Published: June 2012

Abstract
miR-17∼92 is an oncogenic polycistronic cluster encoding six mature miRNAs (MIR-17, MIR-20A, MIR-18A, MIR-19A, MIR-19B, and MIR-92A). This oncogenic cluster is driven by MYC activity and is highly-expressed in many tumor types where it has been shown to promote tumorigenesis through the suppression of oncogene-induced senescence. We recently observed reduced expression of the miR-17∼92 miRNA cluster in a miRNA microarray analysis of MCF-7 and MDA-MB-231 breast cancer cells treated with the pan-HDAC inhibitors (HDACi's) Vorinostat, MS-275, and LAQ824. Treatment with all three HDACi's, at concentrations shown to induce the expression of p21 and acetylated histone-H3, demonstrated this effect which was further validated by qRT-PCR. Furthermore, significant cell cycle arrest and induction of apoptosis and/or senescence were shown with treatment of both MCF-7 and MDA-MB-231 cells with the HDACi's. There was also significant reduction of MYC expression upon treatment with HDACi's which is consistent with studies showing that the miR-17∼92 cluster is driven by MYC. The miR-17∼92 cluster has also been shown to suppress the expression of several cellular targets important in tumor suppression including p21, PTEN, E2F1, and BIM. The expression of these proteins will also be assessed in MCF-7 and MDA-MB-231 cells after treatment with HDACi. The modulation of MYC, the miR-17∼92 cluster and its oncogenic targets will also be confirmed in MDA-MB-231 and MCF-7 tumor xenograft mice treated with the HDACi's. Lastly, antagomirs will be used to inhibit the expression of the miR-17∼92 cluster in MCF-7 and MDA-MB-231 cells in order to compare the functional (apoptosis, senescence, and cell cycle arrest) and cellular (repression of target proteins) effects elicited by HDACi treatment. Together, we have shown that pan-HDAC inhibitors inhibit the expression of MYC and the oncogenic miR-17-92 cluster. This finding could have important utility in the clinical development of pan-HDACi's by identifying MYC and/or the miR-17-92 cluster as potential biomarkers to select patients more likely to respond to pan-HDACi treatment.
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 1146. doi:10.1158/1538-7445.AM2011-1146
Abstract 1150: Genetic variations in microRNA-related genes as predictors for recurrence and progression in patients with non-muscle invasive bladder cancer
Authors: Ke Hung-Lung , Chen Meng , Dinney Colin P. , Wu Xifeng 
Published: June 2012

Abstract
MicroRNAs (miRNAs) are a group of short non-protein-coding RNAs regulating gene expression in eukaryotes, which can act as oncogenes or tumor suppressors. To test the hypothesis that genetic variations in the miRNA biogenesis genes are associated with the prognosis of bladder cancer, we genotyped 76 single nucleotide polymorphisms (SNPs) in 8 genes (DDX20, DGCR8, DICER1, EIF2C1, GEMIN4, RAN, RNASEN and XPO5) from the miRNA biogenesis pathway in 421 patients with non-muscle invasive bladder cancer. Eight SNPs reached significant association with cancer recurrence in patients who received trans-urethral resection (TUR) only, and three SNPs in patients who received intravesical Bacillus Calmette-Guérin (BCG) instillation. The most significant SNP in TUR group was rs197412 in DDX20, with the variant allele conferring a 42% decreased risk of recurrence (HR=0.58, 95% CI=0.40-0.82, P=0.002). The most significant SNP in BCG group was rs563002 in DDX20, with the variant allele conferring an increased risk of recurrence (HR=2.80, 95% CI=1.30-6.04, P=0.009). In addition, seven SNPs showed significant association with cancer progression. The most significant SNP associated with progression was rs3087833 in GEMIN4, with the variant allele conferring an increased risk of progression (HR=9.73, 95% CI=2.31-40.92, P=0.002). Finally, we performed cumulative effect analysis for the number of unfavorable genotype on bladder cancer recurrence and prognosis. These data demonstrated that miRNA-related SNPs may impact the recurrence and progression in bladder cancer patients. Further study in independent large population and functional characterization are needed to validate these results.
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 1150. doi:10.1158/1538-7445.AM2011-1150
Abstract 1154: MicroRNA-221, -222 and -181 regulates tamoxifen resistance in breast cancer by downregulating TIMP3 and facilitating growth factor signaling
Authors: Lu Yuanzhi , Roy Satavisha , Miller Tyler , Ghoshal Kalpana , Ramaswamy Bhuvaneswari , Shapiro Charlie , Jacob Samson T , Majumder Sarmila 
Published: June 2012

Abstract
We have shown earlier that microRNA (miR)-221 and -222 are upregulated in tamoxifen (TAM) resistant breast cancer cell line MCF-7 (OHTR), and in Her2 positive primary human breast tumors compared to the Her2 negative tumors1. In addition, expression of miR-181b was 3.5-fold higher in OHTR cells compared to the MCF-7 cells and endocrine resistant primary tumors. To determine the underlying mechanism of miR-mediated regulation of TAM resistance, we focused on identification of target genes regulated by these miRs. Bioinformatics search revealed presence of seed sequences for all three miRs on 3’-UTR of TIMP3, a tissue metalloprotease inhibitor. Luciferase assay confirmed TIMP3 to be a direct target of these miRs and was found to be regulated at both RNA and protein levels. In situ hybridization and immunohistochemical analysis demonstrated reciprocal relationship between TIMP3 and miR 221/222 expression in primary human tumors, where invasive ductal carcinomas expressed high level of the miRs and normal or non-invasive cancers expressed TIMP3, but not the miRs. Cell proliferation and wound healing assay demonstrated increased sensitization of the TAM resistant cells to the drug upon ectopic expression of TIMP3. In addition, mouse mammary tumors induced with TIMP3 overexpressing cells were found to be more sensitive to TAM compared to the tumors initiated with control cells. Conversely, knocking down TIMP3 by siRNA reduced sensitivity to TAM, both in cell cultures and in mouse mammary tumors.
As TIMP3 is an inhibitor of matrix metalloproteases involved in positive regulation of growth factor signaling, we speculated that reduction in TIMP3 due to high miR-221/222/181 expression could facilitate growth factor signaling in OHTR cells. Indeed, EGF-induced MAPK phosphorylation was significantly higher in OHTR cells compared to MCF-7 cells and miR-221/222 overexpressing MCF-7 cells mimicked this phenomenon. On the contrary, phosphMAPK level was reduced when TIMP3 was overexpressed in OHTR cells and increased upon knocking down of TIMP3 in MCF-7 cells. Similar differences in MAPK phosphorylation was also observed in cells treated with low level estrogen or TAM, agonists for TAM resistant cells.
Based on this data we conclude that overexpression of miR-221/222 and -181b facilitates growth factor signaling in TAM resistant cells by downregulating TIMP3.
1. Miller et. al. J. Biol. Chem 2008; 283 (44): 29897
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 1154. doi:10.1158/1538-7445.AM2011-1154
Abstract 1156: MicroRNA-21 in gliomas: An in situ hybridization study
Authors: Hermansen Simon K. , Dahlrot Rikke H. , Nielsen Boye S. , Hansen Steinbjørn , Kristensen Bjarne W. 
Published: June 2012

Abstract
High-grade gliomas are some of the most lethal forms of human cancers. In glioblastomas, which are the most frequent and malignant type of glioma, microRNA-21 (miR21) has recently been suggested to be strongly upregulated. Until now, miR21 expression analysis has mainly been carried out using PCR methods, hence little is known about the cellular localization of miR21 in gliomas. Studies of other cancers have demonstrated miR21's prognostic value as well as roles in invasion, growth and anti-apoptosis. This suggests that miR21 is a potential therapeutic target as well as a promising novel prognostic marker in gliomas. The aim of the present study was therefore to investigate the expression of miR21 in gliomas and correlate it with tumor grade and overall survival using the new possibilities of locked nucleic acid (LNA) based in situ hybridization. We used 193 formalin-fixed paraffin embedded astrocytic and oligodendroglial brain tumors of increasing grade (WHO I-IV). Sections from these tumors were stained by a robust in situ hybridization assay using high-affinity LNA probes that specifically detect miR21. The expression of miR21 was revealed as a blue chromogenic staining reaction. Using advanced image analysis, the area of the staining reaction was measured by a trained pixel classifier on images recorded by stereological principles. The optimal sampling fraction was estimated to be 10%. The results showed that the miR21 signal was localized to blood vessels and populations of dispersed single cells. Moreover, the characteristic gemistocytic tumor cells seemed to display a distinct staining reaction. The miR21 signal increased with tumor grade and a very high individual signal variation was observed, especially among glioblastomas. When comparing the miR21 signal with overall survival, a high signal was associated with shorter survival, but in multivariate analysis this was not independent of grade. In conclusion miR21 is localized in both tumor cells and blood vessels in gliomas. A high miR21 expression appears to be associated with tumor grade and shorter survival underlining the importance of miR21 in glioma biology.
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 1156. doi:10.1158/1538-7445.AM2011-1156