bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2080: miR-124 and miR-203 are epigenetically silenced tumor-suppressive microRNAs in hepatocellular carcinoma
Authors: Furuta Mayuko , Kozaki Ken-ichi , Tanaka Shinji , Arii Shigeki , Imoto Issei , Inazawa Johji 
Published: February 2011

Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNAs that, in general, negatively regulate gene expression. They have been identified in various tumor types, showing that different sets of miRNAs are usually deregulated in different cancers. Some miRNA genes harboring CpG-islands undergo methylation-mediated silencing, a characteristic of many tumor-suppressor genes. To identify such miRNAs in hepatocellular carcinoma (HCC), we first examined the methylation status of 43 loci containing CpG-islands around 39 mature miRNA genes in a panel of HCC cell lines and non-cancerous liver tissues as controls. Among 11 miRNA genes frequently methylated in HCC cell lines but not in non-cancerous liver tissues, 3 miRNA genes, i.e. miR-124, miR-203, and miR-375, were selected as silenced miRNAs through CpG-island methylation by comparing methylation and expression status and evaluating restored expression after treatment with 5-aza-2′-deoxycytidine. In primary tumors of HCC with paired non-tumorous liver tissues, only miR-124 and miR-203 showed frequent tumor-specific methylation, and their expression status was inversely correlated with methylation status. Ectopic expression of miR-124 or miR-203 in HCC cells lacking their expression inhibited cell growth, with direct down-regulation of possible targets, cyclin-dependent kinase 6 (CDK6), vimentin (VIM), SET and MYND domain containing 3 (SMYD3), and IQ motif containing GTPase activating protein 1 (IQGAP1) or ATP-binding cassette, sub-family E, member 1 (ABCE1), respectively. Our results suggest that miR-124 and miR-203 are novel tumor-suppressive miRNAs for HCC epigenetically silenced and activating multiple targets during hepatocarcinogenesis.
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 2080.
Abstract 2089: MiR-205 role in triple negative breast cancer
Authors: Iorio Marilena V. , Piovan Claudia , Leva Gianpiero Di , Casalini Patrizia , Tortoreto Monica , Plantamura Ilaria , Taccioli Cristian , Croce Carlo M. , Tagliabue Elda 
Published: February 2011

Abstract
An increasing number of experimental evidences show that microRNAs can have a causal role in breast cancer tumorigenesis as a novel class of oncogenes or tumor suppressor genes, depending on the targets they regulate. miR-205, down-modulated in breast cancer versus normal breast tissue, was originally associated to absence of vascular invasion and shown to be involved in the EMT. Moreover, we recently demonstrated that miR-205 directly targets HER3 receptor and impairs the Akt-mediated survival pathway, thus inhibiting clonogenic potential of SKBr3 cells and increasing the responsiveness to tyrosin-kinase inhibitors.
Considering the striking evidences of a major role of miR-205 as oncosuppressor in breast cancer, we decided to investigate its possible involvement in another tumor subgroup, extremely aggressive and still lacking a specific therapy: triple negative breast tumors. Here we show that re-introduction of miR-205 in the triple negative breast cancer cell line MDA-MB-231 led to a dramatic reduction of both proliferation and clonogenic potential as well as migration capability. Notably, miR-205 also significantly inhibited the in vivo growth in xenograft models obtained injecting stable clones of MDA-MB-231 cells transfected with a miR-205-encoding plasmid or the empty vector.
Investigating alternative pathways potentially regulated by miR-205 in this model, we noticed that many of the predicted targets are actually interconnected and related to adhesion and migration processes. Indeed, this microRNA seems to be involved in the control of cell-cell and cell-matrix adhesion regulating the expression of extracellular matrix-related molecules. Among them, we focused on LAMC1, reported to be involved in cell adhesion, differentiation, migration, signaling and metastasis. By Western Blot and Luciferase assay, we demonstrated that miR-205 directly targets LAMC1 in MDA-MB-231 cells.
In conclusion, miR-205 exerts a role as oncosuppressor gene also in triple negative breast cancer: it exerts a dramatic inhibition of proliferation and migration in triple negative MDA-MB-231 cell line, at least partially through direct regulation of LAMC1. These evidences not only underline the consistent role of miR-205 in the biology of different breast cancer subgroups, but provide the rational bases for a therapeutic intervention miRs-based.
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 2089.
Abstract 2091: MiR-145 functions as a potential tumor suppressor in hepatocellular carcinoma
Authors: LAW Priscilla TY , Ching Arthur KK , Wong Queenie WL , Lai Paul BS , Wong Nathalie 
Published: February 2011

Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The pathogenesis of HCC has been associated with various genetic and epigenetic alterations, including microRNA dysregulation. In defining the differentially expressed miRNAs in HCC, we previously reported on HCC-specific microRNA deregulations by array-based profiling, which revealed common down-regulations of miR-145. Subsequent verification of miR-145 expression in an independent cohort of 72 HCC cases by qRT-PCR corroborated significant down-regulations in tumors compared to their non-malignant counterparts (49%; paired t-test p=0.026). Transfection of miR-145 into HCC cell lines, HKCI-C2 and HKCI-9, showed a consistent inhibitory effect on both cell viability and proliferation as indicated by MTT and colony formation assays. Flow cytometric analysis on HKCI-C2 further indicated that miR-145 could induce G2/M cell cycle arrest and increase apoptosis. MiR-145 has been shown to target insulin receptor substrate 1 (IRS1) in colorectal cancer. It is known that IRS1 is a substrate of insulin-like growth factor receptor (IGF-1R) in the IGF signaling pathway. In-silico prediction by Targetscan, miRNAda and RNAhybrid suggested that miR-145 might also target IGF-1R and IRS2 along the IGF axis. The effects of miR-145 on these IGF components were hence investigated. Our results from Western blot indicated that IRS1 expression was down-regulated in the presence of miR-145, suggesting that it might also be a target of miR-145 in HCC. Taken together, we found that miR-145 could induce cell cycle arrest and apoptosis in HCC cells, possibly through its effect on IRS1. This study reveals for the first time that miR-145 may act as a tumor suppressor in the liver tumorigenesis.
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 2091.
Abstract 2093: Functional screening of tumor-suppressive microRNAs silenced by DNA hypermethylation in oral squamous cell carcinoma
Authors: Kozaki Ken-ichi , Uesugi Atsushi , Furuta Mayuko , Imoto Issei , Inazawa Johji 
Published: February 2011

Abstract
In human cancer, the DNA hypermethylation of CpG-sites located within CpG islands is one of important molecular mechanisms causing the down-regulation of microRNAs (miRNAs) in a similar manner to that demonstrated for classical tumor-suppressor genes. In this study, to identify tumor-suppressive miRNAs (TS-miRs) silenced by hypermethylation during oral carcinogenesis, we first performed function-based screening for TS-miRs in 327 miRNA in 2 oral squamous cell carcinoma (OSCC) cell lines with Pre-miR™ miRNA Precursor Library-Human V2. Remarkable growth inhibition was observed in 110 miRNAs (33.6%) as compared with precursor negative control, and 61 miRNAs of these miRNAs were localized around CpG-islands. Among these 61 miRNAs, we further analyzed DNA hypermethylation by combined bisulfite restriction analysis (COBRA) in 33 loci containing CpG-islands around 33 mature miRNAs, except 28 miRNAs which have been already reported as TS-miRs or targets for DNA methylation for silencing in cancer cells, resulting in identification of some miRNAs as the candidate TS-miRs silencing by CpG island hypermethylation. Expression levels of these candidate miRNAs were inversely correlated with their DNA methylation status, and were restored by treatment with 5-aza 2’-deoxycytidine in OSCC cells. Moreover, the ectopic transfection of these miRNAs into OSCC lines lacking their expressions significantly reduced cell growth. Taken together, our results clearly demonstrate that these candidates are TS-miRs epigenetically silenced during oral carcinogenesis.
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 2093.
Abstract 2095: The functional significance of microRNA-145 in prostate cancer
Authors: Zaman Mohd S. , Deng Guoren , Shahryari Varahram , Suh Seong O. , Chen Yi , Tanaka Yuichiro , Dahiya Rajvir 
Published: February 2011

Abstract
MicroRNAs are small noncoding RNAs that play important roles in numerous cellular processes including development, proliferation, and apoptosis. Recent studies have demonstrated aberrant expression of miRNAs in prostate cancer tissues and cell lines. miRNAs microarray data, showed that miR-145 is down-regulated in prostate cancer. Therefore, we investigated the expression and functional significance of miR-145 in prostate cancer. The expression of miR-145 was found to be low in all of the prostate cell lines tested (PC3, LNCaP and DU145). The level of miR-145 expression in adjacent normal regions was found to be significantly higher as compared to the matched cancerous regions. Over expression of miR-145 in PC3 transfected cells resulted in a significant increase in apoptosis and an increase in cells in the G2/M phase, as detected by flow cytometry. Our results also show that methylation of the promoter region of miR-145 in cell lines and carcinoma samples as one of the reasons for its low expression. To identify potential targets for miR-145, we performed microarray analyses in miR-145 over-expressing PC3 cells and observed up regulation of the pro apoptotic gene TNFsf10 which was confirmed by real-time PCR and Western analysis. This is the first report to show that miR-145 acts as a tumor suppressor in prostate cancer through cell cycle arrest and induction of apoptosis. Since a major target for miR-145 is the pro apoptotic TNFsf10 gene, modulation of miR-145 may provide a therapeutic approach for the management of prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2095.
Abstract 2096: The role of microRNA-1 as a candidate tumor suppressor in cutaneous squamous cell carcinoma
Authors: Gable Dustin L. , Fleming Jessica L. , Toland Amanda Ewart 
Published: February 2011

Abstract
Cutaneous squamous cell carcinoma (SCC) is the second most common form of skin cancer, affecting over 250,000 people in the United States annually. Using miRNA expression arrays, we identified lower levels of microRNA-1 (miR-1) expression in skin from FVB/NJ mice, which are susceptible to chemically-induced skin cancer, compared to skin from Spr/EiJ mice, which are resistant to chemically-induced skin cancer. Additionally, murine SCC cell lines showed greatly reduced levels of miR-1 compared to normal skin. We hypothesize that decreased expression of miR-1 in susceptible mice and SCC cell lines suggests a possible role of miR-1 as a tumor suppressor in skin. To test this hypothesis, we transfected a precursor for miR-1 into a murine SCC cell line, A5, and measured proliferation and cell viability via an MTT assay at 24, 48, and 72 hours post-transfection. The growth rate for cells transfected with miR-1 was significantly decreased at 48 to 72 hours post-transfection relative to those mock-transfected cells and corresponded to miR-1 expression levels. These data are consistent with our hypothesis that miR-1 may act as a tumor suppressor in the skin. Using in silico prediction programs, we identified a number of putative targets of miR-1. The transcription factor oncogene, Ets1, emerged as an interesting potential direct target of miR-1. Ets1 has three predicted target binding sites for miR-1. Quantitative PCR and Western analyses revealed decreased Ets1 mRNA and protein expression in A5 cells transfected with miR-1 compared to mock-transfected A5 control cells. Ets1 mRNA expression is also decreased in a normal keratinocyte cell line, C5N, compared to A5 cells. From these experiments we showed that Ets1 expression shows an inverse correlation with miR-1 levels. These results suggest Ets1 is regulated by miR-1. Future studies will determine whether Ets1 is a direct target of miR-1. We will also clarify the role of Ets1 in SCC cell proliferation and migration and identify other tumor-related phenotypes associated with miR-1.
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 2096.
Abstract 2100: Down regulation of HOXD10 by microRNA-10b enhances proliferation of glioblastoma multiforme derived cell lines
Authors: Gaur Arti B. , Israel Mark A. 
Published: February 2011

Abstract
We sought to elucidate the role of a potentially oncogenic microRNA, microRNA-10b (mir-10b), in mediating the pathology of glioblastoma multiforme (GBM). MicroRNAs are small noncoding RNAs that play a critical role in developmental and physiological processes and are implicated in the pathogenesis of several human diseases including cancer. MicroRNAs function by regulating target gene expression post-transcriptionally. We have previously assessed the expression pattern of 241 mature human microRNAs in the NCI60 panel of cell lines and in a set of corresponding normal tissues (Gaur et al., 2007, Cancer Research. 67(6):2456-68). We found that microRNA expression patterns mark specific biological characteristics of tumors and/or mediate biological activities important for their pathobiology. In CNS tumor-derived cell lines, we identified mir-10b as a candidate oncogene, as it is expressed at higher levels in human GBM lines an primary GBM tissue than it is in normal brain tissue. Using several target prediction algorithms we identified a member of the homeobox family, Homeobox D10 (HOXD10), as a potential target of mir-10b. Our in vitro studies demonstrate that down regulation of mir-10b in GBM-derived cell lines results in increased expression levels of HOXD10. Additionally, our data indicate that down-regulation of mir-10b in human GBM lines leads to decreased proliferation and decreased anchorage independent colony formation in soft agar. Importantly, using a xenograft model in immune-deficient nude mice, we have observed human that GBM lines in which mir-10b expression is inhibited exhibit decreased tumor formation and growth in vivo. Furthermore, the decreased colony formation in soft agar observed as a result of mir-10b inhibition in GBM-derived cell lines is significantly antagonized by expression of siRNAs complementary to HOXD10 mRNA. Also, over expression of HOXD10 in GBM cell lines results in differentiation and decreased proliferation. Further experiments are ongoing to identify the specific role of HOXD10 in mediating the pathologic characteristics of GBM. An understanding of the pathways mediated by HOXD10 signaling may provide novel opportunities for therapeutic intervention. The National Brain Tumor Society (ABG) and the Theodora B. Betz Foundation (MAI) supported this work.
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 2100.
Abstract 2101: GBM: miR-34a acts as a tumor suppressor and prognosis maker as well as modulating EGFR
Authors: Yin Dong , Ogawa Seishi , Kawamata Norihiko , Thoennissen Nils H. , Chen Weikai , Leiter Amanda , Ham Michelle , Doan Ngan B B. , Said Jonathan W. , Black Keith L. , Koeffler H. Phillip 
Published: February 2011

Abstract
The whole genomic gene copy number was measured using single nucleotide polymorphism DNA microarray (SNP-Chip). Chromosome 1p36.23 was frequently deleted (19 of 55 clinical samples, 35 %) and EGFR was often amplified (35 of 55, clinical samples 66 %) in glioblastoma multiform (GBM). microRNA 34a (miR-34a) localizes in this minimum common deleted 1p36.23 region. We hypothesized that miR-34a may act as a tumor suppressor in the brain. Interestingly, we found that the mean survival time was significantly shorten (p &lt; 0.05) in the patients whose GBM showed both EGFR amplification and miR-34a deletion compared to those with either EGFR amplification, miR-34a deletion or normal levels of EGFR and miR-34a. Expression of miR-34a was significantly lower in GBM samples compared to normal brain tissue as examined using real-time RT PCR. Forced expression of miR-34a in GBM cell lines decreased their cell growth both in liquid culture and in immunodeficient mice; and the latter was associated with decreased angiogenesis. These cells also had decreased ability to migrate as detected by Boyden chamber and had profoundly low levels of cell cycle proteins (Cyclin -A1, -D1, -D3 and -B1, CDK2, as well as, E2F1, −3, and −4) and increased expression of cyclin kinase inhibitor (CKI) proteins, p21 and p27. Furthermore, the protein expression of EGFR was decreased in the cells with overexpression of miR-34a. Taken together, GBMs often acquire a miR-34a deletion and have low expression of this microRNA. The miR-34a probably normally acts as a tumor suppressor by inhibiting growth of GBM cells in vitro and in vivo associated with moderating the expression of cell cycle proteins and EGFR. Individuals whose GBM have both deletion of miR-34a and amplification of EGFR have a particularly poor prognosis.
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 2101.
Abstract 2105: miR-125b promotes the tumor growth of prostate cancer cells in intact and castrated male nude mice
Authors: Shi Xu-Bao , Xue Lingru , deVere White Ralph W. 
Published: February 2011

Abstract
Non-coding microRNAs (miRNAs) negatively regulate protein-coding genes, and aberrant expression of certain miRNAs has been reported to play a key role in the pathogenesis of human cancer including prostate cancer. Our previous studies have shown that miR-125b was highly expressed in a majority of clinical prostate cancer tissues we examined and ectopic expression of miR-125b stimulated the in vitro growth of LNCaP cells in the absence of androgens. In this study, we performed in vivo experiments to further determine whether this miRNA promotes prostatic xenograft growth. To this end, a miR-125b lentiviral vector (lenti-miR-125b) that expresses a ∼500-base pre-miR-125b was used to infect androgen-dependent PC-346C prostate cancer cells that have a limited ability to form tumors in intact nude mice and fail to grow in castrated nude mice. Quantitative RT-PCR exhibited a 39-fold increase in miR-125b level in lenti-miR-125b infected cells compared to that in lenti-vector control cells. The effect of miR-125b on xenograft tumor growth was then evaluated in intact and castrated male nude mice. After inoculation with lenti-miR-125b cells or control cells, tumors formed in all intact mice. However, the palpable lenti-miR-125b tumors appeared in approximately 7 days, while the vector control tumors took 15-20 days. The volume of xenograft tumor was markedly enlarged in all lenti-miR-125b mice compared to that in control mice. Surgery castration was performed when the tumor volume reached ∼0.5 cm3. Castratation resulted in temporary growth regression of miR-125b tumors followed by rapid growth of these tumors. To understand the molecular mechanism by which miR-125b promotes tumor growth in intact and castrated nude mice, xenograft tumors were examined by Western blot analyses of the expression of p53, Puma and Bak1 that have been validated to be the direct targets of miR-125b. Marked reduction of these three pro-apoptotic molecules was observed in miR-125b tumors compared to that in control tumors. Our data indicate that miR-125b acts as an oncogenic molecule, and overexpression of miR-125b stimulates the in vivo growth of prostate cancer cells as well as promotes the progression of prostate cancer cells to an androgen-independent status.
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 2105.