bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4022: Antioxidant-induced modification of INrf2C151 and PKCdelta-mediated phosphorylation of Nrf2S40 are both required for stabilization and nuclear translation of Nrf2 and increased drug-resistance
Authors: Niture Suryakant K. , Jain Abhinav K. , Jaiswal Anil K. 
Published: February 2011

Abstract
Antioxidants cause dissociation of nuclear factor erythroid 2-related factor 2 (Nrf2) from inhibitor of Nrf2 (INrf2) and so Nrf2:INrf2 can serve as a sensor of oxidative stress. Nrf2 translocates to the nucleus, binds to antioxidant response element (ARE) and activates defensive gene expression, which protects cells. Controversies exist regarding the role of antioxidant-induced modification of INrf2 cysteine 151 or protein kinase C (PKC)-mediated phosphorylation of Nrf2 serine 40 in the release of Nrf2 from INrf2. In addition, the PKC isoform that phosphorylates Nrf2S40 remains unknown. Here, we demonstrate that antioxidant-induced PKC-delta -mediated phosphorylation of Nrf2S40 leads to release of Nrf2 from INrf2. This was evident from specific chemical inhibitors of PKC isoenzymes in reporter assays, in vitro kinase assays with purified Nrf2 and PKC isoenzymes, in vivo analysis with dominant-negative mutants and siRNA against PKC isoforms, use of PKC-delta+/+ and PKC-delta −/− cells, and use of Nrf2S40 phospho-specific antibody. The studies also showed that antioxidant-induced INrf2C151 modification was insufficient for the dissociation of Nrf2 from INrf2. PKC-delta-mediated Nrf2S40 phosphorylation was also required. Nrf2 and mutant Nrf2S40A both bind to INrf2. However, antioxidant treatment led to release of Nrf2 but not Nrf2S40A from INrf2. In addition, Nrf2 and mutant Nrf2S40A both failed to dissociate from mutant INrf2C151A. Furthermore, antioxidant-induced ubiquitylation of INrf2 in PKC- delta+/+ and PKC-delta −/− cells occurred, but Nrf2 failed to be released in PKC-delta −/− cells. The antioxidant activation of Nrf2 reduced etoposide-mediated DNA fragmentation and promoted cell survival in PKC- delta+/+ but not in PKC- delta−/− cells. These data together demonstrate that both modification of INrf2C151 and PKC- delta-mediated phosphorylation of Nrf2S40 play crucial roles in Nrf2 release from INrf2, antioxidant induction of defensive gene expression, promoting cell survival, and increasing drug resistance.
J. Cell Science in press 2009.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4022.
Abstract 4026: Suppression of carcinogenic phenotypes by DSG3 silencing occurs via a plakoglobin-mediated signaling pathway
Authors: Chen Yin-Ju , Chiu Ching-Chi , Cheng Ann-Joy 
Published: February 2011

Abstract
DSG3 has been reported to act as an oncogene in head and neck cancers (HNCs), but the underlying mechanism of its oncogenic activity is unclear. In this study, we aimed to validate the proposed oncogenic function of DSG3 and investigate its downstream regulatory mechanisms. When we stably transfected HNC cells with a short hairpin DSG3-RNAi (shDSG3) to suppress DSG3 expression, reductions in cell growth (70%) and colony formation (&gt;90%) were observed, in addition to cell cycle arrest at the G0/G1 phase. Both cell migration and invasion abilities were also decreased, to 10% and 16%, respectively, after one day. Because DSG3 is associated with plakoglobin in desmosomes, we examined whether or not the phenotypic alterations that occur following DSG3 knockdown were mediated through the plakoglobin signaling pathway. Immunoprecipitation and immunofluorescent staining analyses revealed that DSG3 knockdown disrupted the interaction of DSG3 with plakoglobin and induced the translocation of plakoglobin from the cytoplasm to the nucleus. Using a luciferase reporter assay and western blot analysis, we found that DSG3 knockdown significantly reduced TCF/LEF transcriptional activity and subsequently suppressed the expression of the downstream target genes of the TCF/LEF transcription factors, including c-myc, cyclin D1, and MMP7, which are involved in the regulation of cell proliferation and invasion. An in vivo xenograft study showed that knockdown DSG3 expression significantly inhibited tumor growth for 2 months in BALB/C nude mice and also reduces c-myc, cyclin D1 and MMP7 expression. In conclusion, we found that DSG3 has an oncogenic function in HNC. The suppression of DSG3 expression can interfere with the plakoglobin-mediated signaling pathway, subsequently leading to a reduction of pathogenicity in HNC cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4026.
Abstract 4035: MicroRNA-221 levels correlate with aggressive and clinically recurrent prostate cancers
Authors: Gordanpour Aida , Stanimirovic Aleksandra , Nam Robert , Moreno Carlos , Leyland-Jones Brian , Sugar Linda , Seth Arun 
Published: February 2011

Abstract
One of the most important challenges in prostate cancer research is to identify biomarkers that are predictive of cancer aggressiveness and future tumor recurrence following radical prostatectomy. Recent studies have shown that altered expression of microRNAs (miRs) is involved in the development of prostate cancer, and among the differentially expressed miRNAs, miR-221 may be critical in metastatic induction/regulation. While the precise role of this miRNA in facilitating malignant progression remains unclear, expression of miR-221 in prostate cancer may correlate with disease state/status and serve as a surrogate biomarker for tumor recurrence and/or aggressiveness. In the present study, we sought to investigate whether miR-221 is differentially regulated in patients with aggressive and non-aggressive tumors relative to control normal prostate cell line RWPE-1 and, more specifically, whether this miRNA can be used as biomarker for disease recurrence. To address this question, we initially chose to assess the relative expression of miR-221 in a series of aggressive (n=69) and non-aggressive (n=45) primary carcinoma tissues derived from clinically resected prostates by quantitative real-time PCR. Aggressive tumors were categorized based on clinicopathological parameters such as Gleason score of 8 or higher, high PSA levels, presence of metastasis, invasion to the seminal vesicles, and recurrence after radical prostatectomy. Relative expression of mature miR-221 in tumors was quantified in comparison to control prostate epithelial cell line, RWPE-1, which was set to be 1x. Levels of miR-221 expression were found to be variable. Among all aggressive and non-aggressive cancer patients, expression of miR-221 transcript levels was differentially expressed relative to control sample. However, when we divided this group of patients on the basis of miR-221 expression levels, 72% of the patients with aggressive tumors had miR-221 less than 5-fold the RWPE-1 levels and only 28% of the patients had miR-221 expression equal to or more than 5-fold RWPE-1 levels. On the other hand, 53% of the patients with non-aggressive tumors had miR-221 less than 5-fold the RWPE-1 levels compared to 47% of the patients with miR-221 equal to or more than 5-fold RWPE-1 levels. Our results show that miR-221 is lower in majority of aggressive prostate cancer and differential expression may have utility as a biomarker for disease recurrence.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4035.
Abstract 4040: MicroRNAs that chemosensitize the apoptotic effect of 17-AAG
Authors: Hwang Larn , Treece Tina , Desai Neil , Trieu Vuong 
Published: February 2011

Abstract
Background: 17-allylamino-demethoxy geldanamycin (17-AAG) inhibits the chaperone function of heat shock protein 90 (Hsp90) and promotes the proteasomal degradation of its client proteins. 17AAG also induced the mitochondrial release, accumulation of mitochondrial-derived activator of caspases, resulting in apoptosis. 17-AAG is currently in development for the treatment of cancer. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate expression of many genes and play a significant role in cancer and possibly in Hsp90 signaling. Therefore, a screen of miRNA mimics and inhibitors was conducted for chemosensitization to 17-AAG.
Methods: To identify individual microRNAs that synergizes with 17AAG, microRNA libraries were screened for apoptotic activity against HT29 cells when co-treated with 17AAG. The microRNAs were transfected into HT29 cells 48 hrs before treatment with 17AAG. After 72 hrs of 17AAG exposure, apoptosis was quantitated by the release of caspase 3/7. The effects of these miRNA on cellular protein, mRNA, and miRNA profile were also examined using microarray technology.
Results: Four miRNAs were identified which had potent chemosensitization effect on cells exposed to 17-AAG. These miRNA are different in sequence and did not synergize with one another. Alone they did not induce apoptosis; however, when combined with 17-AAG, they increased the apoptotic activity of 17-AAG up to 4 folds. Possible mechanism of action for these miRNAs was examined by microarray analysis which suggested that they act on the Hsp90/70 pathway to enhance the activity of 17-AAG.
Conclusions: Four miRNAs were identified as chemosensitizers for 17-AAG. These miRNAs could provide the basis for determination of tumor types that will be sensitive to 17-AAG, as well as a potential biomarker for predicting 17-AAG effectiveness.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4040.
Abstract 405: HTLV-1 infection of humanized SCID mice recapitulates adult T-cell leukemia/lymphoma (ATLL) development
Authors: Banerjee Prabal , Feuer Gerold , Crawford Lindsey , Lairmore Michael , Beilke Mark 
Published: February 2011

Abstract
Human T-lymphotropic virus type-1 (HTLV-1) is the etiologic agent of Adult T-cell leukemia/lymphoma (ATLL), an aggressive CD4+/CD25+ T cell malignancy. The early molecular events induced by HTLV-1 infection as well as the role of various viral genes in the induction of leukemia remain unclear, predominantly due to the lack of an animal model that recapitulates ATLL development. We have previously demonstrated that HTLV-1 is capable of infecting human hematopoietic progenitor and stem cells (CD34+ HP/HSCs) and that infection of CD34+ HPCs has dramatically different biological effects in comparison to infection of mature T lymphocytes. To determine if HTLV-1 infection of CD34+ HP/HSCs recapitulates leukemogenesis in vivo, human hematopoiesis was reconstituted in NOD/SCID mice by injection of human CD34+ HPCs infected ex vivo with HTLV-1. Humanized NOD/SCID (HU-SCID) mice infected with HTLV-1 (HTLV-1-HU-SCID) consistently developed CD4+CD25+ T cell lymphomas with clinical characteristics associated with ATLL at ∼10 weeks post-reconstitution and show significantly elevated levels of HTLV-1 infected human CD4+ T cells in the thymus, mesenteric lymph node, spleen and peripheral blood. Lymphoma cells successfully engrafted in naïve NOD/SCID mice when injected into the peritoneal cavity and maintain the expression of viral proteins, gp46env and p19gag. Moreover these infected mice showed hyperproliferation of infected human stem cells (CD34+CD38−) in the bone marrow suggesting that HP/HSCs represents viral reservoir target cells which maintain HTLV-1 infection for extended periods of time in vivo. We speculate that HTLV-1 infection of hematopoietic stem cells establishes a virally-infected “cancer stem cell” which subsequently gives rise ATL in patients. Notably, CD34+ HPCs isolated from HTLV-1 infected patient PBL demonstrate proviral integrations, suggesting that these cells harbor infection in humans. CD34+ HPCs transduced with a lentivirus vector expressing the HTLV-1 Tax gene (Tax1) also results in CD4+/CD25+ T cell leukemia/lymphoma in HU-SCID mice, suggesting that Tax1 expression is sufficient for lymphomagenesis. HTLV-1 infection of humanized NOD/SCID mice represents a novel in vivo model which recapitulates viral lymphomagenesis and provides a compelling system to investigate and characterize molecular events in human stem cells in the initiation and progression to ATLL.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 405.
Abstract 4050: Normalization of TaqMan human microRNA array data using average expression of controls
Authors: Chandramouli Gadisetti VR , Maxwell G. Larry , Risinger John I. 
Published: February 2011

Abstract
The growing interest on microRNA (miRNA) expression in cancer motivates the need for improvement of technical aspects. TaqMan Human MicroRNA Arrays with comprehensive coverage of 667 unique miRNAs from Sanger miRBase are now available (Applied Biosystems, Foster city, CA) to quantitatively assay miRNA expression. A recent study reported that these qRT-PCR arrays perform better than miRNA microarrays which utilizes U6 RNA as an endogenous control for normalization. However, the choice of control for normalization varies depending on the tissue under examination. The TaqMan Low Density Arrays (TLDA) arrays A and B include six different controls with at least quadruplet assays for each. A recent study indicated that the average expression normalization including all miRNAs on array performed better than other normalization methods indicating a further need to examine normalization of TaqMan miRNA array data. The choice of a suitable control other than an average expression over the entire array is a more general approach for qRT-PCR data since constant average expression may not be valid for these arrays. Hence, we combined both concepts to determine a normalization constant. We examined miRNA expressions of 5 endometrial cancer cell lines assayed by these TaqMan Low Density Arrays for miRNA. Each cell line was assayed in triplicate. The cycle threshold (Ct) values of positive controls U6 (MammU6), RNU48, RNU44, RNU24, RNU6B, RNU43 in these were found to be in the range of 15 to 39 where RNU6B and RNU43 had low expressions. In some cases, we observed failures in endogenous control U6 and differences between arrays A and B. Therefore multiple controls were included for normalization but with appropriate weighting for highly expressed controls. This was done by calculating the average of 2−Ct values for controls that had Ct-values below a threshold level (Ct &lt; 25) and transforming this average back to logarithmic scale to the base 2. We then compared the normalized Ct-values by this method with the normalization using geometric average method. This weighted average normalization method resulted in smaller replicate variances of controls than the geometric average method.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4050.
Abstract 4051: MiR-181b expression levels decreases during the progression of the Chronic Lymphocytic Leukemia: a new potential prognostic tool
Authors: Visone Rosa , Veronese Angelo , Rassenti Laura Z. , Balatti Veronica , Taccioli Cristian , Kipps Thomas J. , Croce Carlo M. 
Published: February 2011

Abstract
In patients with Chronic Lymphocytic Leukemia (CLL) the prognosis is extremely variable, ranging from a very short to a normal lifespan. Classic clinical stages, based on biologic and clinical parameters, have been the most important factor for assessing prognosis in CLL patients; however, they are not devoid of limitations. Therefore, investigations are ongoing for searching new parameters in an attempt to add prognostic power to clinical stages. In this study we performed a genome-wide microRNA expression profiling to investigate the role of microRNA genes in the progression of CLL and to develop better prognostic indicators of these disease. We compared paired samples from CLL patients having an indolent and stable disease with their progressed aggressive form. We found that miR-181b was consistently down-regulated in the aggressive form of the disease compared to its previous stable counterpart. Further studies on serial time points from the same patient demonstrated that the strong decrease of the miR-181b expression levels occurs before the disease is clearly aggressive Moreover, we observed that the miR-181b expression remain constant over the time in two time points from CLL patients having a stable course; entailing a decreased levels of the miR-181b in the aggressive form of the CLL as a specific effect due to the progression of the disease. Finally in this study we investigate the biological role of the putative prognostic indicator related to the TCL1A, which is a critical gene in the pathogenesis of the CLL. In conclusion our data hint a prognostic role of the miR-181b in CLL.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4051.
Abstract 4052: Analysis of the matrix metalloproteinase family reveals MMP8 is often mutated in melanoma
Authors: Wei Xiaomu 
Published: February 2011

Abstract
Matrix Metalloproteinases (MMPs) have long been associated with multiple biological processes and a variety of pathological conditions, including cancer because of their ability to degrade extracellular matrices, which facilitates invasion and metastasis. We performed a mutational analysis of the Matrix Metalloproteinase gene family in human melanoma and identified 28 somatic mutations in eight MMPs, affecting 23% of melanomas. Five mutations in one of the most commonly mutated genes, MMP8, reduced MMP-8 enzyme activity. Expression of wild-type but not mutant MMP-8 in human melanoma cells inhibited growth on soft agar in vitro and tumor formation in vivo, suggesting that wild-type MMP-8 has the ability to inhibit melanoma progression. Our findings emphasize the need to test the role of each MMP in an individual manner and to precisely define its functional role in cancer. This may allow the development of individualized therapy based on the mutant MMP present in specific tumors. To extend our knowledge of fundamental roles of proteases in cancer progression, we will compliment the studies by performing a systematic sequence analysis of all ADAMs (A Disintegrin And Metallproteinase) and the related ADAMTS family. Similar to MMPs, ADAM/ADAMTS belong to a super family of zinc-based proteinases, the metzincins. Many members of the ADAM/ADAMTS family have been associated with tumorigenesis and tumor progression. Therefore, our comprehensive genetic studies will provide insight into melanoma pathogenesis. In-depth illustrations of the biochemical and biological effects of the mutated genes will permit the design of personalized treatments for melanoma patients.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4052.
Abstract 4064: Development of ALN-VSP: An RNAi therapeutic for solid tumors
Authors: Toudjarska Iva , Buck Tim , Brodsky Joshua , Akinc Akin , Racie Timothy , MacLachlan Ian , Sah Dinah W. , Gollob Jared , Bumcrot David 
Published: February 2011

Abstract
Malignancies of the liver, including primary (hepatocellular carcinoma) and secondary (metastatic) tumors, represent a significant unmet medical need. In most patients with liver metastases, extra-hepatic tumors are also present. We are developing a therapeutic for solid tumors that is comprised of lipid particle (SNALP)-formulated small interfering RNAs (siRNAs) targeting VEGF and the mitotic kinesin, KSP (Eg5). For each target, potent siRNA duplexes were selected following extensive screening in tissue culture cells. A SNALP-formulated combination of the KSP and VEGF siRNAs (referred to as ALN-VSP) was tested in orthotopic liver tumor models, as well as models of extra-hepatic tumors. To generate orthotopic liver tumors, human hepatoma (Hep3B) or colorectal carcinoma (HCT116) cells were implanted directly into the livers of immunocompromised mice. These cell lines were also used to establish tumors at extra-hepatic sites including the lymph nodes and peritoneal cavity.
Studies in which tumor-bearing mice were treated with ALN-VSP demonstrated that each siRNA makes a distinct contribution to efficacy. ALN-VSP treatment led to accumulation of aberrant mitotic figures (monoasters), a hallmark of KSP inhibition, in both types of orthotopic liver tumors, as well as in extra-hepatic tumors of different origin. Evidence of therapeutic VEGF inhibition was shown by marked reductions in tumor microvessel density and intratumoral hemorrhage in orthotopic tumors. Similar effects on tumor vasculature were obtained with a SNALP formulation of the VEGF siRNA alone. Finally, we demonstrated that multi-dose administration of ALN-VSP significantly prolongs survival of mice harboring advanced orthotopic liver tumors. A Phase 1 clinical trial of ALN-VSP is ongoing.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4064.
Abstract 4074: Alterations of NDP kinase A/ NM23-H1 deregulate c-myc transcription
Authors: Chan Kai-Hui , Paris Larry , Ma Lin-Jen , Wei Renn-Shiuan , Tan Choon-Yee , Chang Christina L. 
Published: February 2011

Abstract
Altered expression and mutations of NDP kinase A (NDPK-A), encoded by nm23-H1, have been detected in patients with metastatic tumors. One of new functions of NDPK-A is to participate in gene regulation. However, its role in regulating c-myc transcription remains unclear. Here we demonstrate for the first time that NDPK-A specifically bound nuclease hypersensitive element (NHE) III1 of the c-myc promoter in vitro and in vivo. Metastasis-associated S120G mutation of NDPK-A (NDPK-AS120G), but not S120G and N82S double mutations (NDPK-AS120G/N82S), retained the DNA-binding activity. In human NB69 neuroblastoma and HeLa cervical cancer cells, a high level of ectopic NDPK-A or NDPK-AS120 suppressed c-myc transcription based on the CAT reporter and RT-PCR. In contrast, shRNA-mediated knockdown of NDPK-A enhanced c-myc transcription. Without the DNA-binding activity, however, NDPK-AS120G/N82S did not display an effect on c-myc transcription. NDPK-A appears to exert transcriptional suppression via not only NHE III1 but also upstream cis-element(s) of c-myc promoter. The role of NDPK-A in regulating c-myc transcription was supported by nuclear localization of NDPK-A in cells and by negative correlation of NDPK-A and c-myc mRNA levels in several human cancer subtypes. Our findings provide a link between NDPK-A alterations and c-myc transcriptional deregulation in cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4074.