bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1353: Protein tyrosine phosphatases PTP-1B, SHP-2 and PTEN facilitate Rb/E2F-associated apoptotic signaling
Authors: Morales Liza D. , Capetillo Mario , Pavon Edgar Casillas , Shin Jun W. , Garcia Alexander , Lieman Jonathan H. , Kim Dae J. 
Published: May 2015

Abstract
To maintain tissue homeostasis, apoptosis is functionally linked to cell proliferation via the retinoblastoma tumor suppressor (Rb)/E2F complex. Rb/E2F-associated apoptosis is a robust apoptotic response initiated by loss of constitutive Rb/E2F transcriptional repression and mediated by caspase-8. It is characterized by inactivation of focal adhesion kinase (FAK) through dephosphorylation by protein tyrosine phosphatase(s). In the current work, we report that three protein tyrosine phosphatases, PTP-1B, SHP-2, and PTEN, are involved in Rb/E2F-associated apoptosis. Induction of apoptosis in an osteoscarcoma cell line that conditionally expresses a dominant negative mutant of E2F-1 (ER-dnE2F-1) by treatment with 4-hydroxytamoxifen (4-OHT) led to a significant increase in levels of PTP-1B, SHP-2, and PTEN mRNA expression in comparison to untreated cells. Chromatin immunoprecipitation assays showed that E2F-1 specifically binds to putative E2F-1 binding sites identified within the three PTP promoters. Knockdown of SHP-2, PTEN, or PTP-1B using siRNA increased cell viability and decreased cell death in 4-OHT-treated ER-dnE2F-1 cells compared to control. Consistent with this observation, knockdown of SHP-2 or PTEN significantly inhibited caspase-8 activity in 4-OHT-treated ER-dnE2F1 cells in comparison to control while knockdown of SHP-2, PTEN, or PTP-1B significantly inhibited caspase-3 activity in 4-OHT-treated ER-dnE2F-1 cells compared to control. Combined, our results indicated PTP-1B, SHP-2, and PTEN are required to regulate Rb/E2F-associated apoptotic signal transduction. Furthermore, our findings suggest PTP-1B, SHP-2, and PTEN can contribute to tumor suppression through an Rb/E2F-associated mechanism.
Citation Format: Liza D. Morales, Mario Capetillo, Edgar Casillas Pavon, Jun W. Shin, Alexander Garcia, Jonathan H. Lieman, Dae J. Kim. Protein tyrosine phosphatases PTP-1B, SHP-2 and PTEN facilitate Rb/E2F-associated apoptotic signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1353. doi:10.1158/1538-7445.AM2014-1353
Abstract 136: PTEN phosphatase inhibits metastasis through negatively affecting Entpd5/IGF1R pathway
Authors: Yu Yanlin 
Published: May 2015

Abstract
Migration of cancer cell is the key event in metastasis. Recent data suggest that PTEN phosphatase activity may be required for inhibiting cell migration; however, little in vivo experimental evidence exists directly demonstrating the efficacy of PTEN phosphatase in tumor metastasis. We showed here that PTEN loss was correlated with progression to metastatic state using tissue array analysis and UV-irradiated HGF/SF transgenic-PTEN deficient mouse melanoma model. Analysis of various human melanoma cell lines demonstrated that PTEN expression was related to metastatic behavior. To further dissect the role of PTEN activity in metastasis, we have established a model system containing mutant PTEN with various phosphatase activities. We found that wild type PTEN could inhibit cell motility and invasiveness. Moreover, wild type PTEN was able to reduce metastatic potential of melanoma cells in a dose-dependent manner; in contrast, PTEN phosphatase dead mutant promoted metastatic behavior of melanoma cell. To gain more insight into the regulation of tumor cell migration, invasion and metastasis by PTEN, we performed a microarray analysis of cells with various PTEN phosphatase mutants. We found that a protein N-glycosylation and folding promoter, Entpd5 was negatively regulated by PTEN phosphatase. Down regulation of Entpd5 by shRNA in cells with PTEN phosphatase dead mutant blocked PTEN phosphatase dead mutant mediated tumor metastasis in vivo, promoted cell ER stress and growth inhibition as well as reduction of IGF1R. In contrast, overexpression of Entpd5 in cell with PTEN wild-type form enhanced PTEN wild-type-inhibited tumor metastasis in vivo, inhibited cell ER stress, promoted cell growth and abundance of IGF1R. We provide mechanistic insight toward regulation of metastasis by PTEN phosphatase and demonstrate a link between PTEN and Entpd5/IGF1R activation in metastatic process.
Citation Format: Yanlin Yu. PTEN phosphatase inhibits metastasis through negatively affecting Entpd5/IGF1R pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 136. doi:10.1158/1538-7445.AM2014-136
Abstract 1360: DNA methylation analysis in self-sampled material as a triage test in hrHPV positive women
Authors: Boers Aniek , Bosgraaf Remko P. , Leeuwen Roland W. van , Schuuring Ed , Massuger Leon FAG , Bulten Johan , Melchers Willem J. , Zee Ate GJ van der , Bekkers Ruud L. , Wisman Bea 
Published: May 2015

Abstract
Background: Primary hrHPV testing in cervical cancer screening shows relatively low specificity. To decrease the number of unnecessary referrals for colposcopy, triage testing is necessary. In this study, DNA methylation analysis was compared with routine cytology for triage testing in hrHPV positive women. Moreover, feasibility of DNA methylation analysis directly on original brush-based self-sampled specimens was assessed.
Methods: Non-responding women from population-based screening were invited to self-collect a cervico-vaginal specimen for hrHPV testing; hrHPV positive women were referred to a physician for liquid-based sampling. For this pilot study, DNA methylation analysis was performed on 128 triage samples and on 50 matched Evalyn brush self-samples with QMSP for C13ORF18, EPB41L3, JAM3 and TERT.
Results: In the physician-taken triage material, DNA methylation analysis of JAM3 showed the highest specificity (88%) combined with a high sensitivity (82%) for detection of CIN3+, whereas cytology showed a specificity of 48% and a sensitivity of 91%. Out of 39 women with abnormal cytology and normal histology (false positive by cytology), 87% were negative for JAM3 and 90% for C13ORF18 methylation. The agreement for DNA methylation analysis performed directly on the matched self-sampled material and the physician-taken samples was 90% for C13ORF18 (κ=0.77; p&lt;0.001) and 88% for JAM3 (κ=0.75, p&lt;0.001).
Conclusion: DNA methylation analysis as a triage test in hrHPV positive women outperformed cytology due to higher specificity without losing its sensitivity and is also feasible to be performed directly on Evalyn Brush self-samplers. This might result in more correct referrals to the gynecologist and eliminate the need for a new scraping taken by a medical professional thereby offering great logistic and financial advantages.
This study was financed by the Dutch Cancer Society (RUG-NKB2009-4577).
Citation Format: Aniek Boers, Remko P. Bosgraaf, Roland W. van Leeuwen, Ed Schuuring, Leon FAG Massuger, Johan Bulten, Willem JG Melchers, Ate GJ van der Zee, Ruud LM Bekkers, Bea Wisman. DNA methylation analysis in self-sampled material as a triage test in hrHPV positive women. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1360. doi:10.1158/1538-7445.AM2014-1360
Abstract 1361: The clinicopathological significance of LSD1 in esophageal cancers
Authors: Kosumi Keisuke , Baba Yoshifumi , Karashima Ryuichi , Ida Satoshi , Imamura Yu , Ishimoto Takatsugu , Iwagami Shiro , Sakamoto Yasuo , Miyamoto Yuji , Yoshida Naoya , Sakamoto Akihisa , Hino Shinjiro , Nakao Mitsuyoshi , Baba Hideo 
Published: May 2015

Abstract
Background: Lysine-specific demethylase 1 (LSD1) is the first discovered histone demethylase which specially removes H3K4me1/2 through a flavin-adenine-dinucleotide (FAD). Previous studies have indicated that LSD1 is associated with cell proliferation, cell invasion and epithelial-mesenchymal transition in human malignant tumors. Recently, it is accepted that LSD1 epigenetically regulates energy-expenditure genes in adipocytes depending on the cellular FAD availability. As a PET scan with a FDG tracer can detect cancers, the method is exceedingly useful for tumor staging or therapeutic effect determination of esophageal cancers. The aim of this study is to investigate the expression and function of LSD1 in esophageal cancer cell-lines and, to analyze the relationships between the LSD1 expression and clinicopathological data including SUVmax (standardized uptake value).
Methods: The influence of LSD1 on cell proliferation and invasion was evaluated by knockdown experiments. Using 113 resected esophageal cancer specimens, we evaluated the LSD1 expression by immunohistochemistry and devided them into two groups; a low expression group (LEG) and a high expression group (HEG). We compared these two groups and analyzed the relationships between LSD1 expression and clinicopathological data.
Results: In vitro analysis, knockdown of LSD1 did not impact cell proliferation, but suppressed cell invasion. In the immunohistochemical study, the HEG's age was significantly higher (P=0.021), and this group had esophageal cancers at lower locations (P=0.058). HEG was significantly correlated with the T-stage (P=0.020), lymph and blood vessels invasion (P=0.020, P=0.001), and a higher SUVmax (P=0.0088) and lower overall survival (P=0.0017).
Conclusions: Our study demonstrated the relationships between the expression of LSD1 and T-stage, lymph and blood vessels invasion, and the SUVmax in esophageal cancers. It is suggested that LSD1 has a potential to impact the malignancy of the esophageal cancer, and may be a therapeutic target in patients with esophageal cancers.
Citation Format: Keisuke Kosumi, Yoshifumi Baba, Ryuichi Karashima, Satoshi Ida, Yu Imamura, Takatsugu Ishimoto, Shiro Iwagami, Yasuo Sakamoto, Yuji Miyamoto, Naoya Yoshida, Akihisa Sakamoto, Shinjiro Hino, Mitsuyoshi Nakao, Hideo Baba. The clinicopathological significance of LSD1 in esophageal cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1361. doi:10.1158/1538-7445.AM2014-1361
Abstract 1362: Nuclear morphometry measures progressive atypia in the development of pancreatic carcinoma
Authors: Glazer Evan S. , Hill Kimberly A. , Zhang Hao (Helen) , Bartels Peter , Watkins Joseph , Alberts David S. , Krouse Robert S. 
Published: May 2015

Abstract
Pancreatic lesions that are not clearly benign are often treated as malignant despite uncertainty in the true diagnosis due to the nearly universally fatal nature of pancreatic carcinoma (PC). Nuclear morphometry is a technique to quantify nuclear features too complex for the human eye to discern. We hypothesized that nuclear atypia can be quantified with morphometry in order to distinguish between chronic pancreatitis, IPMN, and PC. We retrospectively analyzed 14 specimens of chronic pancreatitis, 16 IPMN lesions, and 19 PC lesions. Clinicopathologic data were obtained. Nuclear morphometry determined overall atypia based on the average nuclear abnormality of 95 distinct nuclear features (a nuclear signature). For PC lesions, 5 nuclear features defined a classification score (CS) representing the proportion of aggressive nuclei in a given PC lesion. Statistical significance was determined with ANOVA and the Kruskal-Wallis test. The average age for all patients was 63 ± 15 years while 62% were male; there were no differences between the 3 groups. The follow up was approximately 4 years in all groups as well. The average nuclear atypia of chronic pancreatitis was 0.80, 0.99 for IPMN, and 1.08 for PC (P = 0.02). Importantly, based on 5 nuclear features, the CS for PC lesions that recurred was 87% while it was only 56% for those PC lesions that did recur (P = 0.04). The research describes a precise, accurate, and objective method to distinguish IPMN from PC. The CS and overall atypia score provides a method to not only objectively describe a given lesion, but it importantly describes where in the progression from benign to malignant lesion an unknown lesion exists. Clinically, this may be of great utility in risk stratifying unknown pancreatic lesions at the time of diagnosis or tissue biopsy.
Citation Format: Evan S. Glazer, Kimberly A. Hill, Hao (Helen) Zhang, Peter Bartels, Joseph Watkins, David S. Alberts, Robert S. Krouse. Nuclear morphometry measures progressive atypia in the development of pancreatic carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1362. doi:10.1158/1538-7445.AM2014-1362
Abstract 1364: Epigenetic regulation of SPARC in ovarian cancer
Authors: Matthews Dylan P. , Taylor Sherine , Said Neveen A. 
Published: May 2015

Abstract
Epithelial Ovarian cancer (OvCa) is the leading cause of death from gynecologic malignancies as most patients are diagnosed at late stages. Despite aggressive surgical debulking and cytoreduction, recurrence is common with poor patient survival. Constitutive progressive inflammation is the hallmark of OvCa and is contributed by the interaction of transformed OvCa cells with cues from the peritoneal microenvironment, activating multiple signaling pathways that converge in the (trans)activation of NFκB which not only induces the transcription of myriad inflammatory mediators but represses tumor suppressor genes (TSGs) creating a vicious circle of disease progression, recurrence and chemoresistance. Therefore there is a pressing need to identify new diagnostic, prognostic biomarkers as well as new. Our earlier studies indicated Secreted protein acidic and rich in cysteine SPARC is a tumor suppressor in OvCa in vitro and in vivo. In addition, we found that SPARC suppresses OvCa cells interactions with environmental cues within the peritoneal milieu. We also found that the expression of SPARC was decreased in established OvCa cell lines and microdissected OvCa cells from advanced tumors consistent with hypermethylated of its promoter. However, the mechanisms of epigenetic regulation of SPARC in OvCa (and other morbidities) are unraveled. Mapping of SPARC promoter revealed consensus binding sites for NFB subunits. Pharmacologic inhibition of NFκB as well as knockdown of p65-RelA and p50 subunits restored SPARC expression and function in OvCa cells. Furthermore, treatment of OvCa cells with demethylating agent 5′azacytidine indicated that NFκB-mediated SPARC repression is due to methylation. In OvCa tissue microarrays, the expression of SPARC in cancer cells inversely correlated with nuclear p65-RelA and DNMT3a expression. Together these findings indicate that activated NFκB integrates inflammatory signals to exert epigenetic pressure suppressing tumor cell SPARC through promoter methylation.
Citation Format: Dylan P. Matthews, Sherine Taylor, Neveen A. Said. Epigenetic regulation of SPARC in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1364. doi:10.1158/1538-7445.AM2014-1364
Abstract 1365: Epigenetic modification of LY6K in CGI shore and CGI regulates LY6K gene activation and metastatic function in breast cancer
Authors: Kong Hyun Kyung , Park Sae Jeong , Kim Ye Sol , Park Jong Hoon 
Published: May 2015

Abstract
Lymphocyte antigen 6 complex locus K (LY6K) is associated with development of the immune response and carcinogenesis. Elevated LY6K by AP-1 activation induces cell invasion and metastasis through activating the Raf-1/MEK/ERK signaling pathway. However, the exact epigenetic mechanism of LY6K gene expression has yet to be clarified. To elucidate the epigenetic mechanism of LY6K gene regulation and expression, CpG island and 5′CGI shore in the region around transcription start site of the LY6K were predicted using UCSC genome browser and Methprimer software. We performed MSP, bisulfite pyro-sequnecing, and bisulfite sequencing to investigate the DNA methylation status of CpG sites from -400 to +500 on the LY6K CGI and 5′CGI shore. Breast cancer cells with low LY6K expression were highly methylated in the both CGI and 5′CGI shore region, whereas high LY6K expression cell lines had low methylation levels. Moreover, 5-Aza-dC, demethylaing agent, treatment of cells with low LY6K expression caused elevation of LY6K expression and finally leads wound healing. To further validate the inverse correlation between LY6K 5′CGI shore methylation and LY6K expression in vivo seen in breast cancer cell lines, we performed bisulfite pyro-sequencing and tissue microarray using breast carcinoma samples. LY6K expression inversely correlates with methylation status and histone modification of 5′CGI shore in the LY6K promoter in human breast cancers. An understanding of epigenetic changes in LY6K may contribute to the diagnosis of carcinogenic risk and to prediction of outcome in patients with breast cancer.
Citation Format: Hyun Kyung Kong, Sae Jeong Park, Ye Sol Kim, Jong Hoon Park. Epigenetic modification of LY6K in CGI shore and CGI regulates LY6K gene activation and metastatic function in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1365. doi:10.1158/1538-7445.AM2014-1365
Abstract 1367: An epigenetic screen unmasks metallothioneins as putative contributors to renal cell carcinogenesis
Authors: Krause Hans , Al-Kamal Imad , Ikromov Odiljon , Miller Kurt , Kempkensteffen Carsten 
Published: May 2015

Abstract
Transcriptional silencing, as a result of aberrant promoter hypermethylation, is a common mechanism through which genes in cancer cells become inactive. Functional epigenetic screens using demethylating agents to re-express transcriptional silenced genes may identify such inactivated genes for further evaluation. We aimed to identify renal cell carcinoma (RCC) genes so far not known to be inactive due to promoter hypermethylation.
The RCC cell line A-498 was treated with the DNA methyltransferase inhibitor zebularine under low cytotoxicity conditions. Expression changes of the transcriptome of treated and untreated cells were compared using RNA expression microarrays (Affymetrix Human Genome U133A v. 2.0). Eight candidate genes (criteria: upregulation more than 3-fold, presence of CpP islands in the promoter region, in silico predicted downregulation in tumors) were evaluated by Q-PCR in 49 paired normal and RCC tissues of patients (39 ccRCC, 7 pRCC, and 3 cRCC), who underwent radical nephrectectomy in our clinic between 2009 and 2010. Members of the metallothionein group were remarkably downregulated in tumor tissues. Metallothionein 1G (MT1G) was downregulated in 48 of 49 tumor tissues (p&lt;0.0001), MT1H was downregulated in 42 out of 43 tumor tissues (p&lt;0,0001), and MT2A expression was decreased in 73% (34/49) of all cases. The remaining 5 candidates (EFNB2, RRAD, TGM2, ITGA2, and MBD4) were found either upregulated in the majority of RCCs or without reasonable expression differences between normal und tumor tissues. To prove the consistency of our epigenetic screening approach we compared expression data of 308 upregulated transcripts (≥ 1.5-fold) to similar screens performed by other groups that revealed a high number of shared candidates.
Although a possible contribution of metallothioneins to renal cell carcinogenesis is not fully understood, our discovery of an almost exclusively downregulation of selected MT genes in RCC tissues emphasizes a plausible link between deregulated metabolism and tumor development. In the context of an ever-increasing demand for suitable markers for clinical decision-making and a better understanding of renal cell carcinogenesis, selected members of the MT group may serve as appropriate candidates for these tasks.
Citation Format: Hans Krause, Imad Al-Kamal, Odiljon Ikromov, Kurt Miller, Carsten Kempkensteffen. An epigenetic screen unmasks metallothioneins as putative contributors to renal cell carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1367. doi:10.1158/1538-7445.AM2014-1367
Abstract 1368: Genome-wide screening of DNA methylation markers to predict the presence of lymph node metastasis in esophageal squamous cell carcinoma
Authors: Kozaki Ken-ichi , Nagata Hiroaki , Tanimoto Kousuke , Fujiwara Naoto , Imoto Seiya , Ichikawa Daisuke , Miyano Satoru , Kawano Tatsuyuki , Otsuji Eigo , Inazawa Johji 
Published: May 2015

Abstract
Lymph node metastasis (LNM) of esophageal squamous cell carcinoma (ESCC) is well-known to be an early event that is associated with poor prognosis of ESCC patients. In the last few years, tumor-specific aberrations in DNA methylation of CpG islands around promoter regions of tumor-related genes have been investigated as possible biomarkers for early diagnosis, treatment and prognosis of human cancers. But, there are few DNA methylation markers that can predict the presence of LNM in patients with ESCC. To identify DNA methylation markers correlated with LNM of ESCC, we performed a genome-wide screening of DNA methylation status in a discovery cohort of 67 primary ESCC tissues and their paired normal esophageal tissues by Illumina Infinium HumanMethylation450 BeadChip (covers more than 450,000 CpG sites). In this screening, we focused on some differentially methylated regions (DMRs), which were significantly associated with LNM of ESCC, as prime candidates for DNA methylation markers. In addition, these significant relationships were also confirmed by quantitative bisulfite pyrosequencing analysis in the same discovery cohort. Consequently, these results led us to consider that our selected DMRs might be useful epigenetic biomarkers for the prediction of the presence of LNM in primary ESCC cases. Therefore, we are continuing further analyses of these DMRs in an independent external validation cohort of ESCC patients.
Citation Format: Ken-ichi Kozaki, Hiroaki Nagata, Kousuke Tanimoto, Naoto Fujiwara, Seiya Imoto, Daisuke Ichikawa, Satoru Miyano, Tatsuyuki Kawano, Eigo Otsuji, Johji Inazawa. Genome-wide screening of DNA methylation markers to predict the presence of lymph node metastasis in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1368. doi:10.1158/1538-7445.AM2014-1368