bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1064: MicroRNA-based diagnosis and therapy in NRF2-stabilized tumor
Authors: Inoue Jun , Fujiwara Naoto , Yamamoto Shinsuke , Kawano Tatsuyuki , Inazawa Johji 
Published: July 2016

Abstract
NRF2 is a master transcriptional regulator that integrates cellular stress responses and is negatively regulated by KEAP1 at the posttranslational level. In human cancers, aberrantly stabilized NRF2, either by mutation of NRF2 or KEAP1, plays a vital role in chemoresistance and tumor cell growth through the transcriptional activation of target genes, suggesting that targeted inhibition of NRF2 is a potential therapy for NRF2-stabilized tumors. Some tumor-suppressing microRNAs (miRNAs) target multiple oncogenes concurrently and therefore may be useful as cancer therapeutic agents. Further, such miRNAs may be useful to address chemotherapeutic resistance in cancer, which remains a primary clinical challenge in need of solutions. Thus, cytoprotective processes upregulated in cancer cells that are resistant to chemotherapy are a logical target for investigation.
By using a reporter-coupled miRNA library screening, we have recently identified four miRNAs (miR-507, -634, -450a, and -129-5p) that negatively regulate the NRF2 activity by directly targeting. Importantly, downregulation of these miRNAs, in addition to the somatic mutation of NRF2 or KEAP1, is associated with stabilized NRF2 and poor prognosis in esophageal squamous cell carcinoma (ESCC). Interestingly, we found that overexpression of miR-634 activates the mitochondrial apoptotic pathway by direct concurrent targeting of genes associated with mitochondrial homeostasis, antiapoptosis, and autophagy, together with NRF2-mediated antioxidant ability. In particular, we showed how enforced expression of miR-634 enhanced chemotherapy-induced cytotoxicity in a model of ESCC, where resistance to chemotherapy remains clinically problematic. Our findings illustrate how reversing miRNA-mediated cytoprotective processes may offer a broadly useful approach to improving cancer therapy.
Citation Format: Jun Inoue, Naoto Fujiwara, Shinsuke Yamamoto, Tatsuyuki Kawano, Johji Inazawa. MicroRNA-based diagnosis and therapy in NRF2-stabilized tumor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1064.
Abstract 1088: Efficient detection of germ cell cancer related miRNAs in serum using the TaqMan miRNA ABC purification bead kit in combination with the Taqman advanced miRNA assays
Authors: Looijenga Leendert HJ , Van Agthoven Ton , Gillis Ad 
Published: July 2016

Abstract
Malignant germ cell tumors, also known as germ cell cancers (GCC), are the most frequent cancer in young Caucasian males, with an increasing incidence during the last decades. They are clinically and histologically subdivided into seminomas and nonseminomas. The last can be composed of different elements, including embryonal carcinoma (the stem cell component), teratoma (TE) (somatic lineage) as well as yolk sac tumor (YST) and choriocarcinoma (CHC) (extra-embryonic lineages). The currently used serum markers, informative for both diagnosis as well as follow-up are AFP and hCG, predominantly indicative for the presence of the YST and CHC components. Recently, we reported that a selected set of miRNAs are highly expressed in all histological elements of GCC, with the exception of TE, including the miR 371-3 cluster. In addition to the presence in the primary cancers, they can also be identified in the serum of patients with such a malignancy, outperforming the classical markers AFP and hCG (Gillis and Rijlaarsdam et al. Molec. Oncol. 2013; Rijlaarsdam et al. Andrology, 2015). Here we demonstrate the power of the TaqMan Advanced miRNA Assays (PN 478007, Applied Biosystems) in combination with the use of the TaqMan miRNA ABC Purification Kit (PN 4473087, Applied Biosystems), starting with 50 μL human serum. The protocol includes polyadenylation of the miRNA targets at the 3’ end, followed by an adapter ligation at the 5’ end. Universal forward and reverse primers are used for amplification, followed by detection using the Applied Biosystems 7500 RealTime PCR System. Quality controls were added using dilution experiments of the cell lines, also included as inter-plate control, as well as for cDNA synthesis and RT-PCR efficiency. The non-human spike-ins ath-miR159a and cel-miR-39-3p were added as exogenous controls, while hsa-miR-30b-5p was used as endogenous control for normalization (reference). In total 30 GCC-related sera as well as 10 normal controls proved the informativity as well as efficiency of the developed pipeline in a standardized laboratory setting.
Citation Format: Leendert HJ Looijenga, Ton Van Agthoven, Ad Gillis. Efficient detection of germ cell cancer related miRNAs in serum using the TaqMan miRNA ABC purification bead kit in combination with the Taqman advanced miRNA assays. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1088.
Abstract 1109: AAGUGC-microRNAs are an integral part of an oncogenic signaling network driving non-small cell lung cancer proliferation
Authors: Zhou Yan , Frings Oliver , Fredlund Erik , Boekel Jorrit , Branca Rui M. , Orre Lukas M. 
Published: July 2016

Abstract
microRNA dysregulation is a common feature of cancer cells, but the complex roles of microRNAs in cancer are not fully elucidated. Here we used functional genomics to identify oncogenic microRNAs in non-small cell lung cancer (NSCLC) and to evaluate their impact on response to EGFR targeting therapy. Our data demonstrates that microRNAs with an AAGUGC-motif in their seed-sequence increase both cancer cell proliferation and sensitivity to EGFR inhibitors.
Using miR-372 as a prototypic AAGUGC-miRNA we set out to identify target mRNAs and an explanation to the discovered phenotype. Global transcriptomics, proteomics and target prediction, resulted in the identification of more than 500 candidate target mRNAs, including several tumor suppressors involved in the G1/S transition. The clinical relevance of our findings were evaluated by analysis of public domain data of NSCLC patients, revealing that almost 200 of the candidate target mRNAs showed a negative correlation to AAGUGC-miRNAs. In addition, the analysis of NSCLC clinical data supported the link between this microRNA seed-family and cancer cell proliferation and indicated that high expression of this type of microRNAs is associated with shorter relapse free survival.
Expanding the analysis to include additional types of cancer revealed large differences in expression of AAGUGC-miRNA both within and between cancer types. In general the results from the analysis of NSCLC was replicated in other cancer types, where expression of AAGUGC-miRNAs was associated with decreased mRNA levels of tumor suppressor targets and increased expression of genes involved in proliferation.
In conclusion we propose that AAGUGC-microRNAs are an integral part of an oncogenic signaling network, and that these findings have potential therapeutic implications, especially in selecting patients for EGFR-targeting therapy.
Citation Format: Yan Zhou, Oliver Frings, Erik Fredlund, Jorrit Boekel, Rui M. Branca, Lukas M. Orre. AAGUGC-microRNAs are an integral part of an oncogenic signaling network driving non-small cell lung cancer proliferation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1109.
Abstract 1128: Role of STAT3 in pediatric sarcoma cell lines
Authors: Hariharan Seethalakshmi , Phelps Doris A. , Houghton Peter J. 
Published: July 2016

Abstract
Signal transducer and activator of transcription-3 (STAT3) is a transcription factor that plays a major role in embryonic development, cell growth, differentiation and apoptosis. STAT3 becomes activated in the cytosol via phosphorylation at tyrosine-705 by JAK-1/2 kinases, in response to stimulation of either cytokine receptors or receptor tyrosine kinases. Phospho-STAT3 forms dimers, which then translocate into the nucleus to function as a transcription factor. Various pro-survival and anti-apoptotic genes including VEGF, Bcl-xL, Bcl-2 and survivin have been identified as STAT3 gene targets. Constitutive activation of STAT3 is observed in various cancers including breast, lung, pancreatic cancers and sarcomas. Since our studies indicate that STAT3 is upregulated in a number of pediatric sarcomas as well, we set out to understand the functional significance of STAT3 activation in these tumors in the context of tumor cell proliferation, survival, migration and resistance to apoptosis.
High basal expression levels of phospho-STAT3 (Tyr705) were detected in a number of rhabdomyosarcoma, Ewing's sarcoma and osteosarcoma xenografts and cell lines. Interleukin-6 (IL-6) was capable of inducing STAT3 (Tyr705) phosphorylation in these cell lines in a time-dependent manner. On the other hand, stimulation with insulin-like growth factors-1 and 2 or IGF-1/2 resulted only in a weak induction in STAT3 phosphorylation during early timepoints. Treatment with a potent JAK-1/2 inhibitor, ruxolitinib suggested that STAT3 phosphorylation in these cell lines is dependent on JAK-1/2 activities.
To understand the role of STAT3 in tumorigenesis, STAT3 was either knocked down using siRNAs or STAT3 phosphorylation was attenuated using ruxolitinib in sarcoma cell lines that express constitutively activated STAT3. Neither complete knockdown of STAT3, nor inhibition of STAT3 phosphorylation by ruxolitinib inhibited proliferation or decreased survival. These results indicate that activation of STAT3 may not have a significant role in tumor cell proliferation and survival under culture conditions. However, STAT3 inhibition resulted in decreased cell migration implicating STAT3 in regulation of tumor cell migration and invasion.
Overall, our data demonstrates a role for STAT3 activation in sarcoma cell migration and invasion and we speculate that targeting STAT3 might serve as a useful therapeutic approach to control tumor invasion and metastasis. Supported by USPHS grant CA165995.
Citation Format: Seethalakshmi Hariharan, Doris A. Phelps, Peter J. Houghton. Role of STAT3 in pediatric sarcoma cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1128.
Abstract 1138: Prognostic impact of BRAF-V600E expression and correlation with mutation status in cutaneous melanoma
Authors: Hugdahl Emilia , Kalvenes May Britt , Puntervill Hanne , Ladstein Rita , Akslen Lars A. 
Published: July 2016

Abstract
Around 50% of primary cutaneous melanomas harbour BRAF mutations, but their prognostic impact has not been clear. Recently, a BRAF-V600E mutation-specific antibody has become available for immunohistochemistry (IHC). Here, we investigated for the first time the prognostic impact of BRAF-V600E protein expression in primary melanoma. In a patient series of 248 nodular melanomas, BRAF-V600E and total BRAF expression were assessed by IHC using tissue microarray sections of paraffin-embedded archival tissue. Mutation status was assessed by real-time PCR. Positive BRAF-V600E expression was present in 86 (35%) of the cases and was significantly associated with increased tumor thickness, presence of tumor ulceration and reduced survival. Further, BRAF-V600E expression was an independent prognostic factor by multivariate survival analysis. There was 88% concordance between BRAF-V600E expression and mutation status. Our findings indicate that BRAF-V600E expression is a novel prognostic marker in primary melanoma.
Citation Format: Emilia Hugdahl, May Britt Kalvenes, Hanne Puntervill, Rita Ladstein, Lars A. Akslen. Prognostic impact of BRAF-V600E expression and correlation with mutation status in cutaneous melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1138.
Abstract 1142: E2F1 impairs all-trans retinoic acid-induced osteogenic differentiation of osteosarcoma by promoting ubiquitination-mediated degradation of RARa
Authors: Zhou Qian , Ying Meidan , Yang Bo , He Qiaojun 
Published: July 2016

Abstract
Objective: All-trans retinoic acid (ATRA) is a widely-used differentiation drug that can effectively induce osteogenic differentiation of osteosarcoma cells, but the underlying mechanism remains elusive, which limits the clinical application for ATRA in osteosarcoma patients. In this study, we identified E2F1 as a novel regulator involved in ATRA induced osteogenic differentiation of osteosarcoma cells.
Methods: Osteosarcoma cell lines were used as our research models. (1) Protein levels were detected by Western blotting; (2) The interactions between E2F1 and RARalpha were determined by immunofluorescence, immunoprecipitation and GST pull-down assay; (3) The mRNA levels were determined by RT-PCR; (4) Related proteins and genes were investigated via transfection; (5) RARE activity were detected by luciferase reporter assay. (6) Alkaline phosphatase activity was assessed by colorimetric assay using BCIP/NBT Alkaline Phosphatase Color Development kit. Results: We observed that osteosarcoma cells are coupled with individual differences in the expression levels of E2F1 in patients, and E2F1 impairs ATRA-induced differentiation of osteosarcoma cells. Moreover, remarkable anti-proliferative and differentiation-inducing effects of ATRA treatment are only observed in E2F1 low to negative expressed primary osteosarcoma cultures. These results strongly suggested that E2F1 may serve as a potent indicator for the effectiveness of ATRA treatment in osteosarcoma. Interestingly, E2F1 is found to down-regulate retinoic acid receptor (RAR), a key factor determines the effectiveness of ATRA. E2F1 specifically binds to RAR and promotes its ubiquitination-mediated degradation; as a consequence, RAR-mediated differentiation is inhibited in osteosarcoma.
Conclusion: E2F1 may serve as a potent biomarker as well as a therapeutic target for ATRA-based differentiation therapeutics, and raise the hope of using differentiation-based approaches for osteosarcoma patients.
Citation Format: Qian Zhou, Meidan Ying, Bo Yang, Qiaojun He. E2F1 impairs all-trans retinoic acid-induced osteogenic differentiation of osteosarcoma by promoting ubiquitination-mediated degradation of RARa. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1142.
Abstract 1143: Pro-proliferative function of SIRT3 in a human melanoma xenograft mouse model
Authors: George Jasmine , Nihal Minakshi , Ndiaye Mary A. , Ahmad Nihal 
Published: July 2016

Abstract
Melanoma is one of the most aggressive forms of skin cancer and is often lethal, if not treated early. Therefore, it is necessary to try to develop novel target-based strategies to combat this neoplasm. SIRT3 is a nicotinamide adenine dinucleotide (NAD+) -dependent mitochondrial protein deacetylase involved in metabolism- and aging- related disorders, including certain cancers. Interestingly, studies have suggested both tumor suppressor as well as tumor promoter roles of SIRT3 in cancer. However, its role in melanoma is not well-established. Previously, we have shown that SIRT3 was upregulated in human melanoma cells and its lentiviral knockdown resulted in anti-proliferative effects in human melanoma cells. We also found that SIRT3 knockdown resulted in the G1-phase arrest of the cell cycle, induction of senescence, and decrease in cell migration. This study was designed to determine the relevance of our in vitro findings to the in vivo situation, in human melanoma xenograft models. Employing immunodeficient mice (Crl:NU-Foxn1nu, homozygous; Strain 088), we first determined the effect of SIRT3-knockdown on melanoma tumorigenesis. The mice were subcutaneously implanted with shNS-SK-MEL-2 (control) and shSIRT3-SK-MEL-2 (SIRT3-knockdown) melanoma cells, followed by assessing tumorigenesis of melanoma cells. We found that compared to shNS-SK-MEL-2 cells, shSIRT3-SK-MEL-2 cells showed a significantly decreased tumorigenic potential in these mice, in terms of average tumor volume (measured weekly) and average tumor weight (measured at termination of the study). Further, the Kaplan-Meier analysis showed that SIRT3 knockdown resulted in a significant survival advantage, in terms of reaching the cutoff tumor size (2.0 cm in one dimension). In an additional strategy, we determined the tumorigenicity of SIRT3 overexpressing melanoma cells (Hs294T-SIRT3) in NU/NU mice. Our data demonstrated that compared to control Hs294T-pcDNA cells, the SIRT3 overexpressing Hs294T-SIRT3 cells demonstrated a significantly enhanced tumorigenic potential (average tumor volume and tumor weight) in NU/NU mice. Overall, our study provides evidence supporting a pro-proliferative role of SIRT3 in melanoma and suggests that SIRT3 needs to be further evaluated as a potential druggable therapeutic target for melanoma management. However, detailed mechanistic and in vivo studies in relevant melanoma models are needed to further validate our findings.
Citation Format: Jasmine George, Minakshi Nihal, Mary A. Ndiaye, Nihal Ahmad. Pro-proliferative function of SIRT3 in a human melanoma xenograft mouse model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1143.
Abstract 1145: Zhx2 promotes survival of B-cell acute lymphoblastic leukemia cell lines
Authors: Sharma Namit , Hou Huayun , Wilson Michael D. , McGlade. Catherine Jane 
Published: July 2016

Abstract
Zhx2, a zinc finger containing transcription factor is frequently overexpressed in B cell malignancies including B cell acute lymphoblastic leukemia (B-ALL), however its role in development of B cell malignancies remains unknown. Previously, dysregulated activity of transcription factors due to mutation e.g. Myc or overexpression e.g. Sox11 has been shown to perturb B cell differentiation leading to malignant phenotypes, resistance to chemotherapeutics and genetic heterogeneity. Zhx2 is required for normal neuronal and erythropoietic differentiation and has been identified as a tumor suppressor in hepatocellular carcinoma. Furthermore, analysis of public databases shows that Zhx2 is highly overexpressed in several cell lines representing B cell malignancies including B cell acute lymphoblastic leukemia (B-ALL) and B cell lymphoma. Consistently, Zhx2 is also overexpressed in patient samples derived from different subtypes of B cell malignancies. Quantification of Zhx2 mRNA expression obtained from human donors showed a marked upregulation during transition from common lymphoid progenitor to Pro B-cell stage suggesting potential role in B cell differentiation. Here we report that Zhx2 is overexpressed in Philadelphia chromosome positive (Ph+) B-ALL and T-ALL cell lines as well as Ph- B-ALL cell line. Zhx2 silencing in BV-173 (Ph+ B-ALL) and CMLT1 (Ph+ T-ALL) showed enhanced apoptosis with low doses of Dasatinib, a dual Src/Abl kinase inhibitor. Furthermore, global gene promoter and gene expression analysis on Zhx2 silenced cells identified putative Zhx2 regulated genes including CREB and YY1. Both of these transcription factors have roles in B cell differentiation, survival, proliferation and are commonly deregulated in B cell malignancies. We propose that Zhx2 regulates a B cell differentiation program and that overexpression of Zhx2 could lead to blocked differentiation of B cell progenitors promoting the malignant phenotype. Therefore, Zhx2 could be exploited as a chemo-therapeutic target in B cell malignancies.
Citation Format: Namit Sharma, Huayun Hou, Michael D. Wilson, Catherine Jane McGlade. Zhx2 promotes survival of B-cell acute lymphoblastic leukemia cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1145.
Abstract 1148: A muscle specific protein “myoferlin” modulates IL-6/STAT3 signaling by chaperoning activated STAT3 to nucleus
Authors: Yadav Arti , Kumar Bhavna , Teknos Theodoros N. , Kumar Pawan 
Published: July 2016

Abstract
Recently, we made a provocative and novel discovery in our laboratory that a muscle-specific protein, myoferlin, is markedly upregulated in head and neck cancer cells. Myoferlin is a member of ferlin family of membrane proteins and most of the studies related to myoferlin's biological and molecular function(s) were carried out on muscle cells, as it was assumed that myoferlin is predominantly present only in the muscle cells. Recent studies have shown that myoferlin is also expressed in endothelial and cancer cells and it modulates VEGFR-2 and EGFR stability and function. Based on these reports, we hypothesized that myoferlin might be regulating IL-6 signaling by modulating IL-6R stabilization and recycling. However, in our immunoprecipitation (IP) experiments, we did not observe myoferlin binding with IL-6R. Instead, we observed that myoferlin is bound to EHD2 protein in the resting cells and when the cells are treated with IL-6, myoferlin dissociates from EHD2 and binds to activated STAT3. Interestingly, myoferlin knock-down did not affect STAT3 phosphorylation, but completely blocked STAT3 translocation to nucleus and expression of its target proteins including Snail and Nanog. In addition, inhibition of STAT3 phosphorylation by phosphorylation defective STAT3 mutants or JAK inhibitor blocked STAT3 binding to myoferlin and nuclear translocation. Myoferlin knockdown significantly decreased IL-6-mediated tumor cell migration, tumorsphere formation and ALDH positive cancer stem cell population, in vitro. Furthermore, myoferlin knockdown significantly decreased IL-6-meditated tumor growth and tumor metastasis, in vivo. Based on these results, we have proposed a novel model for the role of myoferlin in chaperoning phosphorylated STAT3 to the nucleus.
Citation Format: Arti Yadav, Bhavna Kumar, Theodoros N. Teknos, Pawan Kumar. A muscle specific protein “myoferlin” modulates IL-6/STAT3 signaling by chaperoning activated STAT3 to nucleus. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1148.