bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A8: Defining specific microRNAs that cooperatively regulate GRP78, an ER chaperone and signaling regulator, in cancer
Authors: Su Sheng-Fang , Lee Amy S. , Liang Gangning 
Published: April 2013

Abstract
GRP78, a major endoplasmic reticulum (ER) chaperone and signaling regulator, is commonly over-expressed in cancer and contributes to cancer cell proliferation, survival and tumorigenesis. Moreover, induction of GRP78 by a variety of anti-cancer drugs, including histone deacetylase inhibitors, confers chemo-resistance to cancer. Thus, targeting GRP78 to inhibit tumor survival and proliferation, sensitize tumor cells to chemotherapeutic drugs and consequently induce apoptosis serves as a promising avenue in anti-cancer therapy. As endogenous regulators, microRNAs (miRNAs) play important roles in modulating gene expression; therefore, we sought to identify miRNA(s) that target GRP78. We report that multiple miRNAs (miR-30d, miR-181a, miR-199-5p) commonly down-regulated in human cancer cell lines can repress GRP78 and lead to increased apoptosis in C42B prostate cancer cells. Luciferase reporter assays indicate that these miRNAs act as negative regulators of GRP78 by directly targeting the 3′ untranslated region of GRP78. Importantly, the combination of multiple miRNAs cooperated resulting in greater inhibition on GRP78 than individual miRNAs, suggesting the efficacy of tumor suppression by combined miRNAs. In addition, we showed that transfection of the multiple miRNAs in C42B cells increased sensitivity of cancer cells to trichostatin A (TSA), a histone deacetylase inhibitor, induced apoptosis, and inhibited cell proliferation and colony formation. Therefore, we suggest that delivery of combinations of specific miRNAs could be a novel anti-cancer approach capable of suppressing GRP78 and in turn inhibiting GRP78-mediated tumorigenesis.
Citation Format: Sheng-Fang Su, Amy S. Lee, Gangning Liang. Defining specific microRNAs that cooperatively regulate GRP78, an ER chaperone and signaling regulator, in cancer [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr A8.
Abstract A9: De novo sequencing of circulating microRNAs identifies novel markers predicting clinical outcome of locally advanced breast cancer
Authors: Wu Xiwei , Somlo George , Palomares Melanie , Yen Yun , Rossi John , Gao Harry , Wang Shizhen Emily 
Published: April 2013

Abstract
Purpose: MicroRNAs (miRNAs) have been recently detected in the circulation of cancer patients, where they are associated with clinical parameters. Discovery profiling of circulating small RNAs has not been reported in breast cancer (BC), and was carried out in this study to identify blood-based small RNA markers of BC clinical outcome.
Patients and Methods: The pre-treatment sera of 42 stage II–III locally advanced and inflammatory BC patients who received neoadjuvant chemotherapy (NCT) followed by surgical tumor resection were analyzed for marker identification by deep sequencing all circulating small RNAs. An independent validation cohort of 26 stage II–III BC patients was used to assess the power of identified miRNA markers.
Results: More than 800 miRNA species were detected in the circulation, and exhibited patterns associated with the histopathological profiles of BC. Groups of circulating miRNAs differentially associated with ER/PR/HER2 status and inflammatory BC were identified. The relative levels of selected miRNAs measured by PCR showed consistency with their abundances determined by deep sequencing. Two circulating miRNAs, miR-375 and miR-122, exhibited strong correlations with clinical outcomes, including NCT response and relapse with metastatic disease. In the validation cohort, higher levels of circulating miR-122 specifically predicted metastatic recurrence in stage II–III BC patients.
Conclusion: Our study indicates that certain miRNAs can serve as potential blood-based biomarkers for NCT response, and that miR-122 prevalence in the circulation predicts BC metastasis in early-stage patients. These results may allow optimized chemotherapy treatments and preventive anti-metastasis interventions in future clinical applications.
Citation Format: Xiwei Wu, George Somlo, Melanie Palomares, Yun Yen, John Rossi, Harry Gao, Shizhen Emily Wang. De novo sequencing of circulating microRNAs identifies novel markers predicting clinical outcome of locally advanced breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr A9.
Abstract B17: Inhibition of lung tumor progression in a metastatic mouse model following intravenous delivery of siRNA nanocomplexes
Authors: Fewell Jason G. , Anwer Khursheed , Polach Kevin , Matar Majed , Rice Jennifer , Rea-Ramsey Angela , Sparks Jeff , McClure Diane , Pence Casey , Brunhoeber Elaine , Wilkinson Leslie 
Published: April 2013

Abstract
Exploiting the RNAi pathway offers the potential to advance the treatment of many diseases through highly specific and efficient silencing of gene products. Unfortunately, the requisite safe and efficient delivery of nucleic acids to target cells remains a fundamental problem for the development of RNA and DNA based therapeutics. We have developed a versatile lipopolyamine based delivery system that has been optimized for in vivo delivery by incorporating functional groups onto the core cationic lipopolyamine structure. The direct modification of the core structure (named Staramine) allows for the generation of nanoparticle formulations with a wide range of physicochemical properties and does not require the co-formulation of commercial helper or pegylated lipids. We have previously reported safe, efficient and persistent siRNA mediated transcript knockdown specifically in the lung endothelium using the Starmaine delivery system. Here we extend those observations by administering a siRNA that targets vascular endothelial growth factor receptor 2 (VEGFR-2; KDR/Flk-1) in an animal model of metastatic lung cancer. VEGFR-2, a receptor tyrosine kinase, has been shown to be mainly expressed on endothelial cells and plays a critical role in cell proliferation and differentiation and consequently is also important in angiogenesis associated tumor growth and metastasis. Repeated intravenous administration of nanocomplexes comprised of Staramine formulated VEGFR-2 siRNA (~2 mg/kg/dose) resulted in a significant (40%) reduction of VEGFR-2 transcript levels in isolated tumors from the lungs of mice compared to control injected animals. Similar levels of transcript knockdown were not achieved in tumors when using siRNAs against targets not having the high level of endothelial cell restriction that is seen with VEGFR-2. Immunohistopathology of the lungs of tumor bearing mice administered VEGFR-2 siRNA indicated a significant decrease in vascular density in lung tumors and was consistent with an overall reduction in tumor burden in the mouse lungs. These results support the continued evaluation of using Staramine to deliver siRNAs and other similar molecules as potential therapies for diseases of the lung where the vascular endothelium may be involved.
Citation Format: Jason G. Fewell, Khursheed Anwer, Kevin Polach, Majed Matar, Jennifer Rice, Angela Rea-Ramsey, Jeff Sparks, Diane McClure, Casey Pence, Elaine Brunhoeber, Leslie Wilkinson. Inhibition of lung tumor progression in a metastatic mouse model following intravenous delivery of siRNA nanocomplexes [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr B17.
Abstract B20: Breast cancer progression suppressor miR-290 targets breast cancer biomarker Arid4b
Authors: Goldberger Natalie , Walker Renard , Kim Chang Hee , Hunter Kent 
Published: April 2013

Abstract
Several microRNAs (miRNAs) have been classified as metastasis regulators in breast cancer, yet few studies have examined how germline variations may promote metastasis via miRNA dysregulation. To explore this concept, highly metastatic MMTV-PyMT mice were crossed with 25 AKXD (AKR/J × DBA/2J) recombinant inbred strains to produce F1 progeny with varying metastatic indices. All mammary tumors in the F1 progeny were evaluated by miRNA microarray and correlated with metastatic index to produce miR-290 (containing mature miR-290-3p and miR-290-5p) as one of the top candidates. Further analysis showed miR-290-3p was downregulated in normal lung and breast tissue from highly metastatic AKR/J strains versus less metastatic DBA/2J strains, thereby supporting a germline component to miR-290 regulation. Next, when miR-290 was ectopically expressed in Mvt-1 and 6DT1, and orthotopically injected into FVB/N mice, a significant reduction in both mammary tumor burden and the number of pulmonary metastases was observed. Computational analysis identified breast cancer biomarker Arid4b as a top target of miR-290-3p, which was confirmed by luciferase reporter assay. In conclusion, these results suggest germline genetic changes may reduce miR-290 expression, in turn increasing Arid4b expression, to create a predisposition towards breast cancer progression.
Citation Format: Natalie Goldberger, Renard Walker, Chang Hee Kim, Kent Hunter. Breast cancer progression suppressor miR-290 targets breast cancer biomarker Arid4b [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr B20.
Abstract IA12: Long-term, efficient inhibition of miRNA function in mice using Tough Decoys delivered by Adeno-associated virus vectors
Authors: Zamore Phillip D. 
Published: April 2013

Abstract
Understanding the function of individual miRNA species in mice would require the production of hundreds of loss-of-function strains. To accelerate analysis of miRNA biology in mammals, we combined recombinant adeno-associated virus (rAAV) vectors with miRNA ‘Tough Decoys’ (TuDs) to inhibit specific miRNAs. Intravenous injection of rAAV9 expressing anti-miR-122 or anti-let-7 TuD depleted the corresponding miRNA and increased its mRNA targets. rAAV producing anti-miR-122—but not anti-let-7—TuD reduced serum cholesterol by 40% for 18 weeks in wild-type mice. High throughput sequencing of liver miRNAs from the treated mice confirmed that the targeted miRNAs were depleted and revealed that TuD RNAs induce miRNA tailing and trimming in vivo. rAAV-mediated miRNA inhibition thus provides a simple way to study miRNA function in adult mammals and a potential therapy for dyslipidemia and other diseases caused by miRNA deregulation.
Citation Format: Phillip D. Zamore. Long-term, efficient inhibition of miRNA function in mice using Tough Decoys delivered by Adeno-associated virus vectors [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr IA12.
Abstract IA13: MicroRNA control of muscle development and disease: from new biology to new therapeutics
Authors: Olson Eric N. 
Published: April 2013

Abstract
We seek to define the gene regulatory networks that govern muscle and cardiovascular development and disease. The signaling pathways and transcriptional networks that control these processes are intertwined with a collection of microRNAs (miRNAs) that act as negative regulators of gene expression. We have identified miRNAs associated with muscular dystrophy and diverse cardiovascular disorders, including cardiac hypertrophy, heart failure, myocardial infarction, and angiogenesis. Gain- and loss-of-function studies in mice have revealed striking functions for these miRNAs in numerous processes, such as the control of muscle regeneration, nerve-muscle interactions, myosin expression, fibrosis, hypoxia, myocyte survival, and metabolism. Identification of miRNA targets has revealed new mechanisms and regulators of development and disease. Disease-inducing miRNAs can be persistently silenced in vivo through systemic delivery of miRNA inhibitors, allowing for therapeutic modulation of disease mechanisms. Opportunities for manipulating miRNA biology in the settings of muscle disease will be discussed.
Citation Format: Eric N. Olson. MicroRNA control of muscle development and disease: from new biology to new therapeutics [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr IA13.
Abstract IA16: The ceRNA hypothesis and the non-coding revolution in cancer research and therapy
Authors: Pandolfi Pier Paolo 
Published: April 2013

Abstract
The central dogma of molecular biology, as proposed by Francis Crick, demonstrates that genetic information is transferred from DNA in our genomes to the generation of functional proteins, through a messenger RNA (mRNA) intermediate. This suggests that the key function of each mRNA is to encode for protein.
We have demonstrated that mRNAs can exert a biological activity that is independent of the protein for which they encode. Since this phenomenon is dependent on sequences contained in RNA transcripts, this phenomenon applies to protein-coding genes, pseudogenes, of which 19,000 have been predicted in the genome as well as long non-coding RNAs that have been recently identified to be pervasive in the cell and in biology.
This new function is brought about by the ability of mRNAs—and RNAs in general—to bind and sequester microRNA molecules. microRNAs specifically repress the expression levels of many genes and have consequently been shown to play important roles in diseases including cancer. We show that any messenger RNA and RNA molecule can sequester microRNA molecules acting as a “competitive endogenous RNAs.” We therefore term them ceRNAs. Given that microRNAs can bind to multiple mRNAs, we argued that mRNAs compete for the binding to a given microRNA. We originally tested this hypothesis and proved its validity by studying the interaction between the mRNA encoding for the PTEN tumor suppressor gene and its closely related pseudogene, PTENP1, which we show to act as a tumor suppressor through this new mechanism. We therefore identify PTENP1 as well as the several thousand uncharacterized RNA molecules as potential human disease genes.
We have now expanded this analysis to the whole transcriptome. Our findings therefore defines a new biological dimension that will allow for the rapid identification and functional characterization of new disease genes.
Citation Format: Pier Paolo Pandolfi. The ceRNA hypothesis and the non-coding revolution in cancer research and therapy [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr IA16.
Abstract IA19: New therapeutic strategies for lymphomas inspired by functional and structural genomics
Authors: Staudt Louis M. 
Published: April 2013

Abstract
Seeking an unbiased method to discover therapeutic targets in cancer, we developed a loss-of-function genetic screen using genomic-scale libraries of small hairpin RNAs that mediate RNA interference. These “Achilles heel” screens are designed to reveal genes essential for cancer cell proliferation and survival. In a parallel structural genomics approach, we are using RNA-seq to globally identify somatic mutations and other structural abnormalities in cancer. RNA-seq also provides an unprecedented view of gene expression that provides more accurate quantitative data than traditional microarray approaches. The intersection of the RNA interference and RNA-seq data sets has helped us to discover novel pathogenetic pathways that control the proliferation and survival of the aggressive lymphoma subtypes. The malignant phenotype is seen as an aberrant regulatory network that includes oncogene-induced microRNAs, deregulated transcription factors and aberrant signaling from cell surface receptors. This view suggests several therapeutic opportunities using targeted agents that might initially augment and eventually supplant the more toxic chemotherapeutic regimens used to treat these cancers today.
Citation Format: Louis M. Staudt. New therapeutic strategies for lymphomas inspired by functional and structural genomics [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr IA19.
Abstract IA20: Targeting of microRNAs for therapeutics
Authors: Kauppinen Sakari 
Published: April 2013

Abstract
microRNAs act as important post-transcriptional regulators of gene expression by mediating mRNA degradation and translational repression. Moreover, there is ample evidence that perturbations in the levels of individual or entire families of miRNAs are strongly associated with the pathogenesis of a wide range of human diseases. Besides cancer, miRNAs have also been implicated in viral infections, cardiovascular and muscle diseases and CNS disorders. Thus, disease-associated miRNAs represent a potential new class of targets for oligonucleotide-based therapeutics, which may yield patient benefits unobtainable by other therapeutic approaches.
LNA is a bicyclic high-affinity RNA analogue, in which the ribose ring is locked in an RNA-like, N-type (C3′-endo) conformation by the introduction of a 2′-O,4′-C methylene bridge. Transfection of LNA-modified antimiR oligonucleotides into cells results in potent and specific inhibition of miRNA function with concomitant derepression of direct target mRNAs. In addition, systemically delivered, unconjugated LNA-antimiRs with a phosphorothioate backbone show high metabolic stability and uptake in many tissues in mice, coinciding with long-term miRNA silencing in vivo. These findings support the utility of LNA-modified antimiR oligonucleotides in the development of therapeutic strategies aimed at pharmacological inhibition of disease-associated miRNAs. We will describe recent progress in targeting of disease-implicated miRNAs for therapeutics using LNA-antimiRs and present an update on the clinical development of antimiR-122 for treatment of hepatitis C virus infection.
Citation Format: Sakari Kauppinen. Targeting of microRNAs for therapeutics [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr IA20.
Abstract IA6: Elucidation of enhancer-like RNAs
Authors: Shiekhattar Ramin 
Published: April 2013

Abstract
Spatial and temporal regulation of gene expression is achieved through the instruction provided by the distal transcriptional regulatory elements known as enhancers. How enhancers transmit such information to their targets has been a subject of intense investigation. Recent advances in high throughput analysis of the mammalian transcriptome have revealed a surprising result indicating that a large number of enhancers are transcribed to non-coding RNAs. While long non-coding RNAs were initially shown to confer epigenetic transcriptional repression, recent studies have uncovered a role for a class of such transcripts in gene-specific activation often from distal genomic regions. We will discuss the recent findings on the role of long non-coding RNAs in transcriptional regulation with an emphasis on new developments on the functional links between long non-coding RNAs and enhancers.
Citation Format: Ramin Shiekhattar. Elucidation of enhancer-like RNAs [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr IA6.
Abstract PR1: BRAFV600E remodels the melanocyte transcriptome and induces BLNCR1 to regulate melanoma cell migration
Authors: Flockhart Ross J. , Webster Dan E. , Qu Kun , Mascarenhas Nicholas , Kovalski Joanna , Kretz Markus , Khavari Paul A. 
Published: April 2013

Abstract
Aberrations of protein-coding genes are a focus of cancer genomics, however, the impact of oncogenes on expression of the ~50% of transcripts without protein-coding potential, including long non-coding RNAs (lncRNAs), is largely uncharacterized. Activating mutations in the BRAF oncogene are present in 60% of melanomas, 90% of which produce active mutant BRAFV600E. To define the impacts of oncogenic BRAF on the melanocyte transcriptome, massively parallel cDNA sequencing (RNA-Seq) was performed on genetically matched normal human melanocytes with and without BRAFV600E expression. To enhance potential disease relevance by verifying expression of altered genes in BRAF-driven cancer tissue, parallel RNA-Seq was also undertaken on two BRAFV600E-mutant human melanomas. BRAFV600E regulated expression of 1,027 protein-coding transcripts and 39 annotated lncRNAs, as well as 70 un-annotated, potentially novel, intergenic transcripts. Coding potential analysis of these 70 transcripts suggested that most may represent newly identified non-coding RNAs. BRAF-regulated long non-coding RNA 1 (BLNCR1) was identified as a recurrently, highly expressed, previously un-annotated 693 bp transcript on chromosome 9 with a potential functional role in melanoma cell migration. Combining RNA-Seq of oncogene-expressing normal cells with RNA-Seq of their corresponding human cancers may represent a useful approach to discover new oncogene-regulated RNA transcripts of potential clinical relevance to cancer.
This abstract is also presented as Poster A11.
Citation Format: Ross J. Flockhart, Dan E. Webster, Kun Qu, Nicholas Mascarenhas, Joanna Kovalski, Markus Kretz, Paul A. Khavari. BRAFV600E remodels the melanocyte transcriptome and induces BLNCR1 to regulate melanoma cell migration [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr PR1.