bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2050: MicroRNA-124a: A master regulator of glioblastoma migration
Authors: McDonald Kerrie L. , Fowler Adam , Thomson Daniel , Giles Keith , Leedman Peter , Robinson Bruce G. 
Published: February 2011

Abstract
For most patients diagnosed with a glioblastoma multiforme (GBM), the invasiveness of this tumor and its resistance to treatment predicts a poor outcome with no realistic possibility of a cure. Although brain tumor cells rarely metastasize outside the brain, they have an extraordinary capacity to migrate long distances and infiltrate normal brain, making complete surgical removal impossible. New therapeutic strategies are needed to target the invading cell population to further reduce tumor cell spread and a better understanding of the mechanisms promoting tumor migration and invasion are urgently needed.
MiR-124a, a microRNA, normally abundantly expressed in normal adult brain tissue, shows marked down regulation (&gt;1000 fold) in GBM cell lines (A172, T98G, MO59J, MO59K and U87MG). Conversely, a predicted miR-124a target, IQGAP1, is over-expressed in GBM cell lines and tissue samples. We previously demonstrated IQGAP1 overexpression in 86% of GBM patients and associated high levels with poor prognosis. IQGAP1 expression was prominent in the actively migrating and rapidly dividing palisading neoplastic cells that surround the necrotic foci.
We hypothesized a reciprocal interaction between miR-124a and IQGAP1. To show this, GBM cell lines were transfected with a synthetic miR-124a precursor molecule to increase endogenous miR-124a expression. Cell migration was measured by impedence of a current (ECIS 9600) and tumor cell invasion was measured using transwell inserts. The interaction between miR-124a and IQGAP1 was ascertained using quantitative PCR, Western Blot analysis and luciferase reporter assays.
Transfected miR-124a-GBM cells did not show any alterations in cell proliferation however significant reductions in tumor cell migration and invasion were observed when compared to control cells. Reducedmigration and invasion was also observed when GBM cells were transiently transfected with siRNA directed at IQGAP1. A direct effect of miR-124a on IQGAP1 expression levels was demonstrated at the mRNA and protein levels via miR-124a targeting the IQGAP1 mRNA 3’-UTR.
In summary, we show that miR-124 functions as a tumour suppressor miRNA being downregulated in GBM which results in overexpression of IQGAP1. Additional migratory proteins commonly overexpressed in GBM also possess predicted miR-124a target sites and are currently been evaluated. miR-124a may therefore act as a master regulator of GBM invasiveness. Furthermore, delivery of miR-124a into GBMs may represent as a novel therapeutic approach to limit GBM invasion both alone and in combination with convential chemotherapy treatments.
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 2050.
Abstract 2051: DNA (cytosine-5-)-methyltransferases 3A (DNMT3A) is a direct target of miR-194 in breast cancer
Authors: Le Xiao-Feng , Spizzo Riccardo , Mao Maggie , Wu Yun , Calin George A. , Bast Robert C. 
Published: February 2011

Abstract
microRNAs (miRNAs) are small non-coding RNAs of 19-25 nucleotides in length that can modulate gene expression that regulate biological and malignant processes. DNA methylation is catalyzed primarily by three DNMTs - DNMT1, DNMT3A, and DNMT3B and contributes to cancer initiation and progression. While DNMT3A protein overexpression has been detected in colon, lung, skin and testis cancers, its expression in breast cancer has not been previously reported. Targets and function for miR-194 have not been well defined. In this study, we investigated the expression of miR-194, DNMT3A, and the possible role of miR-194 in regulating DNMT3A in breast cancer cells. Expression of miR-194 precursor in breast cancer cell lines specifically downregulated DNMT3A mRNA and protein levels. miR-194 specifically inhibited the luciferase activity of wild type DNMT3A 3’-UTR construct, but not that of mutant vector, indicating that DNMT3A is a direct downstream target of miR-194. Furthermore, miR-194 expression appeared to correlate inversely with DNMT3A mRNA or protein expression in breast cancer cell lines and patient samples. An increase in miR-194 expression stimulated tumor suppressors cyclin G2, p27Kip1 and ADAM23 expression, which can be regulated by DNA methylation. Overexpression of miR-194 inhibited cell motility of breast cancer cells without alteration of the cell cycle distribution. Most DNMT3A protein localized in the nucleus, but a small fraction of DNMT3A protein was found in the cytoplasm. The prognostic value of miR-194 and DNMT3A in breast cancer is being studied using a breast cancer tissue array, quantitative real time PCR and immunohistochemical staining. In summary, this report demonstrates DNMT3A as a direct target of miR-194 in breast cancer 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 2051.
Abstract 2052: MicroRNA-101 promotes apoptosis and suppresses proliferation in esophageal squamous cell carcinoma by repressing the polycomb group protein EZH2
Authors: Hiyoshi Yukiharu , Kamohara Hidenobu , Kurashige Junji , Kinoshita Kouichi , Hayashi Naoko , Watanabe Masayuki , Baba Hideo 
Published: February 2011

Abstract
Background: MicroRNAs (miRNAs) are ∼22 nucleotide non-coding RNA molecules that regulate gene expression post-transcriptionally. Although aberrant expression of miRNAs has been observed in various types of human cancer, their pathophysiologic role and their relevance to tumorigenesis are still largely unknown. Overexpression of the enhancer of zeste homolog 2 (EZH2) protein, a known repressor of gene transcription, has been reported to be associated with biological malignancy in several types of cancer.
Purpose: The aim of this study was (1) to analyze the expression and function of microRNA-101 (miR-101) in esophageal squamous cell carcinoma (ESCC), (2) to elucidate the regulation of the EZH2 expression by miR-101 as its target gene.
Methods: miR-101 expression was investigated in 27 matched normal esophageal epitheliums and ESCCs and 12 ESCC cell lines (TE1, 4, 6, 8, 9, 10, 11, 12, 13, 14, 15, KYSE30) by TaqMan quantitative real-time-polymerase chain reaction (qRT-PCR). To evaluate the role of miR-101, cell proliferation and apoptosis was analyzed with pre-miR-101-precursor transfected cells. Next, the regulation of EZH2 by miR-101 was analyzed by real-time PCR and western blotting. In addition, to elucidate the role of EZH2 gene in ESCC, we immunohistochemically examined the expression of EZH2 protein in 120 resected ESCC specimens and determined its association with the clinicopathological characteristics and prognosis.
Results: In matched 27 resected specimens, the expression of miR-101 was significantly down-regulated in ESCCs compared with normal epitheliums. All 15 ESCC cell lines also showed down-regulation of miR-101. Pre-miR-101-precursor transfected cells promote cellular apoptosis and showed significant reduction in cellular proliferation. Pre-miR-101-precursor transfected cells significantly repressed EZH2 expression in both mRNA level and protein level. In the immunohistochemical analysis of EZH2, 78 (65%) showed positive staining, while 42 (35%) lacked the staining. Positive staining for EZH2 was associated with a poor prognosis significantly. Conclusions: miR-101 promotes apoptosis and suppresses proliferation in ESCC by repressing EZH2 expression as a tumor-suppressive-microRNA. It plays an important role in progression of ESCC and may serve as a novel therapeutic target.
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 2052.
Abstract 2053: Regulation of microRNA-10b by CCN5/WISP-2 in breast cancer: A novel mechanism of CCN5/WISP-2 mediated suppression of invasive front
Authors: Haque Inamul , Banerjee Snigdha , Mehta Smita , Phillips Teresa A. , Dhar Gopal , Kambhampati Suman , Banerjee Sushanta K. 
Published: February 2011

Abstract
Metastatic cells are a subset of primary tumor cells that have the skill to complete multi-step metastatic cascades, including dissemination, migration, extravasation, and eventual proliferation) at a discontinuous secondary site. Understanding the molecular biology of cancer metastasis may provide novel intervention strategies to control metastatic lesions, and/or to improve the quality of life for the patients with these advanced diseases. MicoRNAs are naturally occurring single-stranded RNA molecules that posttranscriptionally regulate the expression of target mRNA transcripts. Many of these target mRNA transcripts are involved in cell proliferation, differentiation and apoptosis, processes commonly altered during tumorigenesis. Recent findings have shown that microRNA-10b (miR-10b) is highly expressed in metastatic breast cancer cells and positively regulates cell migration and invasion. Expression of miR-10b is induced by Twist, a transcription factor that binds to putative promoter of miR-10b. We hypothesized that whether nullification of CCN5/WISP-2, an antiinvasive gene has any role in miR-10b expression. We found that nullification of CCN5/WISP-2 in ER-positive noninvasive breast tumor cell upregulates the miR-10b expression. Interestingly, we also found the upregulation of Twist by silencing CCN5/WISP-2. Collectively, we conclude that CCN5/WISP-2 may be a critical regulator of miR-10b expression through the HIF-1α-Twist signaling.
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 2053.
Abstract 2055: miR-17-3p suppresses tumorigencity of prostate cancer through inhibiting mitochondrial antioxidant enzymes
Authors: Xu Yong , Fang Fang , Josson Sajni , Clair Daret K. St. , Clair William H. St. 
Published: February 2011

Abstract
Aberrant micro RNA (miRNA) expression has been implicated in pathogenesis of cancer. Recent studies have shown that miR-17-92 cluster is overexpressed in many types of cancer (Venturini et al Blood 2007; Mendell Cell 2008). The oncogenic function of mature miRNAs encoded by the miR17-92 cluster was identified from the 5’ arm of six precursor including miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92-1. However, function of the miRNAs produced from the 3’ arm of these precursors remains to be elucidated. The present study demonstrates that miR-17-3p is able to suppress multiple primary mitochondrial antioxidant enzymes including manganese superoxide dismutase (MnSOD or SOD2), glutathione peroxidase-2 (GPX2), and thioredoxin reductase-2 (TXNRD2). Transfection of miR17-3p into prostate cancer PC-3 cells significantly reduced levels of the three antioxidant proteins and activity of the luciferase reporter under the control of identified miR-17-3p blinding sequences located in the 3’-untranslated regions of the three target genes. Disulfiram, a drug used to treat chronic alcoholism and also shown to have anticancer effect, induces the level of mature miR-17-3p and apoptotic cell death in PC-3 cells, which can be attenuated by transfection of antisense miR-17-3p. Increasing miR17-3p level in PC-3 cell by a Tet-on-based conditional expression system markedly suppressed its tumorigencity and enhanced its radiosensitivity. These results suggest that miR-17-3p may suppress aggressiveness of prostate cancer through inhibition of mitochondrial antioxidant enzymes.
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 2055.
Abstract 2059: The role of microRNA-196b in cervical cancer
Authors: How Christine , Hui Angela B. , Fyles Anthony W. , Liu Fei-Fei 
Published: February 2011

Abstract
Introduction: MicroRNAs (miRs) are ∼22-nucleotide, non-coding RNAs that regulate gene expression post-transcriptionally. Recent data have indicated that miRs are aberrantly expressed in almost all human malignancies, including cervical cancer. In order to better understand how miRs might mediate tumor progression in cervical cancer, dysregulated miRs were identified and functional studies performed for miR-196b.
Experimental Procedures: miR expression was measured in 3 cervical cancer cell lines (SiHa, ME-180 and HT3) and 3 normal cervix tissues using a quantitative real-time PCR approach examining 365 miRs and 3 endogenous controls. SiHa cells were transfected with Pre-miR miRNA Precursor Molecules (Ambion) to determine the effects of miR-196b overexpression. Candidate miR-196b targets were elucidated using a tri-pronged approach combining in silico target prediction algorithms, clinical mRNA expression data, and in vitro mRNA expression data following transfection of cell lines. To test for direct binding of miR-196b to the HOXB7 3’ UTR, a luciferase reporter assay was performed. Reporter vectors were constructed containing either the HOXB7 3’ UTR sequence (pMIR-REPORT-HOXB7/UTR), or the HOXB7 3’ UTR sequence with a mutation in the predicted miR-196b binding site (pMIR-REPORT-HOXB7/mut). SiHa cells were serially transfected with: a) miR-196b pre-miR or negative control pre-miR, and b) pMIR-HOXB7/UTR or pMIR-HOXB7/mut, and luciferase activity was measured 24 hours later. To determine the effect of knocking down HOXB7, SiHa cells were transfected with siHOXB7 (Qiagen).
Results: Twenty-seven miRs were observed to be downregulated in all three cell lines compared to normal cervix. One of the 27 downregulated miRs, miR-196b, was shown to inhibit cell growth and colony-forming ability when overexpressed in SiHa cells. HOXB7 was identified as one of the candidate targets of miR-196b using our tri-pronged approach. Knocking down HOXB7 recapitulated the inhibition in cell growth and clonogenicity that was observed following mir-196b overexpression. When the luciferase reporter assay was performed, miR-196b overexpression resulted in a significant reduction in luciferase activity in cells transfected with pMIR-HOXB7/UTR, but not in cells transfected with pMIR-HOXB7/mut, demonstrating direct and specific binding of miR-196b to the 3’ UTR of HOXB7.
Conclusion: miR-196b is downregulated in cervical cancer and negatively regulates HOXB7.
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 2059.
Abstract 207: Distinct TRAIL resistance mechanisms can be overcome by proteosome inhibition
Authors: Menke Christina R. , Bin Lianghua , Thorburn Jacqueline , Behbakht Kian , Ford Heide , Thorburn Andrew 
Published: February 2011

Abstract
A major impediment to the use of Tumor Necrosis Factor-Like Apoptosis Inducing Ligand (TRAIL) Receptor targeted drugs is that many tumors evolve resistance to these agents. On the other hand however, multiple different kinds of drugs are reported to be able to synergize with TRAIL. This raises the question of whether it is possible to overcome resistance using the same drugs that cause synergy. We tested this idea by creating a series of isogenic tumor cells with acquired TRAIL resistance or defined mechanisms of resistance that are known to occur in human tumors then compared these cells to the TRAIL-sensitive parental cell line. Although diverse classes of anti-cancer drug were all able to synergize with TRAIL most of these agents were unable to overcome resistance and there was no correlation between the amount of synergy that is seen with a particular agent and its ability to overcome acquired resistance. Proteosome inhibitors were however able to overcome diverse resistance mechanisms suggesting that one should select drugs for TRAIL R agonist combination therapy based not just on their ability to synergize but rather on their ability to both overcome resistance and synergy.
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 207.
Abstract 2070: Mir-199a is downregulated in hypoxia and targets HIF1α in ovarian cancer cells
Authors: Joshi Hemant , Subramanian Indira , Ghosh Goutam , Zeng Yan , Zhao Min , Ramakrishnan Sundaram 
Published: February 2011

Abstract
HIF1 is the main transcriptional regulator of the hypoxic response in mammalian cells and plays an important role in the adaptation of tumor cells to hypoxic microenvironments. While normally degraded under normoxic conditions via oxygen-dependent, ubiquitin-based mechanisms, HIF1α protein, which, with the constitutively expressed HIF1β forms the HIF1 heterodimer, is stabilized in hypoxic tumor cells. Stabilization of HIF1α protein under hypoxia leads to transactivation of a variety of angiogenic and tumorigenic genes including VEGF and matrix metalloproteinase 2. Clinically, high levels of HIF1 in tumors translate to increased patient morbidity and mortality. Our studies show that HIF1α, in addition to being regulated at the protein level, is also directly regulated by microRNAs, small 20-22 base ribonucleotides that specifically bind to the 3’ untranslated regions (UTRs) of target mRNA to inhibit translation or induce degradation. Based on bioinformatics and microRNA-target databases, we determined that HIF1α contains a potential binding site in its 3’ UTR for mir-199a, which, based on our microarray and RT-qPCR data, is significantly downregulated in hypoxic ovarian cancer cells compared to normoxia. Using a luciferase reporter construct in which luciferase expression is under control of the HIF1α 3’ UTR, we showed that overexpression of mir-199a in A2780 or MA148 cells leads to suppression of the luciferase signal. Mutation of the mir-199a binding site in the HIF1α 3’ UTR resulted in no change in luciferase signal with mir-199a overexpression, indicating that mir-199a directly targets the HIF1α 3’ UTR. Furthermore, decreasing mir-199a levels, either by incubating cells in hypoxia or using a morpholino specifically targeting mir-199a, leads to increased levels of HIF1α protein as determined by western blot and increased transcripts of HIF1-activated genes such as VEGF as measured by RT-qPCR. Conversely, overexpression of mir-199a leads to decreased HIF1α protein and VEGF transcript levels. Together, our findings have significant implications in the study of HIF1α regulation in cancers. Mir-199a may have a role in future therapeutic strategies to modulate the tumor microenvironment to limit hypoxia-driven tumor progression and metastasis.
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 2070.
Abstract 2075: MicroRNA-21 expression levels are accompanied by respective alterations in pdcd4 protein levels in non-small cell lung cancer
Authors: Sourvinou Ioanna S. , Markou Athina , Kaklamanis Loukas , Tsaroucha Emily G. , Ozaki Iwata , Matsuhashi Sachiko , Lianidou Evi S. 
Published: February 2011

Abstract
Introduction: MicroRNA-21 is a well characterized cancer associated miRNA as it has been found overexpressed in nine types of solid tumors and in other malignancies. The role of miR-21 is related with diverse carcinogenesis processes. The downregulation of tumor suppressor genes through the overexpression of miR-21 has been demonstrated for PTEN and TPM1. Very recently, it was revealed that programmed cell death 4 (PDCD4) is another target of miR-21 in colon and breast cancer cell lines. As it has not been yet studied the correlation between miR-21 and PDCD4 levels in clinical samples, we conducted the present study to investigate the possible regulation of pdcd4 protein levels by mature miR-21.
Materials and Methods: Forty pairs of NSCLC fresh-frozen tissues and their corresponding noncancerous tissues were analyzed for the expression of mature miR-21 using quantitative real-time RT-PCR, as previously described (Markou et al., 2008). In parallel, PDCD4 protein levels were evaluated by immunohistochemistry. Deparaffinized sections cut from paraffin-embedded tissue samples were stained with a specific anti-PDCD4 antibody (1:100 dilution) (Ozaki et al., 2006) using HRP DAB kit (DAKO) for the detection. The tumor types and stages were determined according to the WHO classification. All samples were analyzed histologically to access the amount of tumor component (at least 70% of tumor cells) and the quality of material.
Results: Among the 40 NSCLC tissue specimens studied, suppresion of miR-21, in respect to their adjacent non-neoplastic tissues, was detected in 24 samples (60 %). In 15 out of these 24 patients (62.5%), we observed that the supression of miR-21 was accompanied by increase of PDCD4 protein levels. Mature miR-21 was overexpressed in 16 out of 40 patients (40%), and in 8 out of these 16 patients (50%) we detected reduced PDCD4 protein levels. Totally, in 23 out of 40 samples (57.5%), the altered miR-21 expression levels correlated with changed PDCD4 protein levels.
Conclusion: Our data indicate for the first time that PDCD4 protein expression levels are regulated by miR-21 in non small cell lung cancer tissues.
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 2075.