bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3153: H. pylori infection enhances the degradation of Drosha through regulating its acetylation-ubiquitination switches
Authors: Tang Xiaoli 
Published: August 2012

Abstract
microRNAs are a class of short non-protein coding RNAs with length of ∼22nt which play important regulatory roles in the cell functions by inhibiting their target protein expression. The biogenesis of microRNAs is a multistep process which is initiated in the nucleus by the RNase III enzyme Drosha. Our previous work and the work from others showed that Drosha protein level affected the biogenesis of microRNAs. Accumulating evidence shows that overall microRNA levels in the stomachs of H. pylori-infected patients are decreased and that this may relate to the promotion of gastric cancer by this bacterium. But the underlying mechanisms largely remain unknown. Here we show that H. pylori infection enhances the ubiquitin-proteosome pathway of Drosha degradation which is constitutively active in cells. Of the microRNA regulatory proteins, Drosha is more sensitive to ubiquitin-proteasome pathway-induced degradation than Dicer, DGCR8 or exportin-5. Activated ubiquitin molecules are ligated to the N-terminal lysines of Drosha leading to its degradation. There are 13 lysine residues on the N-terminus of Drosha. Truncation or site-directed mutagenesis showed multiple lysines involved in the ubiquitination-induced degradation of Drosha. Those lysine residues are also the acetylation sites by multiple acetyl transferases such as p300, CBP. Acetylation of Drosha on those N-terminal lysine sites prevents Drosha from ubiquitination and thereby prevents its degradation. Our data indicate that H. pylori infection enhances the degradation of Drosha through regulating the acetylation-ubiquitination switches on Drosha. Our findings provide a potential therapeutic target for mitigating the effects of H.pylori infection, including gastric 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 3153. doi:1538-7445.AM2012-3153
Abstract 316: Peritoneal carcinomatosis depends for growth and spreading on endogenous inflammatory cues generated by infiltrating macrophages
Authors: Cottone Lucia , Valtorta Silvia , Capobianco Annalisa , Monno Antonella , Belloli Sara , Fazio Ferruccio , Moresco Rosa Maria , Rovere-Querini Patrizia , Manfredi Angelo A. 
Published: August 2012

Abstract
Peritoneal carcinomatosis is the most common terminal feature of abdominal cancers. Interfering with the peritoneal immune microenvironment is a promising tool for combinational therapy. Preclinical studies on peritoneal carcinomatosis have been hampered by the limited availability of models as well as non-invasive methods to follow tumor growth. We set up ad hoc models via the orthotopic injection of murine cells lines in immuno-competent mice and followed tumor growth by imaging with [18F]2-fluoro-2-deoxy-D-glucose-PET ([18F]-FDG-PET). Colon carcinoma (MC38), Mouse Ovarian Surface Epithelial Carcinoma cell line (MOSEC) of C57BL/6 origin and adenocarcinoma cells (TS/A) of Balb/C origin were injected intraperitoneally in syngeneic mice. The models nicely recapitulated the histological features of the human disease: carcinoma cells distributed along the cavity and yielded several masses attached to the peritoneal lining. Animals were longitudinally followed by imaging with [18F]-FDG-PET: tumor lesions selectively up-took the radioactive tracer and we observed a significant correlation between lesion dimension and metabolic radioactive volume. We characterized leukocyte composition of the peritoneal liquid of tumor bearing mice by multicolor flow cytometry, performing peritoneal lavage on live animals at various time points during tumor growth. Tumor spreading induced the recruitment of leukocytes, among which the most relevant population was represented by CD45+CD11b+F4/80+ monocytes/macrophages. The depletion of peritoneal monocytes/macrophages, via administration of clodronate encapsulated in liposomes, lead to a substantial reduction of tumor burden as well as leukocyte recruitment, and was paralleled by a decrement in the extent of radioactivity distribution when imaging mice with [18F]-FDG-PET. Moreover we found out that colon carcinoma cells upon in-vitro treatment with stress-inducing stimuli, such as starvation and chemotherapeutic agents exposure, produced factors involved in leukocytes recruitment: this behavior was directly linked to the activation of autophagic and apoptotic intracellular pathways. In conclusion, [18F]-FDG-PET imaging allowed the non-invasive detection of peritoneal adenocarcinoma lesions which spreading and growth was dependent on the production of factors involved in leukocytes recruitment, specifically on peritoneal monocytes/macrophages.
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 316. doi:1538-7445.AM2012-316
Abstract 3163: Exploration of microRNA-34a effects in human glioma cell lines
Authors: Kofman Alexander , Guessous Fadila , diPierro Charles G. , Dupart Evan , Bao Yongde , Dhamala Susan , Letson Christopher , Letson Christopher , Park So Yeon , Marcinkiewicz Lukasz , Abounader Roger 
Published: August 2012

Abstract
We have previously demonstrated that miR34a targets and downregulates multiple oncogenes, and therefore it may be considered as a potent tumor suppressor factor. In this report we show that miR34a expression is strictly dependent on the ability of major tumor suppressor protein TP53 to bind to miR34a transcriptional regulatory elements. In order to further investigate the effects of miR34a we generated a panel of human glioma cell lines where both miR34a and copGFP gene reporter are expressed in a tet-inducible manner. The constitutive expression of cyan fluorescent protein, the mutant GFP derived from Aequorea Victoria, and tet-inducible expression of copGFP derived from Anthozoa allows co-localizing and tracking both tet-induced and non-induced cells in vivo. We present data indicating that miR34a-caused inhibition of cell proliferation both in vitro and in vivo is due to the down-regulation of cyclin D1 and transcriptional factors E2F3 and E2F5. We show that miR199a, which targets other cyclins and cyclin-dependent kinases and therefore complements the action of miR34a, is up-regulated upon miR34a overexpression. miR199a-5P and miR199a-3P, but not miR34a, target E2F6 and USP7 correspondingly. Overexpression of miR34a using tet-inducible cell lines and lentiviral vectors downregulated E2F6 and USP7 on the 5th day after induction/transduction. However, at 48-72 hours after p53 overexpression accompanied by the modest upregulation of miR34a no changes in miR199a levels were observed. The results indicate that miR34a induces miR199a overexpression indirectly, most probably at the transcriptional level, thus eliciting the synergistic anti-tumor effects. We have also found that overexpression of miR34a in tet-inducible manner significantly inhibits the growth of brain tumors and prolongs the survival of immunodeficient animals. Finally, we show that miR34a targets and downregulates phosphoprotein enriched in astrocytes-15, which has been reported to promote autophagy and contribute to the resistance to radiation 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 3163. doi:1538-7445.AM2012-3163
Abstract 3164: MiR-134 expression is oncogenic for oral cancer
Authors: Liu Chung-Ji , Lin Shu Chuan , Chang Kuo-Wei , Tsai Meng-Miao Tsai 
Published: August 2012

Abstract
Introduction Oral squamous cell carcinoma (OSCC) is one of the most prevalent malignant diseases around the worldwide. Understanding the pathogenetic basis of these tumors will bestow profound benefits in resolution of this disease, to validate individualized therapy and reduction in medical resources consumption. MicroRNA (miRNA) is a short, non-coding RNA that regulates gene expression by controlling mRNA translation. Which can affect biological and pathological processes. Dysregulation of miRNA function might lead to human disease including human cancers. Upregulation of miR-134 in OSCC was observed in a our previous study. However, the clinical implications and functions of miR-134 in oral tumorigenesis remain unclear. Methods Quantitative RT-PCR was used to analyze the miR-134 expression in OSCC tissue pairs. The oncogenic phenotypes including proliferation, migration and anchorage-independent colony formation were assayed in cells with miR-134 expression or miR-134 blockage. The xenografic tumorigenecity was assayed on nude mice model. TargetScan predicted WW domain-containing oxidoreductase (WWOX) a tumor suppressor gene to be putative targets of miR-134. To test the targeting activity of miR-134, antisense sequences complementary to miR-134 sequences and the 3β untranslatedregion (UTR) of WWOX containing predictive miR-134 target sites were cloned into the pCMV-LacZ plasmid at the 3α-end of the lacZ coding sequence; these reporter plasmids were designated miR-134-asR and pCMV-LacZ-WWOX3αUTR, respectively. Results miR-134 was found to be markedly upregulated in cancerous tissues than in non-cancerous matched tissues in OSCC tissue pairs. Higher miR-134 was associated with the more advanced tumor size and vascular invasion. Transfection of miR-134 precursor transiently upregulated miR-134 expression in OSCC cells. It increased oncogenic potential of OSCC cells. Conversely, the in vitro oncogenic potential of OSCC cells was attenuated after blocking of miR-134 expression. Stable SAS OSCC cell subclone with ectopic miR-134 expression was established by lentiviral delivery. Ectopic miR-134 expression increased the tumorigenicity of SAS subclone. Downregulation of WWOX mRNA expression and protein expression was found in SAS-miR-134 cells compared with controls. Conversely, upregulation of WWOX mRNA expression and protein on miR-134 LNA treatment relative to controls was found. Conclusion This identified for the first time that miR-134 is oncogenic to oral epithelium and its expression level could be validated as a diagnostic marker of OSCC. Our findings suggest that miR-134 contributes to the development of OSCC by targeting WWOX.
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 3164. doi:1538-7445.AM2012-3164
Abstract 3172: Role of miRNA-211in melanocytes and melanoma
Authors: Maddodi Nityanand , Madhavan Shajil , Devi Sulochana , Jayanthy Ashika , Setaluri Vijayasaradhi 
Published: August 2012

Abstract
MicroRNAs (miRNAs) are small non-coding regulatory RNAs that regulate gene expression. Evidence is accumulating that miRNAs are involved in almost all aspects of tumor biology including tumor cell survival, proliferation and migration. Here, we report that miRNA-211, which maps to the sixth intron of TRPM1 gene (a suppressor of melanoma metastasis), is highly expressed in primary melanocytes and its expression is reduced in primary and metastatic melanoma cell lines. Expression of miRNA-211 correlates with expression of TRPM1, a transient receptor potential family member calcium channel protein that we showed to be involved in regulation of melanocyte calcium homeostasis and melanin pigmentation. Inhibition of miRNA-211 expression by anti-miR211 inhibited intercellular Ca+2 update and the growth of rapidly growing melanocytes. Ectopic expression of miRNA-211in melanoma cells inhibit growth and reduced their migration. Regulation of miRNA-211 and its function in melanocytes and melanoma have not been well understood. We show that ectopic expression of p53 (a tumor suppressor) in melanocytes increase miRNA-211 expression and decrease TRPM1 expression. Inhibition of miRNA-211 did not change TPRM1 expression in melanocytes. Additionally, we show that 1.4 kb intron 6 genomic region of TRPM1 which contain miRNA-211 region is sufficient to activate miRNA-211 expression. And 1.4 kb of 6th intron luciferase reporter plasmid transfection followed by luciferase assay showed increase in promoter driven luciferase activity. These data suggests that the presence of putative promoter region of miRNA-211 in the sixth intron of TRPM1 gene. We propose that activation of endogenous miRNA-211 expression or targeted delivery of miR-211 in melanoma is a potential therapeutic option for treatment of cutaneous melanoma.
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 3172. doi:1538-7445.AM2012-3172
Abstract 3226: PKM2 metabolic activator slows lung cancer xenograft growth
Authors: Parnell Mark , Foulks Jason M. , Nix Rebecca , Luo Bai , Senina Anna , Xu Yong , Saunders Michael , Ho Koc-Kan , McCullar Michael V. , Kanner Steven B. 
Published: August 2012

Abstract
Tumor cells primarily utilize aerobic glycolysis, rather than oxidative phosphorylation, to metabolize glucose (the Warburg effect). The M2 splice form of pyruvate kinase (PKM2), the enzyme catalyzing the rate-limiting final step of glycolysis, is highly upregulated in tumors. Unlike the M1 splice form (PKM1), a constitutively active tetramer found predominantly in non-cancerous tissues, PKM2 is an inactive dimer under normal physiological conditions. Tetramerization of PKM2 requires binding of the allosteric activator fructose-1,6-bisphosphate (FBP), an upstream glycolytic intermediate, resulting in a fully active enzyme. Inactivation of PKM2 by cancer cells may allow glycolytic intermediates to be diverted into other biosynthetic pathways necessary for biomass production. The finding that PKM2 rather than PKM1 expression enhances tumorigenicity suggests that activators of PKM2 may have anti-tumor properties. We have identified and developed a series of small molecule PKM2 activators that exhibit low nM activation activity in biochemical and cell-based assays that measure pyruvate and ATP production. The extent of activation of these compounds is equal to or greater than that of FBP in biochemical assays. In addition, preliminary studies show that PKM2 activators inhibit the growth of lung cancer cell lines in vitro. The current lead compound was tested in established subcutaneously implanted A549 lung adenocarcinoma xenografts, where we observed a statistically significant decrease in tumor growth, with no observable toxicity. These data suggest that this class of PKM2 activators is effective as tumor cell metabolic regulators with anti-tumor activity for lung cancer and potentially other malignancies.
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 3226. doi:1538-7445.AM2012-3226
Abstract 3239: The Notch pathway as a new target in gastrointestinal stromal tumors
Authors: Dumont Amaury G. , Hughes Dennis P. , Trent Jonathan 
Published: August 2012

Abstract
Small molecule kinase inhibitors have dramatically improved the survival of patients with Gastrointestinal Stromal Tumors (GIST), yet most patients develop resistance, urging us to understand better the molecular mechanisms underlying this disease and identify new therapeutic strategies. Notch signaling is a conserved developmental pathway known to play a critical role in the development of several cancers, functioning as a tumor promoter or a tumor suppressor. Given that the normal progenitor cell for GIST, the Interstitial Cell of Cajal, has characteristics similar to those of cells of neuroendocrine origin, we hypothesized that Notch pathway impacts the biology of GIST cells. In a previous study, we demonstrated that constitutively active intracellular domain of Notch1 (ICN-1) induced growth arrest in GIST cell lines. Here we report that ICN-1 downregulated KIT protein by a flow cytometric analysis in the three cell lines analyzed (GIST-T1, GIST882, GIST48IM). In parallel, inhibitions of Hes1, a major target gene of ICN-1, with a dominant negative construct, upregulated KIT protein expression in vitro (60% increase on western blot). This anti-tumor effect of Notch1 in GIST leads to a therapeutic opportunity as we showed in the present study that treatment with the histone deacetylase inhibitor, SAHA, caused a dose-dependent upregulation of Notch1 (6 fold increase of the mRNA with SAHA 2 µm/L on GIST-T1, P&lt;0.05), downregulation of KIT and pKIT (9 fold decrease of pKIT on western blot with SAHA 2 µm/L on GIST-T1), increase in apoptosis (25-fold increase in the sub-G1 population with SAHA 2 µmol/L on GIST-T1, P&lt;0.05), decrease in viability of the GIST cells (IC50 = 2 µmol/L on GIST-T1).To confirm the clinical relevance of the Notch pathway on GIST, we performed a retrospective analysis on 15 pre-treated patient tumors and showed that GIST patients with high Hes1 mRNA levels have a significantly longer relapse-free survival than the one with low Hes1 mRNA levels (median of 37 months for the low group versus median not reached at &gt;80 months for the high group; P=0.005). These results identify a novel anti-tumor effect of Notch1 via a crosstalk between the Notch1 and KIT pathways in GIST cells. This finding may lead to new therapeutic strategies for GIST patients, in particular after failure of tyrosine kinase inhibitors.
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 3239. doi:1538-7445.AM2012-3239
Abstract 3251: Linking prostaglandin E2 signaling, lipid rafts, and DNA protein kinase
Authors: Hawk Ernest T. , Menter David G. , Patterson Sherri , Swank Michael W. , DuBois Raymond N. 
Published: August 2012

Abstract
Colorectal cancer (CRC) is the second-leading cause of death from cancer in the USA. Chronic inflammation in the gastrointestinal tract is a significant risk factor for developing CRC. Generally, CRC involves the upregulation of inflammation-induced cyclooxygenase-2 (COX-2) that is blocked by non-steroidal anti-inflammatory drugs (NSAIDS). Among the downstream prostaglandin synthases that produce bioactive prostaglandins (PGs), prostaglandin E2 (PGE2) synthase products are proinflammatory. After export from cells, PGE2 can bind to G-protein coupled PG cell surface receptors EP2/4 and activate adenylate cyclase and elevate cAMP. In turn, cAMP activates downstream effectors such as protein kinase A (PKA) and/or exchange protein directly activated by cAMP (EPAC). We studied effects of PGE2 on PKA activation in CRC cells and their relationship to lipid raft function. After isolating lipid rafts from PGE2 stimulated cells we performed shotgun proteomics. Among the lipid raft proteins identified were DNA-protein kinase (DNA-PK), and heterodimer complex proteins Ku70 and Ku80, which we verified by immunoprecipitation and immunofluorescence. Of these lipid raft proteins, Ku80 contained a PKA consensus phosphorylation sites and phosphorylation increased after stimulation of CRC cells by PGE2. Typically found in the nucleus, Ku70, Ku80 and DNA-PK complexes bind to DNA double-strand breaks and initiate non-homologous end joining DNA repair. These data are the first to demonstrate the Ku70, Ku80 and DNA-PK complexes in a new non-nuclear action, which involves lipid rafts and the DNA repair complex. Furthermore, PGE2 stimulated LS174T CRC cells exhibit an increase in non-nuclear pDNA-PK (S2056). Additionally, treatment of a number of colon cancer cell lines with the selective DNA-PK inhibitor Nu7026 significantly decreased cell viability in the absence of any overt DNA damaging stimuli, suggesting that non-nuclear, and in particular, lipid raft localized DNA-PK complex may play an important role in cell growth. Finally, treatment with both PGE2 and Nu7026 causes a profound change in cell morphology involving numerous spindle-like processes. These data suggest there are important downstream effects of proinflammatory PGE2 on CRC cells that influence lipid raft associated Ku70, Ku80 and DNA-PK complexes as well as cell proliferation. Support: T. Boone Pickens Distinguished Chair for Early Prevention of Cancer to E.T.H., R37 DK47297, NCI P01 CA77839, CPRIT-RP100960, Ellen F. Knisely Distinguished Chair in Colon Cancer Research, The National Colorectal Cancer Research Alliance to R.N.D. and 5U54CA151668-02 to D.G.M.
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 3251. doi:1538-7445.AM2012-3251
Abstract 3414: Role of FGFR2 in invasion and metastasis through different activation of downstream signaling in gastric cancer
Authors: Lee Won Suk , Park Kyu Hyun , Kim Jeong Min , Lee Myung Eun , Kim Tae Soo , Kim Hyo Song , Jeung Hei Cheul , Chung Hyun Cheol , Rha Sun Young 
Published: August 2012

Abstract
Activation of fibroblast growth factor receptors (FGFRs), the family of receptor tyrosine kinase (RTK), initiates intracellular signaling networks for key cellular processes. Previous reports show that FGFR2 amplification induces activation of downstream signaling in gastric cancer influencing cell proliferation and survival. In this study, we evaluated activation of FGFRs and related downstream pathways, and also determine the effect of FGFRs in tumor invasion and metastasis in gastric cancer. First, we performed phospho-RTK array in 25 gastric cancer cell lines and found that FGFR2 and FGFR3 were more frequently phosphorylated than FGFR1 or FGFR4 in gastric cancer. Next, we observed genomic amplification status and phosphorylation level of FGFR2 using real-time PCR and Western blot. KATO III and SNU-16 with higher expression of FGFR2 showed high correlation between DNA amplification and phosphorylation status. Then, using invasion assay, cells with higher FGFR3 showed higher invasiveness compare to cells with FGFR2 overexpression. When we observed the activation status of downstream signaling molecules, cells with higher FGFR2 were more dependent on PI3K-AKT-mTOR pathway, while cells with higher FGFR3 were more dependent on ERK pathway. In conclusion, FGFRs have various biological roles through different signaling pathways in gastric cancer, suggesting that FGFRs are the potential molecular targets in gastric 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 3414. doi:1538-7445.AM2012-3414