bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2065: DDX20 deficiency enhances NF-κB by impairing NF-κB suppressive-microRNA function and leads to hepatocarcinogenesis
Authors: Takata Akemi , Otsuka Motoyuki , Kudo Yotaro , Kojima Kentaro , Maeda Shin , Tateishi Keisuke , Ikenoue Tsuneo , Ijichi Hideaki , Hirata Yoshihiro , Yoshida Haruhiko , Omata Masao , Koike Kazuhiko 
Published: February 2011

Abstract
Hepatocellular carcinoma is the third leading cause of cancer mortality worldwide, but the molecular mechanisms in tumorigenesis remain largely unknown. Here, we show that DDX20, a DEAD-box protein identified as a tumor suppressor in a recent comprehensive in vivo screening of murine liver cancer, might have a role in human hepatocellular oncogenesis through previously undefined mechanisms. DDX20 expression was frequently decreased in hepatocellular carcinoma cells compared with the hepatocytes in the noncancerous liver tissues from the same patient, as determined by immunohistochemistry using tissue arrays. DDX20-knockdown cells showed enhanced NF-κB activity and higher interleukin-6 expression, a cytokine known to be related to hepatocarcinogenesis. Our microRNA library screening revealed that several microRNAs expressed in hepatocytes, such as miR-140, normally suppress NF-κB activities. The deficiency of DDX20, a component of microRNA-containing ribonucleoprotein complexes, impaired microRNA function and this led to the impairment of the NF-κB-suppressive microRNA function, and consequently, enhanced NF-κB activity. These results indicate that DDX20 deficiency enhances NF-κB activity by impairing NF-κB-suppressive microRNA function and may contribute to hepatocarcinogenesis. “Functional impairment of microRNAs” identified here, induced by aberrant expression or functional abnormalities of the molecules involved in the microRNA pathway, may also be one of the mechanisms of oncogenesis even in other organs.
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 2065.
Abstract 2069: Combinatorial microRNA activity associated with breast cancer metastasis is revealed through computational analysis of target genes and pathways
Authors: Dombkowski Alan A. , Sultana Zakia , Jamil Hasan , Craig Douglas 
Published: February 2011

Abstract
A recent report identified six microRNAs with repressed expression in highly metastatic MDA-MB-231 breast cancer cell derivatives (miRs 335, 126, 206, 122a, 199a*, and 489). Expression of all six miRs was consistently decreased in cells that produced aggressive lung and bone metastases, as compared to parental cells, indicating that metastatic colonization is exacerbated by the concurrent loss of multiple miRs from this set. With the hypothesis that target genes involved in metastatic progression are regulated by cooperative activity of these six microRNAs, we performed a computational analysis to identify transcripts having multiple binding sites targeted by the collective set of miRs. Using miR-AT!, a new web-based computational tool developed in our laboratory, we identified 767 target transcripts with multiple sites, and we characterized the biological processes and pathways associated with the target genes. Among cellular processes enriched with genes from this set are regulation of cell cycle, cytoskeleton organization, and regulation of cell adhesion. Importantly, perturbation of these processes was recently noted as a common feature among all metastatic tumors. We have identified subsets of the six miRs that are predicted to regulate the genes in each of these critical cellular processes. Additionally, we analyzed signaling pathways downstream of the collective set of target genes to identify key regulatory molecules where the networks converge. The top scoring nodes were cyclin D1 and c-myc, suggesting that dysregulation of target genes due to the collective loss of the microRNAs may have a focused effect on the activity of these two key genes. Access to miR-AT! is available at www.mir-at.org.
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 2069.
Abstract 2074: Association of MnSOD and microRNA-301a regulation with inhibition of pancreatic ductal adenocarcinoma
Authors: Li Yan , Li Xuanshe , Li Yong , Brown Russell E. , Schiffman Suzanne C. , Martin Robert C. 
Published: February 2011

Abstract
Background: Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. Manganese superoxide dismutase (MnSOD) has been found to be low in human pancreatic ductal adenocarcinoma (PDAC). Overexpressing MnSOD in PDAC has decreased growth rate of cancer cells. microRNAs, short 20-25 nucleotide RNA molecules, can function as oncogenes or as tumour suppressors. It has been shown that microRNA-301a is specifically up-regulated in PDAC specimen and inhibition of microRNA-301a has a decreased growth rate of PDAC cells. Aim: This study is to determine the relationship between the level of MnSOD and microRNA-301a regulation regarding the growth inhibition of PDAC. Methods: we carried out two experiments. A total of 60 PDAC specimens, along with 20 normal pancreatic tissues were obtained for immunohistochemistry (IHC) and in situ hybridization (ISH) studies to evaluate MnSOD and microRNA-301a expression. All pathology findings for the specimens were scored by two pathologists who were both blinded to the subjects. We also established a xenograft PDAC mouse model to study the growth rate in vivo. Nude BALB/C mice, 6 weeks old, were injected subcutaneously with 5×106 human PDAC (PanC-1 cells transfected with micro-301a antisence and control). Tumor-bearing animals were maintained for 8 weeks. Tumor growth was followed and tumor volume (TV) was determined using the standard formula, TV = (L xW2)/2. Results: There were significant decreases of MnSOD expression in PDAC specimens (1.5±0.06) compared to normal controls (2.5±0.07; p &lt; 0.05). microRNA-301a expression was significantly increased in PDAC specimens (0.85±0.046) compared to normal controls (0.1±0.05; p &lt; 0.05). The animal study findings indicated that microRNA-301a antisence transfection can significantly decrease the growth rate of inoculated PDAC cells. The decrease the growth rate is associated with the increased MnSOD levels (Fig 1) and decreased NF-kappaB expression. Conclusions: 1) MnSOD levels are negatively associated microRNA-301a expression in PDAC tissues; 2) increased levels of MnSOD are associated with microRNA-301a down-regulation and inhibition of PDAC.
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 2074.
Abstract 2076: Mammary stem cell-like miRNA expression and relation to cancer
Authors: Aydogdu Eylem , Helguero Luisa , Haldosen Lars-Arne , Williams Cecilia M. 
Published: February 2011

Abstract
Mammary stem cells are suggested to be the origin of breast cancer, but are elusive and vaguely characterized. Cancer may be sustained by cancer stem cells, that are resistant to common treatments like irradiation and chemotherapy.
To determine a possible association between mammary stem cells and breast cancer, we have previously made a detailed characterization of the transcriptome in murine mammary epithelial stem-like cell line (HC11) and made a thorough investigation of global gene-expression changes during stepwise differentiation using dual-color comparative microarray technique. Subsequently, we performed a cross-species comparison to reveal conserved gene expression between stem cells and subtype-specific and prognosis gene signatures. Our analysis provided a unique map of the transcriptomic changes and a number of novel mammary stem cell markers. Our comparisons showed a relationship between breast cancers of poor prognosis and stem-like gene expression. In particular the specific subtypes of basal like tumors and Luminal C types, which both have a poor prognosis, showed stem cell like gene expression pattern. We are subsequently investigating regulations of miRNAs during differentiation. We have found very strong miRNA regulation during differentation of the stem cell like cells, and are investigating the functions of key regulated miRNAs. We imply the same miRNAs could be affecting poor prognosis breast cancers.
By defining the association between mammary stem cell like cells and stem cell like tumors, we can start to understand the pathways that will need to be targeted for successful treatment of poor prognosis breast cancers.
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 2076.
Abstract 2078: Deregulation of miR-92a expression is implicated in hepatocellular carcinoma development
Authors: Tanaka Masami , Tsuchida Akihiko , Shigoka Masatoshi , Aoki Tetsuya , Takashina Tomoki , Takanashi Masakatsu , Murakami Yoshiki , Kuroda Masahiko 
Published: February 2011

Abstract
MicroRNAs (miRNAs) belong to a class of the endogenously expressed non-coding small RNAs which primarily function as gene regulators. Growing evidence suggests that microRNAs have a significant role in tumor development and may constitute robust biomarkers for cancer diagnosis and prognosis. Especially, the miR-17-92 cluster is markedly overexpressed in several cancers, and is associated with the cancer development and progression. In this study, we have demonstrated that miR-92a is highly expressed in hepatocellular carcinoma (HCC). In addition, the proliferation of a HCC cell line HepG2 was inhibited by the anti-miR-92a antagomir. On the other hand, we have found that the relative amount of miR-92a in the plasmas from HCC patients is decreased compared with that from the healthy donors. Interestingly, the amount of miR-92a was elevated after surgical treatment. Thus, although the physiological significance of the decrease of miR-92a in plasma is still unknown, deregulation of miR-92 expression in cells and plasma should be implicated in the development of HCC.
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 2078.
Abstract 208: Low-dose actinomycin D decreases Mcl-1 expression and acts synergistically with ABT-737 to induce apoptosis of SCLC cell lines
Authors: Xu Haishan , Humphries Malika , Krystal Geoffrey W. 
Published: February 2011

Abstract
SCLC is initially a highly chemotherapy-responsive disease but relapse and progressive development of chemotherapy resistance is the rule. Overexpression of pro-survival members of the Bcl-2 family, including Bcl-2, Bcl-XL and Mcl-1 are thought to play a role in the pathogenesis and chemotherapy resistance of SCLC. ABT-737, a BH3-mimetic drug which blocks the function of Bcl-2 and Bcl-XL, has shown single agent activity in preclinical models of SCLC and enhances the activity of a variety of cytotoxic agents. Low levels of Mcl-1 expression and high levels of Noxa expression have been characterized as markers of sensitivity to ABT-737 in SCLC and other malignancies. We have also noted that Noxa-mediated downregulation of Mcl-1 expression is absent in 4/4 SCLC cell lines examined, suggesting roles for this defect in the pathogenesis of SCLC and in resistance to ABT-737. Because of the short half-life of Mcl-1 mRNA and protein, we studied the effects of combining ABT-737 and actinomycin D, a general transcriptional inhibitor used in the treatment of Wilms tumor, sarcomas, germ cell and trophoblastic tumors. Actinomycin D decreased Mcl-1 expression in a dose-dependent fashion in the low ng/ml range, 3 logs lower than that required for general transcriptional inhibition. While exposure to actinomycin resulted in a cell line-dependent increase in Noxa expression, Noxa was not required for the decrease in Mcl-1 expression, as it occurred in the H209 cell line, which does not express Noxa, as well as the H69, WBA and H526 cell lines which do. Concentrations of actinomycin D from 0.4-4 ng/ml showed single agent activity across a panel of SCLC cell lines in 72 hr MTT viability assays and specifically induced a high grade G2-M cell cycle blockade. When combined with low micromolar doses of ABT-737, near complete loss of viability was seen with combination indices in the 0.5 range, indicating synergy by Chou-Talalay analysis, without a significant effect on MRC-5 pulmonary fibroblasts. In addition to loss of Mcl-1 expression and enhanced Noxa expression, correlates of apoptosis induced by the combination included marked Bid cleavage. Exposure to 4 ng/ml actinomycin was only required for the first 24 hrs of the combined incubation but the presence of ABT-737 was required for the full 72 hrs to see maximum loss of viability and clonogenic potential. This actinomycin exposure mimics a clinically achievable AUC of 100 ng.hr/ml after bolus administration, suggesting the feasibility of combination studies utilizing bolus actinomycin D administration.
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 208.
Abstract 2082: The microRNA-101 regulates the expression of EP4 receptor in colon cancers
Authors: Chandramouli Anupama , Stankova Lenka , Davenport Jennifer M. , Shanas Renee , Owens Jenae M. , LaFleur Bonnie J. , Bhattacharyya Achyut K. , Nelson Mark A. 
Published: February 2011

Abstract
Colorectal cancer (CRC) is one of the most devastating cancers in the United States and is characterized by the accumulation of prostaglandin PGE2. PGE2 exerts its biological function via four transmembrane G protein coupled receptors (EP1-4), among which the prostanoid EP4 receptor is the most relevant. However, its expression in human CRC specimens has not been fully understood. Therefore, we wanted to clarify the expression of EP4 receptor in human tissue specimens. We collected a total of 40 CRC tissue specimens representing different stages of disease and performed immunohistochemistry (IHC) analysis. The specimens were graded for intensity and extent of staining of the EP4 receptor. Here we show that cancer tissues (n = 15) expressed significantly higher EP4 receptor staining as compared to normal colonic (n = 16) and adenoma (n = 9) tissues. We also performed western blot analysis on paired cancer and normal tissue specimens from this cohort and confirmed that the EP4 protein levels were elevated in cancer as compared to normal tissues whereas there was no difference in the expression of EP2 receptor. By contrast, the mRNA expression of the EP4 receptor gene (PTGER4) was down-regulated in these tumors as compared to paired normal tissue. We postulated that the increased EP4 receptor protein levels observed in tumors occurs by post transcriptional mechanisms. Therefore, to address this issue, we performed in silico analysis of the 3′UTR of PTGER4 gene for microRNA binding sites. We identified a consensus microRNA-101 (miR-101) seed sequence within the 3′UTR, proximal to the coding region, of the PTGER4 gene. Interestingly we observed a correlation between loss of miR-101 levels and increase in EP4 receptor protein levels in human CRC tissue specimens as compared to paired normal colonic tissue, by RT-PCR analysis. In order to directly assess this correlation, we ectopically expressed mir-101 plasmid in colon cancer cells and demonstrated that it could suppress endogenous levels of EP4 receptor protein. Together, these findings show that EP4 receptor is significantly elevated in human CRC and suggest, for the first time, that miR-101 may negatively regulate the expression of EP4 receptor by post-transcriptional mechanisms.
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 2082.
Abstract 2085: Mir-30 acts as an anti-metastatic microRNA and is downregulated in non-small cell lung cancer (NSCLC)
Authors: Regalla Kumarswamy , Mudduluru Giridhar , Ceppi Paolo , Kozlowski Miroslaw , Nikliński Jacek , Allgayer Heike 
Published: February 2011

Abstract
MicroRNAs (miRNAs) are small (around 22 nt) endogenous non-coding RNAs which regulate gene expression by base-pairing to the 3′-UTR of the target mRNA, causing translational repression or mRNA degradation. Recently, miRNAs have been shown to regulate cancer metastasis by virtue of their ability to co-ordinately repress multiple target genes. Epithelial-mesenchymal transition (EMT), which is characterized by repression of E-cadherin expression, and increased cell mobility, plays a very important role in cancer metastasis and fibrosis development. Recent evidence suggests that microRNA-30 (miR-30) acts as an antifibrotic agent and reduces tumor weight in animal models. In the present study, we have identified that the miR-30 family of miRNAs may function as anti-metastatic miRNAs by inhibiting EMT. We have studied the expression of miR-30 in various NSCLC cell lines and found that miR-30 expression is inversely proportional to the invasive capabilities of the cells. Correspondingly, all ‘mir-30 high’ cells are E-cadherin (epithelial marker) positive and N-cadherin (mesenchymal marker) negative, and vice-versa. ‘miR-30 low’ cell lines displayed several fold higher migratory and invasive abilities when compared with ‘miR-30 high’ cell lines. Similarly, in a chicken embryonic metastasis assay, we found that the number of metastasizing cells to lungs and livers of developing chicken was significantly reduced when miR-30 was over-expressed in ‘miR-30 low’ cells compared with mock-transfected cells. Over-expression of miR-30 also inhibited TGF-beta induced EMT in ‘miR-30 low’ cells, confirming the role of miR-30 in EMT inhibition. Search for miR-30 targets, that can modulate E-cadherin expression, using web based target analysis tools, have identified that Snail, which induces EMT primarily via transcriptional repression of E-cadherin, is a putative target of miR-30. Luciferase and Western blotting experiments have confirmed that miR-30 targets Snail. Finally, we have screened the expression of miR-30 in 47 consecutive NSCLC patients and found that miR-30 is down-regulated in tumours of about 80% of patients compared with their corresponding normal tissue. Collectively, these observations suggest that members of miR-30 are down regulated in non-small cell lung cancer, and inhibit EMT by targeting Snail.
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 2085.
Abstract 2086: Regulation of Axl receptor tyrosine kinase expression, invasion and metastasis by miR-34a and mir-199a/b
Authors: Mudduluru Giridhar , Ceppi Paolo , Regalla Kumarswamy , Allgayer Heike 
Published: February 2011

Abstract
Axl is a receptor tyrosine kinase over-expressed in different human cancers which induces proliferation, migration and invasion. In this study, we show that specific microRNAs (miR) can target the 3’-UTR of Axl and can modulate its expression. By a bioinformatics approach, we found conserved target sites for miR-34 and miR-199 within the Axl-3’-UTR at 31-49 nt and 29-56 nt, respectively. Luciferase-reporter assays with wild-type and deleted miR-34 and −199 seed sequences of Axl-3′UTR confirmed the specificity of targeting. An inverse correlation between Axl protein and miR-34a expression in a panel of non-small cell lung cancer (NSCLC), colorectal (CRC) and breast cancer (BRC) cell lines was observed, while no miR-199a or 199b expression was detected. Transient transfection of antagonist-miR or pre-miR for miR-34a and 199a significantly induced and reduced Axl-protein levels, respectively. Pre-miR transfection was able to inhibit in vitro migration and invasion of H1299 and RKO cells and, in vivo, to reduce the number of distant lung- or liver-metastasis in a chicken-embryo-metastasis assay. Moreover, methylation specific PCR on bisulfite-converted DNA obtained from the cell lines showed that the miR-34a promoter methylation status was significantly correlated with Axl expression, and that miR-199a/b promoter regions were methylated in all the cell lines tested. These results suggest that Axl receptor, together with its role in cancer cell growth, invasion and metastasis formation, can be regulated by miR34a and 199a/199b, and that one of the reasons for its over-expression in tumors can be the methylation of DNA that encodes these specific miRs which target Axl expression.
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 2086.
Abstract 2087: miR-483-3p is an oncogene involved in nephroblastoma and in adult tumors with activated β-catenin
Authors: Veronese Angelo , Consiglio Jessica , Visone Rosa , Zanesi Nicola , Ferracin Manuela , Lanza Giovanni , Querzoli Patrizia , Angioni Adriano , Croce Carlo , Negrini Massimo 
Published: February 2011

Abstract
The hsa-mir-483 locus is located within intron 2 of the IGF2 locus. Here, we show that the mature microRNA (miRNA) miR-483-3p is over-expressed and co-regulated with IGF2 in 100% of Wilms’ tumors. Additionally, several types of common adult cancers exhibit high or even extremely high levels of miR-483-3p. We show that the mutation status of the oncoprotein β-catenin is correlated with the expression of the miR-483-3p in hepatocarcinoma and colorectal cancer. These findings suggested an autonomous oncogenic function for this miRNA. Indeed, anti-microRNA oligonucleotide (AMO) against miR-483-3p could inhibit tumorigenicity of HepG2 cells. At the same time, no anti-tumor effect was elicited by inhibition of IGF2. The oncogenic properties of miR-483-3p were further supported by the finding that its ectopic expression could protect cells from apoptosis through the regulation of one important pro-apoptotic protein, Puma. Our results indicate that miR-483-3p can function as an anti-apoptotic oncogene in various human cancers and reveal a new potentially important target for anti-cancer therapy.
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 2087.