bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3052: Role of p53 in cdk inhibitor VMY-1-103-induced apoptosis in prostate cancer
Authors: Ringer Lymor , Sirajuddin Paul , Yenugonda Venkata M. , Brown Milton , Rodriguez Olga , Albanese Chris 
Published: August 2012

Abstract
The mammalian cell cycle is a tightly regulated process that controls cell division and replication. The tumor suppressor p53 plays a crucial role in both the G1/S and mitotic checkpoints, as well as in apoptosis in response to DNA damage. P53 activates p21, which is an inhibitor of cdk/cyclin E complexes, to cause cell cycle arrest. P53 can also function as a mediator of apoptosis by activating either the instrinsic or extrinsic pathway of apoptosis by activating transcriptional targets such as Bax, Bid, and TRAIL R4/5. In prostate cancer (PCa), p53 mutations are frequently associated with advanced staged disease. We recently have developed a novel analog of the CDK inhibitor purvalanol B, termed VMY-1-103 (VMY) which functions as a potent inhibitor of proliferation. To assess the efficacy of this compound in vitro, we tested the ability of VMY to cause cell cycle arrest and apoptosis in LNCaP, DU145, and PC3 prostate cancer cell lines. VMY caused an increase in cells in G2/M in all cell lines tested. Additionally, VMY treatment resulted in a large amount of apoptosis in LNCaP cells, which are p53 wild-type. In contrast, DU145 cells, which are p53 mutant, and PC3 cells, which are p53 null, were significantly less susceptible to VMY-mediated apoptosis, strongly suggesting that functional p53 was required for VMY to induce apoptosis in PCa cells. In order to test this hypothesis, a series of experiments were carried out in these PCa cell lines. Knockdown of p53 by siRNA in LNCaP cells resulted in a decreased sensitivity to VMY, as these cells no longer underwent cell cycle arrest or apoptosis. Further modulation of p53 was performed by overexpressing a wild-type construct in PC3 cells, which greatly sensitized the cells to cell death following VMY treatment. Conversely, introduction of several mutant p53 constructs into LNCaP cells did not decrease sensitivity to the drug whatsoever. Importantly, in DU145 cells, which have two mutations of p53 on opposite alleles, apoptosis was significantly increased when cells were pre-treated with PRIMA-1 to restore WT p53 function. Therefore, our data establishes p53 plays a crucial regulator of sensitivity to VMY and its ability to induce apoptosis in prostate cancer cells. In addition we show that modification of mutant p53 by PRIMA in a p53 deficient cell lines, and the ensuing restoration of drug sensitivity, enhances the potential of VMY as a novel therapeutic for prostate 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 3052. doi:1538-7445.AM2012-3052
Abstract 3062: Ada3, a component of STAGA HAT complex, controls cell cycle by regulating c-myc
Authors: Mohibi Shakur , Gurumurthy Channabasavaiah , Mirza Sameer , Nag Alo , Katafiasz Bryan , Bele Aditya , Naramura Mayumi , Band Hamid , Band Vimla 
Published: August 2012

Abstract
The human homologue of the yeast Ada3 (alteration/deficiency in activation) protein is an essential component of various Histone acetyl transferase complexes (HATs). To gain insight into the physiological importance of Ada3, we established a conditional knockout mouse model and showed that loss of Ada3 led to embryonic lethality at an early stage of development. Using the derived Ada3lox/lox mouse embryonic fibroblast (MEF) cell lines we show that Ada3 deletion causes defects in histone acetylation. Also we show that Ada3 enhances catalytic activity of p300 HAT. We further showed that Ada3 plays an important role in cell proliferation; depletion of Ada3 from cells caused cell lethality. This proliferation defect was reversed by introduction of human Ada3 in Ada3 null MEFs. Ada3 null MEFs also showed delay in transition from G0-G1 phase of the cell cycle to the S phase. These cells also manifested decreased hyperphosphorylation of Retinoblastoma protein (Rb); an increased protein half life of CDK inhibitor p27Kip1 and decrease in Cdk2 kinase activity. The increase in p27 protein was a result of decreased Skp2 protein and mRNA levels which is a direct target of c-myc oncogene. We further show that mRNA levels of c-myc, a direct transcriptional target of Ada3 containing STAGA HAT complex, are reduced on deletion of Ada3. These data suggest an Ada3-myc-skp2-p27 pathway that controls mammalian cell cycle. Taken together, our data suggests an essential role of Ada3 in embryonic development and cell cycle progression.
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 3062. doi:1538-7445.AM2012-3062
Abstract 3119: A synthetic lethal screen identifies genetic determinants for gemcitabine sensitivity in pancreatic cancer
Authors: Landry Jerome C. , Pantazides Brooke G. , Park Wungki , Shelton Joseph W. , Maithel Shishir K. , El-Rayes Bassel , Yu David S. 
Published: August 2012

Abstract
Pancreatic cancer is notorious for its devastating disease course and prognosis. Gemcitabine is a widely used regimen for pancreatic cancer treatment but lack of response and resistance often limits its use. To identify the genes and mechanisms involved in determining gemcitabine sensitivity in pancreatic cancer, we completed a loss of function genetic screen using RNA interference to identify genes which when silenced are synthetically lethal with a low dose of gemcitabine in human pancreatic cancer cells. We optimized an assay using ATR or CHK1 siRNA as positive controls and ATM or non-targeting (NT) siRNA as negative controls. Our siRNA library included 4,474 siRNAs corresponding to 1,006 unique human genes arrayed in a one-gene:one-well format in 96-well plates. Genes chosen for our library consisted predominantly of nuclear enzymes, including but not limited to kinases, phosphatases, ubiquitinylation proteins, sumoylation proteins, acetylases, deactylases, nucleases, helicases, and chromatin modifiers, which we reasoned were more likely to function directly in DNA repair processes and be targetable. MIA PaCa-2 cells were transfected with 25 nM siRNA and treated 48 hours later with or without 13 nM gemcitabine for 72 hours prior to the cell proliferation assay using WST-1 reagent. Using this assay, we identified 87 genes which when silenced caused gemcitabine sensitization and 42 genes which when silenced caused gemcitabine resistance. Positive hits included 16 known genome maintenance genes including well-characterized ATR signaling pathway genes - CHK1, RAD9, HUS1, and CDC25A, 5 putative ATM/ATR substrates, and 20 genes identified in previously published DNA damage sensitivity screens. 21 of the genes are somatically mutated or differentially expressed in pancreatic cancer, suggesting that our gemcitabine sensitivity genes may function as useful predictive biomarkers or novel targets for the treatment of pancreatic 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 3119. doi:1538-7445.AM2012-3119
Abstract 3121: Systematic analysis of the DNA synthesis fidelity of somatic mutations of polymerase beta found in prostate cancer
Authors: Chen Desheng , LeCompte Kimberly , Pursell Zachary , Makridakis Nick 
Published: August 2012

Abstract
Human DNA polymerase beta (polβ) is a monomeric protein of 335 amino acids and functions in base excision repair and meiotic recombination. Human polα is over-expressed in many cancer cells like ovarian, prostate, breast, colon and chronic myelogenous leukemia. To obtain clues of possible functions in vivo, we have determined the fidelity of DNA synthesis of polα with forward mutation assay which scored the sequence errors caused in the lacZ-α gene in M13mp2 during DNA synthesis to fill a 407-nucleotide gap. Three of seven of the somatic polα mutants, p.E232K, p.E123K and pE216K, which we identified previously in prostate tumors, were tested. The results indicated that the somatic mutants of human DNA polymerase beta display altered fidelity. The fidelity for large deletions and complex changes of the pE232K and pE123K muatants are three and 31 times lower respectively, compared to wild type polα. The T&gt;G transversion at position 103, which is the most common feature of polB base substitution error spectrum, is observed six times and two times lower for the pE123K and p.E216K mutants than wild polymerase beta. Our data show that somatic mutations in prostate cancer change both the synthesis fidelity and/or mutation type compared with wild type polymerase beta.
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 3121. doi:1538-7445.AM2012-3121
Abstract 3132: Dynamic changes of epigenetic abnormalities during initiation and progression of adult T-cell leukemia/lymphoma (ATLL)
Authors: Oka Takashi , Al-Kader Lamia Abd , Sato Hiaki , Washio Kana , Shinnou Yoko , Takata Katsuyoshi , Murakami Ichiro , Utsunomiya Atae , Yoshino Tadashi 
Published: August 2012

Abstract
HTLV-1 causes ATLL in 3-5% of infected individuals after a long latent period of 40 to 60 years. ATLL is divided into four stages: namely, smoldering, chronic, lymphoma and acute types. The smoldering and chronic types are indolent, but the acute and lymphoma types are aggressive ATLL characterized by resistance to chemotherapy and a poor prognosis. Such a long latent period suggests that a multi-step leukemogenic/lymphomagenic mechanism is involved in the development of ATLL, although the critical events in the progression have not been characterized. To determine whether epigenetic abnormalities are playing the important role in the progression of ATLL, we analyzed the methylation profiles, showing that number of CpG island methylated genes increased with disease progression and aberrant hyper-methylation in specific genes was detected even in HTLV-1 carriers and correlated with progression to ATLL. The CpG island methylator phenotype (CIMP) was observed most frequently in lymphoma type ATLL and was also closely associated with the progression and crisis of ATLL. The high number of methylated genes and increase of CIMP incidence were shown to be unfavorable prognostic factors and correlated with a shorter overall survival with the Kaplan-Meyer analysis. Dynamic changes of aberrant DNA methylation status in the specific genes were observed during the progression of an ATLL patient. The present findings strongly suggest that the multi-step accumulation of aberrant CpG methylation in specific target genes and the presence of CIMP are deeply involved in the initiation and progression of ATLL not only epidemiologically but also in the clinical course of a specific ATLL patient.
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 3132. doi:1538-7445.AM2012-3132
Abstract 3134: Integrin α6β4 upregulates EGFR ligands in pancreatic cancer cells
Authors: Carpenter Brittany L. , Chen Min , O'Connor Kathleen L. 
Published: August 2012

Abstract
Because of late diagnosis and lack of effective treatments, pancreatic cancer is the 4th leading cause of cancer death in the US, with a death to incidence ratio that is nearly equal. In an effort to improve patient survival, there needs to be a focus on molecular mechanisms that confer a metastatic phenotype. The integrin α6β4 is overexpressed in pancreatic carcinoma and plays a role in cancer progression by promoting tumor invasion and metastasis as well as cell survival. We find that integrin α6β4 overexpression leads to upregulation of cancer promoting genes such as amphiregulin and epiregulin, ligands of the epidermal growth factor receptor (EGFR). The purpose of this study is to address how integrin α6β4 upregulates these ligands. We have identified large CpG islands within the amphiregulin and epiregulin promoters (-1500 to +500 bp from TSS) using CpG plot and CpG Island searcher. This provides a potential site for epigenetic modifications, which are essentially reversible, and therefore an ideal target for treatment. To test whether integrin α6β4 contributes to this regulation through DNA methylation pancreatic cancer cells expressing low levels of α6β4 were treated with DNA methyltransferase inhibitor 5-aza-2′deoxycitidine. Using Q-PCR, our results show that inhibition of DNA methyltransferase increases amphiregulin and epiregulin expression at the mRNA level. In contrast, when cells with high levels of integrin α6β4 were treated with the hypermethylating agent, S-adenosylmethionine, it leads to a decrease in amphiregulin and epiregulin expression. This implicates α6β4 as a regulator of this process allowing us insight into how this pathway might be regulated. Using ELISA, we also provide evidence that integrin α6β4 promotes increased autocrine secretion of amphiregulin after promoter demethylation. This is of particular interest to our lab because autocrine secretion of amphiregulin and epiregulin make it possible for cancer cells to both produce and respond to their own growth factors, promoting cellular invasion and metastasis. This study indicates that overexpression of integrin α6β4 in pancreatic cancer is associated with the hypomethylation of amphiregulin and epiregulin promoters, which may play an important role in the development of a malignant phenotype.
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 3134. doi:1538-7445.AM2012-3134
Abstract 3145: Smyd3 catalyzes a novel methylation mark and regulates cancer cell proliferation
Authors: VanAller Glenn S. , Reynoird Nicolas , Barbash Olena , Huddleston Michael J. , Le BaoChau , Annan Roland S. , Garcia Ben A. , Tummino Peter J. , Gozani Or , Kruger Ryan G. 
Published: August 2012

Abstract
SET and MYND domain-containing protein 3 (Smyd3) is a lysine methyltransferase over-expressed in liver, breast and rectal carcinomas. We have shown that knockdown of Smyd3 has an anti-proliferative effect in cancer cell lines and that this effect can be rescued with wild type but not catalytically inactive Smyd3, directly linking Smyd3 catalytic activity to proliferation. Published reports indicate Smyd3 methylates lysine 4 of histone H3, lysine 20 of histone H4 and VEGFR1. However, activity testing of a peptide library and intact recombinant nucleosomes indicate that a unique methylation mark is catalyzed by Smyd3. LC-MS/MS analysis of in vitro reaction products have identified the location of this novel site of methylation. The existence of this novel mark and its dependence on Smyd3 activity was confirmed in cancer cells and mouse embryonic fibroblasts. We speculate that overexpression of Smyd3 causes aberrant methylation and plays an important role in the deregulation of gene expression leading to uncontrolled cellular proliferation in cancer making Smyd3 a promising target for anti-cancer 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 3145. doi:1538-7445.AM2012-3145
Abstract 315: Immune cells promote hepatocellular carcinoma stemness phenotype
Authors: Wan Shanshan , Vatan Linda , Simeone Diane M. , Kryczek Ilona E. , Zou Weiping , Welling Theodore H. 
Published: August 2012

Abstract
Hepatocellular carcinoma (HCC) is a common cause of cancer-related deaths and recurrence rates can be as high as 50% following resection. Evidence in several tumor types suggests that cancer stem cells (CSCs) contribute to tumorigenicity, therapeutic resistance and recurrence even in the presence of anti-tumor immunity. Furthermore, CSC phenotype may be influenced by tumor microenvironment. Therefore, we aimed to determine whether HCC stemness phenotype may be influenced by immune cell subsets. We have previously identified CD44 as a HCC-CSC marker as evidenced by enhanced tumorigenicity and sphere forming capacity in CD44+ HCC cells. To determine the effects of immune cells on HCC stemness, transwell co-culture experiments were performed using GFP-labeled HepG2 and T cells or monocytes/macrophages. The percentage of CD44+ HCC cells were increased during co-culture with anti-CD3/anti-CD28 activated T cells from donor PBMCs (n=9), suggesting that immune effector cells could enrich CD44+ HepG2 cells. In addition, CD44+ HCC cells were enriched during co-culture with HCC-associated macrophages (TAM) (n=3 HCC patients) or monocytes from healthy donor PBMCs (n=11). CD44+ HCC cells were positively correlated with TAM in primary HCC patients (R=0.69, n=12, p&lt;0.05), suggesting a potential role of TAM in promoting HCC-CSCs. Concordantly, sphere formation capacity was increased in HepG2 cells following co-culture with monocytes. Furthermore, co-culture with HepG2 elevated IL-6 and IL-8 produced by monocytes. IL-6 and IL-8, when added exogenously to HepG2 cells, synergistically expanded CD44+ HCC cells and promoted sphere formation capacity. In conclusion, HCC stemness phenotype is expanded by T cells, HCC associated macrophage and monocytes, as well as cytokines, IL-6 and IL-8. These findings suggest that immune cell derived factors in the tumor microenvironment may contribute to HCC recurrence or progression by promoting a stemness phenotype.
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 315. doi:1538-7445.AM2012-315
Abstract 3156: MicroRNA profiling for the detection of melanoma
Authors: Qu Kevin Z. , Liu Yan , Zhang Ke , Owen Renius X. , Sferruzza Anthony D. 
Published: August 2012

Abstract
Background: Numerous reports have suggested a link between aberrant expression of microRNAs (miRNAs) and various forms of cancer, including melanoma. We examined miRNA expression patterns in melanoma and nevi to identify candidate biomarkers for differentiating between these melanocytic lesions. Method: The study used formalin-fixed paraffin-embedded (FFPE) tissues from 78 patients with melanoma and 98 with nevi (18 compound nevi, 20 intradermal nevi, 20 junctional nevi, 20 blue nevi, and 20 spitz nevi). All lesions were confirmed by at least 2 pathologists. Total RNA was extracted from the FFPE tissue and hybridized onto the Affymetrix GeneChip miRNA array (Affymetrix, Santa Clara, CA), which measure 850 human microRNAs. After determining an optimal set of miRNAs for differentiation using random forest algorithm, we retested specimens for this set using quantitative real-time PCR (qPCR) on a TaqMan miRNA system (Applied Biosystems, Foster City, CA). Results: Expression levels of 257 miRNAs differed significantly between melanomas and nevi (p values &lt; 0.001); 129 miRNAs were downregulated and 128 were upregulated in melanomas relative to nevi. 80 of these miRNAs exhibited area under the ROC curves (AUROCs) of &gt;0.75 for distinguishing melanomas from nevi, and 74 exhibited more than a two-fold difference. An optimized set of 7 miRNAs provided good differentiation of melanomas from nevi, with an AUORC of 0.94 and 87.7% concordance with pathology-determined tissue type. miRNA array data were further validated by qPCR: for 5 of the 7 miRNAs identified above, qPCR results showed significant correlation with the miRNA array results (average Pearson correlation coefficient = 0.95). Conclusions: These data suggest that the miRNA expression pattern from FFPE tissue holds promise for distinguishing melanomas from nevi. Use of this miRNA set as a diagnostic marker requires further validation and exploration in a large-scale study.
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 3156. doi:1538-7445.AM2012-3156
Abstract 3165: microRNA-148a: A novel oncogenic microRNA in glioblastoma
Authors: Kim Jungeun , Zhang Ying , Guessous Fadila , Abounader Roger 
Published: August 2012

Abstract
Glioblastoma is the most common and deadly malignant brain tumor. One main reason of resistance of glioblastoma to therapy is the ability of the tumor cells to migrate and invade the surrounding brain, rendering total surgical removal of the tumor practically impossible. MicroRNAs (miRNA) are small noncoding regulatory RNA molecules with emerging critical roles in cancer. MicroRNAs modulate protein expression by binding to the 3-untranslated region of mRNA and promoting RNA degradation or inhibiting transcription. In this study, we analyzed data from The Cancer Genome Atlas (TCGA) and found that microRNA-148a (miR-148a) was one of few miRNAs that inversely correlated with GBM patient survival. However, nothing is known about the role of this miRNA in cancer and GBM. We therefore started a systematic study of miR-148a in GBM. We first measured miR-148a levels in GBM and found that they were &gt; 3-fold higher in GBM stem cells than in normal astrocytes and ∼15 times higher in tumor specimens than in and normal brain. We then investigated the functional effects of miR-148a on GBM malignancy. Inhibition of miR-148a in GBM stem with anti-miR-148a strongly induced apoptosis. Overexpression of miR-148a in GBM stem cells strongly promoted their self-renewal ability. Transfection of pre-miR-148a into GBM cells strongly promoted cell proliferation, migration and invasion though a membrane coated with collagen IV, a commonly expressed matrix protein in GBM. Therefore, miR-148a acts as an oncogene in GBM cells by promoting cell proliferation, migration and invasion and inhibiting stem cell differentiation. To elucidate the mode of action and targets of miR-148a in GBM, we used a combined approach of miRNA target prediction analysis and immunoblotting to identify oncogenes that are targeted and inhibited by miR-148a. We selected proteins that are known to play roles in GBM and cancer, and were able to confirm inhibition by miR-148a of MIG6 and BIM. MIG6 is a negative regulator of EGFR (an important oncogene in GBM), and BIM is a central pro-apoptotic molecule. Therefore, we predicted that miR-148a might act as an oncogenic microRNA by inducing EGFR expression and activation and inhibiting apoptosis. Using immunoblotting, we demonstrated that miR-148a does in fact induce EGFR expression and activation in GBM cells. Ongoing and future studies will assess the in vivo effects of miR-148a and evaluate its usefulness as a new target for GBM therapy. Altogether, we have uncovered miR-148a a new oncogenic microRNA in GBM that acts via regulation of EGFR and BIM.
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 3165. doi:1538-7445.AM2012-3165