bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2291: Oncogenic hsa-miR-1323 down-regulates MYCN/ALK and reveals PAG1 as a novel tumor suppressor for neuroblastoma
Authors: Ghosh Rajib , Chen Zaowen , Patterson Danielle , Sikorski Denae N. , Kim Eugene S. , Shohet Jason M. , Gunaratne Preethi H. 
Published: August 2012

Abstract
MicroRNAs (miRNAs) are 22-24 nucleotides non-coding RNAs that can simultaneously influence the levels of multiple target genes and therefore have the potential to strongly silence cancer gene networks. MYCN and ALK are well established oncogenes implicated in the pathogenesis and progression of neuroblastoma. Using multiple web based algorithms we have identified potential tumor suppressor miRNAs that can control the pathogenesis and/or progression of neuroblastoma by down-regulating both MYCN and ALK. We found hsa-miR-1323 as a candidate tumor suppressor for neuroblastoma. Lipofectamine based mimic transfection and lentiviral vector based over-expression of miR-1323 in cell lines led to a decrease in MYCN and ALK transcripts as well as signals from luciferase reporter constructs carrying the 3′-UTR of MYCN or ALK validating MYCN and ALK as direct targets of miR-1323. However, unexpectedly for this predicted tumor suppressor microRNA, gain of function studies for miR-1323 in neuroblastoma cell lines demonstrated increased proliferation, colony formation and tumor growth of orthotopic xenograft tumors. As SiRNA against MYCN strongly limits neuroblastoma proliferation, our data suggests that miR-1323 targets an alternative tumor suppressor pathway which by-passes the growth suppressive effects of MYCN inhibition and drives proliferation. Further bio-informatics analysis of putative miR-1323 targets pointed to PAG1 (or Cbp) as a possible tumor suppressor target of miR-1323. The transmembrane adaptor protein PAG1 inhibits proliferation driven by the Src family of kinases (SFKs) through multiple mechanisms and is a known tumor suppressor in leukemia and non-small cell lung cancers. Importantly, analysis of PAG1 in clinical cohorts of neuroblastoma reveals that low expression of PAG1 strongly correlates with poor overall survival compared to patients with high levels of PAG1 expression (p &lt;0.001). We have confirmed that miR-1323 targets PAG1 transcript via qRT-PCR assays, and this is associated with increased p-ERK levels in neuroblastoma cell lines. We therefore propose that miR-1323 mediated repression of PAG1 activates the Src-dependent oncogenic pathways, overriding its effect on MYCN or ALK, and contributing to the aggressive clinical behavior of high-risk neuroblastoma. These studies further demonstrate the complexity of microRNA functions in normal and cancer cells and mandate careful evaluation of putative ‘tumor suppressive’ microRNAs as therapeutic tools.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2291. doi:1538-7445.AM2012-2291
Abstract 2292: Tumor suppressive miR-124 targets androgen receptor and inhibits proliferation of prostate cancer cells
Authors: Shi Xu-Bao , Xue Lingru , Tepper Clifford G. , White Ralph W. deVere 
Published: August 2012

Abstract
Recent studies have revealed that miR-124 functions as a tumor suppressor and is downregulated in several types of human cancer. Until now, however, whether miR-124 is involved in prostate cancer (CaP) is totally unknown. In order to explore the role of miR-124 in CaP, we detected the expression level of miR-124 in prostate cell lines and clinical prostatic tissues using qPCR, and observed a reduced expression of miR-124 in all malignant cell lines tested and in a majority of clinical CaP samples examined, compared to that in the benign cell lines and in benign prostatic hyperplasia (BPH), suggesting that miR-124 is a putative tumor suppressor gene. Since the 3′UTR of androgen receptor (AR) mRNA contains a broadly conserved miR-124-binding site, experiments were performed to validate miR-124-mediated regulation of AR. We found that transfection of synthetic miR-124 mimic (miR-124m) downregulated the AR protein level and its downsteam effectors PSA and miR-125b. To verify that the miR-124 binding site is responsible for regulation by miR-124, the AR 3β UTR was cloned into the pRIM Reporter-luciferase vector, and cotransfected with miR-124m into CaP cells. We observed that transfection of miR-124m resulted in 40% reduction of luciferase activity, indicating a direct interaction between miR-124 and AR mRNA. We then examined whether clinical CaP samples having low level of miR-124 overexpress the AR using IHC analysis, and found a reverse correlation between miR-124 and AR expression levels in 7 of 8 CaP samples. These data suggest that miR-124 targets the AR and down-regulation of miR-124 results in increased expression of the AR in CaP cells. In addition, we tested whether miR-124 inhibits the growth of CaP cells, and found that treatment with miR-124m induced significant inhibition of cell proliferation compared to treatment with miR-NC control. We also evaluated the effect of miR-124 on tumorigenesis of 22Rv1 CaP cells that were transiently transfected with miR-124m. We observed that tumors derived from miR-124-transfected 22Rv1 cells grew substantially slowly, when compared to miR-NC tumors. Taken together, our data suggest that miR-124 is a potential tumor suppressor gene in CaP, and restoration of miR-124 expression may represent a novel therapeutic strategy in CaP therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2292. doi:1538-7445.AM2012-2292
Abstract 2293: MicroRNA-1826 targets VEGFC, beta-catenin (CTNNB1) and MEK1 (MAP2K1) in human bladder cancer.
Authors: Hirata Hiroshi , Hinoda Yuji , Ueno Koji , Shahryari Varahram , Tabatabai Z. Laura , Dahiya Rajvir 
Published: August 2012

Abstract
Introduction and Objective: The Wnt/beta-catenin (CTNNB1) and Ras-Raf-MEK-ERK signaling pathway play an important role in bladder cancer progression. Tumor suppressive miRNAs targeting these cancer pathways may provide a new therapeutic approach for bladder cancer. Methods: We initially identified miRNA-1826 potentially targeting CTNNB1, VEGFC, MEK1 using several target scan algorithms. The expression of miR-1826 was confirmed in bladder cancer tissues and bladder cancer cell lines. Then we performed several functional analyses of miR-1826. Finally 3′UTR luciferase assay and Western blot were performed to look at relationship between miR-1826 and target genes. Results: MiR-1826 expression was significantly lower in bladder cancer tissues and bladder cancer cell lines (J82, T24, TCC-SUP) compared to normal bladder tissues and normal bladder cell lines (SV-HUC-1). The expression of miR-1826 was lower in bladder cancer tissues and inverse correlation of miR-1826 with several clinical parameters (pT, grade) was observed. The functional analyses showed that miR-1826 inhibited bladder cancer cell viability, invasion and migration. Also we also found increased apoptosis and G1 cell cycle arrest in miR-1826 transfected bladder cancer cells. 3′UTR luciferase activity and protein expression of these target genes (CTNNB1, MEK1, VEGFC) were significantly down-regulated in miR-1826 transfected bladder cancer cells (J82, T24). To examine whether the effect of miR-1826 was through CTNNB1 (beta-catenin) or MEK1 knock down, we knocked down CTNNB1/MEK1 mRNA using a si-RNA technique. We observed that CTNNB1 or MEK1 siRNA knockdown resulted in effects similar to those with miR-1826 in bladder cancer cells. Conclusions: Our data suggests that the miR-1826 plays an important role as tumor suppressor via CTNNB1/MEK1/VEGFC down-regulation in bladder cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2293. doi:1538-7445.AM2012-2293
Abstract 2296: Aldose reductase inhibition prevents human colon cancer cells growth by miR-21 and FOXO3a-mediated regulation of PTEN
Authors: Srivastava Satish K. , Saxena Ashish , Ramana Kota V. 
Published: August 2012

Abstract
We have shown earlier that the inhibition of aldose reductase (AR), a NADPH-dependent aldo-keto reductase, prevents growth factor-induced proliferation of colon cancer cells in vitro and in vivo. Recent studies indicate that changes in microRNA (miRNA) expression can contribute to cancer by modulating the functional expression of critical genes involved in cancer growth and metastasis. However, the molecular mechanism(s) by which AR regulates miRNA expression and their dependent mitogenic effects in cancer cells is not known. Therefore, we investigated how AR regulates growth factor -induced expression of miRNAs in colon cancer cells. Our results indicate that inhibition of AR significantly down-regulated growth factor-induced miR-21 expression in HT29, SW480 and Caco-2 human colon cancer cells. Further, AR inhibition also increased PTEN, a direct target of miR-21 that contributes cancer cell growth and invasion. Inhibition of AR also prevented the EGF-induced phosphorylation of PTEN and FOXO3a, which prevents cell proliferation. Treatment of human colon cancer cells with AR inhibitor, fidarestat, prevented the EGF-induced DNA binding activity of AP1, phosphorylation of PI3K, AKT, c-Jun and c-Fos. More importantly, in HT29 human colon adenocarcinoma xenograft tissues, miR-21 expression was lower, and PTEN and FOXO3a levels were significantly higher in AR inhibitor-treated mice compared to controls. Collectively, these results show a novel role of AR in mediation of growth factor-induced colon cancer cell proliferation by increasing miR-21 expression and inactivating or decreasing PTEN and FOXO3a through the ROS/PI3K/AKT/AP1 pathway, indicating that AR inhibitors could be used for the prevention/therapy of colon carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2296. doi:1538-7445.AM2012-2296
Abstract 2297: MicroRNAs inhibit breast canncer metastasis via targeting CXC chemokine receptor 4
Authors: Liang Zhongxing , Huang Ke , Hong Samuel , Ahn Jeffrey , Shim Hyunsuk 
Published: August 2012

Abstract
Overexpressed CXC chemokine receptor (CXCR4) strongly contributes to breast cancer metastasis. However, the underlying mechanisms of CXCR4 overexpression need still to be explored. MicroRNAs (miRNA) have been implicated as a class of critical regulators controlling diverse biological processes. In the present study, we investigated whether miR-302 and miR-588 are involved in the regulation of CXCR4 and play a functional role in breast cancer metastasis. We have shown that miR-302 and miR-588 were downregulated in highly metastatic breast cancer cell lines and tissue specimens compared to low metastatic cell lines and breast cancer tissues. The decreased expression levels were inversely consistent with overexpression of CXCR4 in highly breast cancer cell lines and tissues. In addition, we found that restoration of miR-302 and miR-588 resulted in a dramatic reduction of CXCR4 expression at protein levels by directly targeting its 3′ untranslated region. Furthermore, the elevated expression of miR-302 and miR-588 significantly inhibited the invasion of breast cancer cells. More promisingly, our data have demonstrated that overexpression of miR-302 reduced metastasis and growth of breast cancer in vivo. Our findings describe a new mechanism for the regulation of CXCR4 and metastasis of breast cancer. The newly characterized miR-302/588/CXCR4 link provides potential molecular markers for predicting breast cancer metastasis. MiR-302 and miR-588 may have a therapeutic potential to suppress breast cancer metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2297. doi:1538-7445.AM2012-2297
Abstract 2298: MiR-23a regulates TGF-β-induced epithelial-mesenchymal transition by targeting E-cadherin in pulmonary epithelium cells
Authors: Seike Masahiro , Mengru Cao , Soeno Chie , Noro Rintaro , Minegishi Yuji , Yoshimura Akinobu , Gemma Akihiko 
Published: August 2012

Abstract
Transforming growth factor-β (TGF-β)-induced epithelial-mesenchymal transition (EMT) has been reported to be related to pathogenesis of various diseases including lung cancer and idiopathic pulmonary fibrosis (IPF). Recently, microRNAs (miRNA) have been recognized as a new class of genes involved in human tumorigenesis. MiR-23a/24/27a is a miRNA cluster located in chromosome 19p13.12, which can function as an oncogene in several human cancers. In this study, we analyzed miR-23a/24/27a expression in 10 non-small cell cancer (NSCLC) cell lines by real-time PCR analysis. Correlation between expression of these miRNAs and TGF-β/Smad signaling was evaluated. We found that miR-23a could be regulated by TGF-β1 in a Smad-dependent manner in A549 lung adenocarcinoma cells originated by type II pneumocyte showing the EMT phenomenon. Knockdown of miR-23a partially restored E-cadherin expression under the condition of TGF-β1 stimulation. In contrast, overexpression of miR-23a could suppress E-cadherin expression and stimulate EMT. Furthermore, A549 cells with overexpressed miR-23a were more resistant to gefitinib than the parental cells. These findings suggested that miR-23a regulates TGF-β-induced EMT by targeting E-cadherin in pulmonary epithelium cells and may be useful as a new therapeutic target in pulmonary diseases including NSCLC and IPF.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2298. doi:1538-7445.AM2012-2298
Abstract 2299: Genistein suppresses prostate cancer growth through inhibition of oncogenic miR-151
Authors: Chiyomaru Takeshi , Zaman Mohd Saif , Majid Shahana , Deng Guoren , Yamamura Soichiro , Shahryari Varahram , Saini Sharanjot , Hirata Hiroshi , Ueno Koji , Chang Inik , Tanaka Yuichiro , Enikida Hideki , Nakagawa Masayuki , Dahiya Rajvir 
Published: August 2012

Abstract
Introduction and Objective: Genistein has been shown to suppress the growth of several cancer cell lines in vitro and in vivo, reducing the expression of several oncogenic microRNAs. However, the effects of genistein on the regulation of oncogenic miR-151 have not been reported. In this study, we investigated whether genistein could alter the expression of oncogenic miR-151 and its target genes that are involved in the progression and metastasis of prostate cancer. Methods: The expression levels of miR-151 were analyzed by TaqMan quantitative real-time PCR and normalized to RNU48. Nineteen clinical specimens were obtained from patients at the San Francisco Veterans Affairs Medical Center from 2000 to 2006. For gain-and loss-of-function assay, cell proliferation (MTS assay), migration (wound healing assay), and invasion (matrigel invasion assay) were evaluated in human prostate cancer cell lines, PC3 and DU145. Predicted target genes and their target microRNA binding site seed regions were investigated using TargetScan and microRNA.org. Genistein was administered every day along with a change of medium, and the cells were grown for four days. Results: Real-time RT-PCR showed that the expression of miR-151 was higher in PC3 and DU145 cells compared with RWPE-1 cells. Treatment of PC3 and DU145 cells with 25 μM genistein down-regulated the expression of miR-151 compared with vehicle control. Kaplan-Meier curves and log-rank tests revealed that high expression levels of miR-151 had a significant adverse effect on survival rate. Inhibition of miR-151 in prostate cancer cells by genistein significantly inhibited cell migration and invasion. By in-cilico analysis, several genes (N4BP1, CASZ1, IL1RAPL1, LGI1, SOX17 and TOM1L1) that are suggested to have tumor suppressive function in several types of cancers were detected as candidate target genes of miR-151. Conclusions: We demonstrated that genistein down-regulated miR-151 that functions as an oncogenic miRNA in prostate cancer. This study suggests that genistein mediated suppression of oncogenic miRNAs can be an important dietary therapeutic strategy for the treatment of prostate cancer. Source of Funding: Grants R01CA160079-01, R01CA138642, VA Research Enhancement Award Program (REAP), and VA Merit Review grants
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2299. doi:1538-7445.AM2012-2299
Abstract 230: A novel quantitative phosphoproteomic approach in mouse xenograft models to identify Src oncogenic signaling in colorectal cancer
Authors: Sirvent Audrey , Urbach Serge , Roche Serge 
Published: August 2012

Abstract
The non receptor tyrosine kinase (TyrK) Src mediates signal transduction induced by growth factors and integrins. Src also exhibits oncogenic activity when deregulated, a situation frequently observed in colorectal cancer (CRC). Moreover, the extent of kinase deregulation often correlates with malignant potential, in agreement with an important role Src in this tumorigenic process. However, the exact role of Src in CRC is only partially elucidated. Src has been implicated in growth and invasiveness of various CRC cells. A previous SILAC quantitative phosphoproteomic analysis allowed the characterization of Src signaling leading to CRC cells growth and invasion (Leroy et al, Cancer Res, 2009, 15:2279-86). Interestingly, Src also increased tumor growth in nude mice engraft with human SW620 CRC cells. This biological effect correlated with a strong increase of tyrosine phosphorylation (pTyr) content in Src-positive tumors. Here, we wished to characterize Src oncogenic signaling in these xenograft tumor models. To this end, we have developed an innovative quantitative phosphoproteomic analysis coupled to stable isotope labeling in mice named SILAX for Stable Isotope Labeling in mouse Xenografts. This method is based on tumor heavy isotope labeling in nude mice by addition of [13C]-Lysine into the food. An incorporation level &gt;87% was obtained in subcutaneous tumors after 30 days of heavy lysine diet. This approach allowed the identification of 61 proteins which exhibited a significant increase in and/or association with pTyr upon Src expression in tumors. These mainly include vesicular trafficking, signaling and RNA binding proteins. Interestingly, we identified the novel vesicular trafficking protein TOM1L1 (Franco et al, Mol Cell Biol, 2006, 26:1932-47) as a specific regulator of Src oncogenic signaling of CRC cells in vivo. While TOM1L1 depletion poorly affected Src-induced CRC proliferation in vitro, it significantly inhibited tumor growth in nude mice. This data suggests that vesicular trafficking plays an important role in Src-induced CRC tumor growth and validate SILAX as a valuable approach to decipher TyrK signaling in mouse xenograft models.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 230. doi:1538-7445.AM2012-230
Abstract 2302: Epigenetic activation of miR-200a targets the Nrf2-dependent chemoprevention pathway in breast cancer
Authors: Zhou Qun , Yao Yuan , Gabriel Eades 
Published: August 2012

Abstract
NF-E2-related factor 2 (Nrf2) is an important transcription factor that activates the expression of cellular detoxifying enzymes. Nrf2 expression is largely regulated through Nrf2 association with Kelch-like ECH-associated protein 1 (Keap1), which results in cytoplasmic Nrf2 degradation. Conversely, little is known concerning the regulation of Keap1 expression. Until now, a regulatory role for microRNAs (miRs) in controlling Keap1 gene expression had not been characterized. By using miR array-based screening, we observed miR-200a silencing in breast cancer cells and demonstrated that upon re-expression, miR-200a targets the Keap1 3′ untranslated region (3′UTR) leading to Keap1 mRNA degradation. Loss of this regulatory mechanism may contribute to the dysregulation of Nrf2 activity in breast cancer. Previously, we have identified epigenetic repression of miR-200a in breast cancer cells. Here, we find that treatment with epigenetic therapy, the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA), restored miR-200a expression and reduced Keap1 levels. This reduction in Keap1 levels corresponded with Nrf2 nuclear translocation and activation of Nrf2-dependent NAD(P)H-quinone oxidoreductase 1 (NQO1) gene transcription. Moreover, we found that Nrf2 activation inhibited the anchorage-independent growth of breast cancer cells. Finally, our in vitro observations were confirmed in a model of carcinogen-induced mammary hyperplasia in vivo. In conclusion, our study demonstrates that miR-200a regulates the Keap1/Nrf2 pathway in mammary epithelium and we find that epigenetic therapy can restore miR-200a regulation of Keap1 expression, therefore re-activating the Nrf2-dependent antioxidant pathway in breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2302. doi:1538-7445.AM2012-2302
Abstract 2307: MiR-365 regulates lung cancer and developmental gene TTF-1
Authors: Qi Ji , Rice Shawn J. , Salzberg Anna C. , Runkle Aaron , Liao Jason , Zander Dani S. , Mu David 
Published: August 2012

Abstract
Thyroid transcription factor 1 (TTF-1 or NKX2-1) is an essential fetal lung developmental factor which can be recurrently activated by gene amplification in adult lung cancer. We have discovered the first microRNA (i.e., miR-365) that directly regulates TTF-1 by interacting with its 3′-untranslated region. The finding that miR-365 is expressed in tissues beyond TTF-1 expression suggests the existence of other targets, which was substantiated by a subsequent gene expression profiling assay. In line with the microRNA/target relationship, the expression patterns of miR-365 and TTF-1 were in an inverse relationship in human lung cancer. Exploration of human lung cancer genomics data uncovered that TTF-1 gene amplification was significantly associated with DNA copy number loss at one of the two genomic loci encoding the precursor RNA of mature miR-365 (i.e., mir-365-1). This implies the existence of genetic selection pressure to lose the repressive miR-365 that would otherwise suppress amplified TTF-1. In studying how this microRNA/target relationship affects TTF-1 function in transforming growth factor beta-induced epithelial to mesenchymal transition (EMT), we detected a signaling loop between TGFbeta and miR-365 and this loop reinforced suppression of TTF-1 via miR-365. Surprisingly, mir-365 also targeted an EMT-promoting gene HMGA2, which may at least in part explain the difficulty for detection of EMT related phenotypes associated with miR-365. In summary, these data connect the lung transcriptional program to the microRNA network.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2307. doi:1538-7445.AM2012-2307