bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4074: Prostaglandin E2 promotes intestinal tumor growth via DNA methylation
Authors: Xia Dianren , Wang Dingzhi , Kim Sun-Hee , Katoh Hiroshi , DuBois Raymond N. 
Published: August 2012

Abstract
Both chronic inflammation and DNA methylation have been implicated as early events during colorectal cancer (CRC) carcinogenesis. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk for colorectal cancer (CRC) by 40-50%. NSAIDs exert some of their anti-inflammatory or anti-tumor effects by inhibiting prostaglandin-endoperoxide synthase (PTGS) 1 and 2. PTGS2-derived prostaglandin E2 (PGE2) is a pro-inflammatory mediator and promotes tumor progression. Promoter DNA methylation may promote tumor growth through silencing tumor suppressor or DNA repair genes. Whether chronic inflammation, specifically in this study the pro-inflammatory factor PGE2, plays a role in DNA methylation and contributes to CRC carcinogenesis is unknown. Here we demonstrated that PGE2 upregulated DNA methyltransferase (DNMT) 1 and 3B, which resulted to increased DNA methylation in the promoters of target genes O6-methylguanine-DNA methyltransferase (MGMT), cannabinoid receptor 1 (CNR1), CDKN2B, and MutL homolog 1 (MLH1) in CRC cell lines. Meanwhile, the expression of MGMT, CNR1, CDKN2B, and MLH1 were decreased. EP4 antagonist blocked the upregulation of DNMT1 and DNMT3B while knockdown of DNMT1 or DNMT3B attenuated the dwonregulation of MGMT, CNR1, CDKN2B, and MLH1 by PGE2 in LS-174T cells. In ApcMin/+ mice, PGE2 treatment also increased the expression of DNMT1 and DNMT3B and the DNA methylation of MGMT, CNR1, CDKN2B, and MLH1 promoters, and reduced their expression. All these alterations were accompanied by increases in both polyp number and size in the intestines of ApcMin/+ mice. More intriguingly, a demethylating agent 5-Aza-dC blocked the PGE2-induced DNA methylation and tumor growth in ApcMin/+ mice. And a combination treatment with a selective PTGS2 inhibitor celecoxib and 5-Aza-dC more effectively reduced the polyp number and size in ApcMin/+ mice in comparison with either single agent. Furthermore, the levels of PTGS2 and PGE2 correlated with the expression of DNMT1 and DNMT3B; The DNA methylation of MGMT, CNR1, and MLH1 correlated with the levels of PTGS2, PGE2, DNMT1, and DNMT3B in human colorectal carcinomas. These results suggest that PGE2 can silence tumor suppressor or DNA repair genes via DNA methylation to promote CRC carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4074. doi:1538-7445.AM2012-4074
Abstract 4078: Antitumor effect of the histone deacetylase inhibitor MS-275 in combination with retinoic acid Am80 in human cutaneous T-cell lymphoma
Authors: Kato Yukihiko , Egusa Chizu , Maeda Tatsuo , Tsuboi Ryoji 
Published: August 2012

Abstract
Resistance to chemotherapy is a major hurdle in the treatment of cutaneous T cell lymphoma. Histone deacetylase (HDAC) inhibitors are known to display antitumor activity in different tumor types, including melanoma, and to reverse epigenetic repression of tumor suppressor genes, such as retinoic acid receptor ≤ (RARα). Some HDAC inhibitors have begun to be used for cutaneous T cell lymphoma patients in Japan. In this study, we tested the antitumor effect of the HDAC inhibitor MS-275 in combination with retinoic acid Am80 on two human cutaneous T cell lymphoma cell lines in vitro. Treatment of MS-275 showed a dose-dependent inhibitory effect on SeAx and MJ cell lines in a MTT assay. These cell lines were relatively resistant to Am80. A greater inhibitory effect (up to 80%) was achieved with a combination of MS-275 and Am80 compared with each agent alone. The lack of RARα2 gene expression was associated with histone deacetylation and gene methylation at the promoter level. Treatment with the combination of MS-275 and Am80 restored retinoid sensitivity by reversing RARα2 epigenetic silencing, which was verified by ChIP assay using histone H4. P21 was induced in both cell lines but the biological effect of MS-275 was G1cell cycle arrest in MJ and apoptosis in the SeAx cell line. These results suggest that the HDAC inhibitor MS-275 has a greater antitumor activity in combination with Am80 in cutaneous T cell lymphomas but that the degree of induced cell death may vary. The combination of HDAC inhibitors and retinoids represents a novel therapeutic approach for cutaneous T cell lymphoma that warrants clinical testing.
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 4078. doi:1538-7445.AM2012-4078
Abstract 4092: Cancer-type regulation of MIG-6 expression by 5-Aza-2′-deoxycytidine and Trichostatin A
Authors: Zhang Yu-Wen , Staal Ben , Vande Woude George F. 
Published: August 2012

Abstract
Mitogen inducible gene 6 (MIG-6) is a tumor suppressor gene located in chromosome 1p36 which is frequently lost in many human cancers. It is mainly viewed as a negative feedback regulator of epidermal growth factor receptor (EGFR) family members by directly binding to the receptors and thereby negatively regulating the signaling. Mice with Mig-6 deficiency are prone to develop epithelial hyperplasia or tumors in various tissues including lung, gallbladder, bile duct, uterus and skin. Previously, we reported a few mutations in MIG-6 gene in human lung cancer, but such event is rare. To determine if MIG-6 is regulated by epigenetic silencing, we identified a group of cancer cell lines with low or no MIG-6 expression and investigated the status of DNA methylation and histone deacetylation in MIG-6 promoter. We found that DNA methylation inhibitor 5-Aza-2′-deoxycytidine (5-Aza-dC) induced MIG-6 expression in the melanoma but not in the lung cancer cell lines, while histone deacetylase inhibitor Trichostatin A (TSA) induced MIG-6 expression in lung cancer lines but not in melanoma cell lines. However, the MIG-6 promoter itself does not seem to be directly affected by methylation or histone deacetylation, indicating they are indirectly regulated and most likely mediated by transcription factor(s). Luciferase reporter assays revealed that a short segment of exon-1 in MIG-6 gene is responsible for the induction of its expression by TSA in the lung cancer cells. Our data suggest that MIG-6 gene expression is differentially regulated by the inhibitors of methylation and histone deacetylation in lung cancer and melanoma cells respectively, without directly modifying the promoter.
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 4092. doi:1538-7445.AM2012-4092
Abstract 41: Identification of CXCL5/ENA-78 regulating the interaction of cholangiocarcinoma and cancer-associated fibroblasts
Authors: Okabe Hirohisa , Beppu Toru , Ueda Mitsuharu , Hayashi Hiromitsu , Masuda Toshiro , Mima Kosuke , Nakagawa Shigeki , Miyake Keisuke , Yokoyama Naomi , Baba Yoshifumi , Takamori Hiroshi , Ishiko Takatoshi , Jono Hirofumi , Shinriki Satoru , Ando Yukio , Baba Hideo 
Published: August 2012

Abstract
Background and Aims: Tumor-stromal interaction has been recognized to be essential for understanding tumor development. Cholangiocarcinoma shows very poor prognosis and have fibrous tumor stroma. Hepatic stellate cells are well-known to have a major role in hepatic fibrogenesis. Therefore, we have focused on the interaction of cholangiocarcinoma and hepatic stellate cells and reported their positive interaction (Ann Surg Oncol 2009, 2011). The aim of this study is to identify the key protein which is important for the interaction of cholangiocarcinoma cells and hepatic stellate cells and examine its functional role in tumor progression. Methods: Using co-culture model and proteomic analysis, we analyzed the secreted factors which were considered to be important for their interaction. The functional role of CXCL5 was examined in vitro and clinical significance was validated using human intrahepatic carcinoma samples by immunohistochemistry. Results: Using SELDI-TOF-MS and qTOF-MS/MS analysis, we identified CXCL5 which was remarkably increased when they were co-cultured. CXCL5 which was mainly produced by cholangiocarcinoma cell lines (HuCCT1 and RBE) promoted the invasion, and migration of them in the autocrine fashion. These effects were significantly decreased by inhibition of CXCR2 which was a receptor of CXCL5. IL1β was found to up-regulate in hepatic stellate cells when they were co-cultured by cytokine array analysis, we also found that IL1β accelerated the production of CXCL5 in cholangiocarcinoma cells. In human intrahepatic cholangiocarcinoma, immunohistochemical study showed that there was a significant correlation between stromal myofibroblasts and CXCL5 produced by cholangiocarcinoma cells. Since CXCL5 is identified as epithelial neutrophil activating factor-78 (ENA-78), we researched the presence of CD66b positive immune cells which have been recently reported to be tumor-associated neutrophils. CD66b positive immune cells are more abundant in CXCL5 high expression group. In addition, high CXCL5 expression group showed worse survival than low expression group. Conclusion: We conclude that CXCL5 is important for the interaction of cholangiocarcinoma and stromal myofibroblasts and that the strategies to inhibit tumor-stromal cell interactions may be beneficial in cholangiocarcinoma.
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 41. doi:1538-7445.AM2012-41
Abstract 4101: Prognostic significance of LINE-1 mathylation level in gastric cancer
Authors: Iwagami Shiro , Baba Yoshifumi , Watanabe Masayuki , Shigaki Hironobu , Miyake Keisuke , Kurashige Jyunji , Ishimoto Takatsugu , Iwatsuki Masayuki , Baba Hideo 
Published: August 2012

Abstract
Background: Genome-wide DNA hypomethylation plays a role in genomic instability and carcinogenesis. DNA methylation in the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of the global DNA methylation level. In some types of human neoplasms, the LINE-1 methylation level is attracting interest as a useful marker for predicting cancer prognosis. However, the prognostic significance of LINE-1 hypomethylaiton in gastric cancer remains unclear. Methods: Using 96 resected gastric cancer specimens, we quantified the LINE-1 methylation using bisulfite-pyrosequencing technology. A Cox proportional hazards model was used to calculate the hazard ratio (HR), adjusted for tumor stage. Results: Gastric cancers showed significantly lower LINE-1 methylation levels compared to matched normal gastric mucosa (p&lt;0.0001; N=50). The distribution of the LINE-1 methylation level in the 96 cancers was as follows: mean, 71.0; median, 72.9; SD, 12.2; range, 28.0-97.5; interquartile range, 66.7-77.7 (all in 0-100 scale). LINE-1 methylation level was not associated with tumor stage, T status, or N status (all P&gt;0.05). In univariate analysis, LINE-1 hypermethylation tumor (more than 77.7) tended to have longer overall survival (log-rank p=0.10; univariate HR=0.50, 95% CI 0.19-1.12, p=0.097), although that was not statistically significant. However, in stage-adjusted analysis, LINE-1 hypermethylation was significantly associated with overall survival (HR=0.38, 95% CI 0.14-0.87, p=0.021). Conclusions: LINE-1 hypermethylation in gastric cancer is associated with longer survival, suggesting that it has potential for use as a prognostic biomarker.
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 4101. doi:1538-7445.AM2012-4101
Abstract 4109: The unfolded protein response promotes tolerance to extreme hypoxia through autophagy dependent maintenance of cellular metabolism
Authors: Cojocari Dan , Weljie Aalim , Wen Jing , Rouschop Kasper M.A , Vellanki Ravi , Koritzinsky Marianne , Wouters Bradly G. 
Published: August 2012

Abstract
Oxygenation patterns in solid human tumors are highly heterogeneous both amongst and within tumors, and individual cells can be exposed to mild or extreme hypoxia. Hypoxia is known to influence the behavior of tumor cells in an adverse manner, resulting in poor response to radiotherapy, chemotherapy, and an increased metastatic capacity. The ability of cells to tolerate extreme hypoxia and the unusual metabolic environments found within tumors are not fully understood, but cell phenotype is influenced through at least three important oxygen-sensing pathways: HIF, mTOR and the unfolded protein response (UPR). Previously we have shown that the PERK-eIF2α arm of UPR, which is activated rapidly in response to extreme hypoxia, contributes to hypoxia tolerance in both cell lines and in human tumor xenografts. Furthermore, we found that signaling through PERK results in increased capacity for autophagy through direct transcriptional regulation of the autophagy genes ATG5 and LC3b during hypoxic exposure. We hypothesize that autophagy promotes survival during hypoxia through regulation of metabolic homeostasis and control of proteotoxicity. To elucidate the contribution of PERK signaling and autophagy to cell survival and metabolic homeostasis we created a series of isogenic cell lines with inducible expression of transgenes that cause PERK or autophagy signaling deficiency. We analyzed the changes in metabolism and in global metabolite levels during exposure to extreme hypoxia in wild type, PERK deficient, and autophagy deficient variants. Using liquid chromatography mass spectrometry, we identified a series of metabolites whose concentration varied in a time-dependent manner during hypoxia. Importantly, we found that cells defective in PERK signaling decreased levels of amino acids, increased fatty acids and evidence of oxidative stress products. Both, PERK signaling and autophagy deficiency resulted in accelerated glucose metabolism as evidenced by increased consumption and lactate production during hypoxia compared to controls. Together, these results suggest that PERK-dependent regulation of autophagy contributes to maintenance of bio-energetic status, preventing increased glucose flux and production of reactive oxygen species. Our data also demonstrate that aggressive, therapy resistant hypoxic cells may be selectively targeted by therapies that exploit the dependency of these cells on autophagy for survival.
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 4109. doi:1538-7445.AM2012-4109
Abstract 4112: Prognostic impact of autophagic markers LC3, Beclin 1 and p62/sequestosome 1 in colon carcinomas from patients treated in 5-FU-based adjuvant therapy trials
Authors: Sinicrope Frank A. , Wu Tsung-Teh , Foster Nathan R. , Sargent Daniel J. , Huang Shengbing , Park Jae Myung 
Published: August 2012

Abstract
Background. Autophagy maintains energy metabolism and enables tumor cell survival during cellular stress. Beclin 1 is involved in autophagosome formation during which membrane-bound LC3 binds to p62/sequestosome 1. We reported that ectopic p62 can promote 5-fluorouracil-induced cell death (JBC 286:40002-12, 2011). It is unknown whether these autophagy markers can predict clinical outcome. Materials & Methods. Beclin 1, LC3B, and p62 proteins were analyzed by immunohistochemistry in tissue microarrays containing stage II and III colon carcinomas (N=151) from patients receiving 5-FU or surgery alone. The mean weighted score (intensity x extent) was dichotomized for survival analysis using Cox models. Results. Increased levels of cytoplasmic LC3, Beclin 1, and p62 expression were detected in 21%, 14%, and 68% of cancers, respectively, and were not associated with tumor site, stage or grade. By multivariable analysis, increased LC3 was significantly associated with worse disease-free survival (DFS) (p=0.022), but not overall survival (OS) [p=0.069](Table). Beclin 1 was not prognostic, but increased p62 was significantly associated with improved DFS (p=0.038), but not OS (p= 0.176)[Table]. When restricted to 5-FU-treated patients, increased LC3 was associated with worse DFS [HR= 2.38 (1.19, 4.75, p=0.020), elevated Beclin 1 predicted worse OS [HR=2.83 (1.27, 6.34), p = 0.019], and p62 was not prognostic. Conclusion. LC3 and Beclin 1 overexpression were independently associated with adverse outcome. Increased p62 was associated with better outcome consistent with its ability to promote cell death. These data support strategies to inhibit autophagy for therapeutic advantage.

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 4112. doi:1538-7445.AM2012-4112
Abstract 412: Expression of cancer stem cell markers in pancreatic ductal adenocarcinomas and pancreatic intraepithelial neoplasias
Authors: Kure Shoko , Matsuda Yoko , Hagio Masahito , Suzuki Taeko , Ueda Junji , Yamahatsu Kazuya , Yamamoto Tetsushi , Naito Zenya , Ishiwata Toshiyuki 
Published: August 2012

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a high incidence of distant metastasis. Recent studies have shown that cancer stem cells (CSCs) are important in cancer cell growth, invasion, metastasis, and recurrence. Several studies have revealed some CSC-specific markers for PDAC, such as CD133, CD24, CD44, CXCR4, ESA, and nestin. Some evidence also suggests that PDAC progresses through a multistep process comprised of noninvasive precursor lesions known as pancreatic intraepithelial neoplasias (PanINs). The reports of CSCs in PanINs are limited. We performed a comprehensive analysis of the expression of CSC markers in PDACs, PanINs, and normal pancreatic tissues. Materials & Methods: CD24, CD44, ESA, CD133, CXCR4, and nestin were used as CSC markers. Human PDACs (n=67), PanIN-1 (n=35), PanIN-2 (n=52), PanIN-3 (n=18), and normal pancreatic tissues (n=54), which were obtained from patients who underwent surgical operations in the surgical department of Nippon Medical School, were used for immunohistochemical analysis. Human PDAC cell lines, PANC-1, KLM-1, and MIA PaCa-2, were used for flow cytometric assays and quantitative RT-PCR analysis. Results: Regarding the clinicopathological features, the positivity of CD44 and CD133 showed significant correlations for UICC classifications and histological features In the survival analysis, CD133-positive PDACs led to a significantly poorer prognosis. In the immunohistochemical analysis, CD24, CD44, ESA, CXCR4, and nestin showed a gradual increase of positivity along with the grades of PanINs. Flow cytometric assays and RT-PCR analysis confirmed the expression profile in PDAC. Conclusion: CSC markers were expressed to various extents in PDAC, and the expression of CD133 and CD44 was correlated with the prognosis and stage. Furthermore, CSC markers showed a gradual increase along with the grades of PanINs; therefore, CSC may be involved in the carcinogenesis of PDAC.

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 412. doi:1538-7445.AM2012-412
Abstract 4139: Clinical evaluation of microRNA expression profiling in non-small cell lung cancer
Authors: Markou Athina N. , Vorkas Panagiotis A. , Sourvinou Ioanna , Yousef George M. , Lianidou Evi S. 
Published: August 2012

Abstract
CONTEXT: MicroRNAs (miRNAs) represent a class of small non-coding RNAs that regulate gene expression at the posttranscriptional level. miRNAs play an important role in tumorigenesis since they have functions similar to oncogene or tumor suppressors and represent a new class of powerful tools for cancer prevention and therapeutics. Especially circulating miRNAs in plasma seem to be very promising novel tumor biomarkers, since their expression is correlated to diagnosis, prognosis and prediction of response to treatment. OBJECTIVE: The aim of our study was to evaluate mature miRNAs as novel tumor biomarkers in NSCLC, by exploring global expression profile of miRNAs in NSCLC paired fresh tissues and corresponding plasma samples. METHODS: FlexmiR bead array (Luminex) assay was utilized for miRNA expression profiling in 21 surgically removed NSCLC fresh tissues and their corresponding adjacent non-cancerous tissues. According to our FlexmiR results, evaluated by three different statistical approaches, 23 miRNAs were found to be differentially expressed. Our FlexmiR experiments were validated for four of these microRNAs in 40 paired NSCLC and matched corresponding adjacent non-cancerous tissues by Taqman RT-qPCR microRNA assays (Applied Biosystems). Moreover, total RNA was extracted from 37 corresponding plasma samples and miR-21 expression was quantitated by RT-qPCR. RESULTS: 23 miRNAs were found to be differentially expressed in NSCLC by the FlexmiR assay. Four of these, miR-21, miR-126*, miR-30d and miR-451, were further evaluated by quantitative RT-qPCR. The expression level of miR-21 was significantly higher in NSCLC tissues than in adjacent normal tissues (P=0.002); while miR-126* (P=0.000), miR-30d (P=0.000) and miR-451 (P=0.000) were down-regulated in NSCLC. Interestingly, high miR-21 expression and low miR-126* and miR-30d expression were associated with disease free survival (P=0.027, P= 0.047 and P=0.048 respectively). Levels of circulating miR-21 in plasma of NSCLC patients were significantly higher in NSCLC than in healthy volunteers (P=0.003). Circulating miR-21 in plasma was found to be an independent prognostic factor for NSCLC (P=0.019).
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 4139. doi:1538-7445.AM2012-4139