bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1014: Dihydrotanshione I induces caspase-independent cell death and autophagy in lung cancer cells
Authors: Kim Sung-Hoon , Won Gunho , Jeong Myoung Seok , Yoon Sang Wook , Lee Jihyun , Kim Bonglee , Sohn Eun Jung 
Published: August 2015

Abstract
In the present study the antitumor mechanism of dihydrotanshinone I (DHT) from Salvia miltiorrhiza Bunge was elucidated in lung cancer cells. DHT significantly exerted cytotoxicity and increased the apoptosis by Annexin V assay in NSCLC (A549 and H460 cells) and lung mesothelioma cells (H28, H2452, MSTO). Furthermore, DHT reduced clonogenic ability in A549 cells. Interestingly, DHT increased PARP cleavage, but no activation of caspase-9 and caspase-3, although caspase-8 and, 3 were partially activated. FACS analysis revealed that the pan-caspase inhibitor z-VAD-fmk increased apoptosis induced by DHT. Furthermore, MTT assay showed that z-VAD-fmk treatment did not block cell cytotoxicity induced by DHT. In contrast, DHT induced the features of autophagy, including formation of autophagosomes by immunofluorescence and an increase of LC3II level after DHT exposure. Treatment of 3MA, an inhibitor of autophagy, blocked the expression level of LC3II induced by DHT and induced cytoprotective autophagy in A549 cells. Taken together, our data suggest that DHT induces caspase-independent cell death and autophagy in lung cancer cells as a potent agent for lung cancer treatment.
Citation Format: Sung-Hoon Kim, Gunho Won, Myoung Seok Jeong, Sang Wook Yoon, Jihyun Lee, Bonglee Kim, Eun Jung Sohn. Dihydrotanshione I induces caspase-independent cell death and autophagy in lung cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1014. doi:10.1158/1538-7445.AM2015-1014
Abstract 1027: Apoptotic resistance in arsenic transformed cells attributed to decreased SIRT3-FOXO3A signaling
Authors: Roy Ram V. , Shi Xinglin 
Published: August 2015

Abstract
SIRT3 is the primary mitochondrial protein deacetylase that regulates mitochondrial proliferation and DNA integrity. SIRT3 is the only sirtuin whose increased expression was shown to be associated with extended lifespan in humans. Interestingly, very few studies have examined the role of SIRT3 in cancers. Here, we report cellular function of SIRT3 in Beas-2B cells under arsenic stress, and in AT cells. Upon treatment with arsenic, in Beas-2B cells, SIRT3 levels increased and induced apoptosis - nuclear translocation and binding of SIRT3 to FOXO3A - while AT cells exhibited lower levels of SIRT3 which can be attributed to apoptotic resistance, as over-expression of SIRT3 restores sensitivity to apoptosis. In AT cells, lower expression of SIRT3 caused hyperacetylation and aberrant localization of its target protein - FOXO3A. One of the consequences of low SIRT3 levels is absence of SIRT3-FOXO3A interaction in AT cells, which increases the proportion of transcriptionally hyperactive, highly depolarized mitochondria (high ΔΨm) with higher mitochondrial DNA content compared to passage matched parent Beas-2B cells. Conversely, Resveratrol-induced high expression of SIRT3 improves nuclear-mitochondrial crosstalk (increased FOXO3A binding in the D-loop region) and raises sensitivity towards apoptosis. By disconnecting crosstalk between nucleus and mitochondria (SIRT3-FOXO3A interactions), AT cells increase depolarized mitochondrial number, so that the transformed cells maintain low basal ROS and proliferate rapidly. This is the first time that a study has shown functional role of SIRT3-FOXO3A in promoting apoptosis in Beas-2B cells under arsenic stress, and in AT cells.
Citation Format: Ram V. Roy, Xinglin Shi. Apoptotic resistance in arsenic transformed cells attributed to decreased SIRT3-FOXO3A signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1027. doi:10.1158/1538-7445.AM2015-1027
Abstract 1045: A snapshot of pan-cellular PTM in response to Sorafenib-mediated multikinase inhibition
Authors: Loch Christian M. 
Published: August 2015

Abstract
More fundamentally than regulating specific functions or cascades, PTM affords proteins the mechanical complexity necessary to make human cells function. We believe that specifically modified forms of proteins are what conduct the cells business, and that by monitoring these “proteoforms” we can gain unique insight into cellular physiology. To test this, we treated HepG2 hepatocellular carcinoma cells with the multi-kinase inhibitor Sorafenib, and observed pharmacodynamic changes to PTM across the cellular proteome. Our novel approach, referred to as Snapshot Proteomics, revealed changes in phosphorylation to known targets of this drug. Intriquingly, we also observed changes to proteins whose roles make them strong candidates for mediating the clinical side effects of Sorafenib treatment. We also observed that the changes mediating the therapeutic response were far from the most dramatic ones observed, suggesting other, unexpected proteins as better putative pharmacodynamic biomarkers. Finally, we found that manipulating cellular phosphorylation pharmacologically had dramatic and interesting effects on other PTM pathways as well, ubiquitin in particular. This confirmed the already established crosstalk between these pathways, and supports our contention that no PTM occurs in a vacuum.
Citation Format: Christian M. Loch. A snapshot of pan-cellular PTM in response to Sorafenib-mediated multikinase inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1045. doi:10.1158/1538-7445.AM2015-1045
Abstract 1048: Chromatin remodelers are frequently disrupted by epigenetic and genetic alterations at an early stage of carcinogenesis
Authors: Takeshima Hideyuki , Niwa Tohru , Takahashi Takamasa , Ando Takayuki , Taniguchi Hirokazu , Katai Hitoshi , Sugiyama Toshiro , Ushijima Toshikazu 
Published: August 2015

Abstract
Chromatin remodeling factors (chromatin remodelers), such as SWI/SNF and ISWI complexes, regulate gene transcription by modulating chromatin accessibility. Genes encoding subunits of chromatin remodelers are frequently disrupted by loss of function mutations in various types of cancers. In contrast, inactivation of chromatin remodelers by epigenetic alterations, such as aberrant DNA methylation, is unknown. In this study, we aimed to clarify 1) whether or not chromatin remodelers are inactivated by aberrant DNA methylation, and 2) the timing of this occurrence.
DNA methylation statuses of 16 genes encoding chromatin remodelers with promoter CpG islands were analyzed in non-cancerous tissues of male gastric cancer patients using an Infinium HumanMethylation450 BeadChip array. Among the 16 genes, two genes, ACTL6B and SMARCA1, were frequently methylated in non-cancerous gastric tissues. Among these genes, SMARCA1 was expressed at high levels in normal gastric tissues, but ACTL6B was not. In four of 50 primary gastric cancers, SMARCA1 was aberrantly methylated. It was re-expressed after treatment with a DNA demethylating agent, 5-aza-2′-deoxycytidine (5-aza-dC), in gastric cancer cell lines, AGS and GC2. Somatic mutations of 18 genes encoding chromatin remodelers were analyzed using a next-generation personal sequencer in the 50 primary gastric cancers. Nine genes, ARID1A, ARID1B, ARID2, SMARCA1, SMARCA2, SMARCA4, SMARCB1, PBRM1, and PHF10, were mutated in one or more of the 50 gastric cancers. The mutant allele frequency was close to the cancer cell content in cancer samples with a specific mutation of a chromatin remodeler. Depletion of a chromatin remodeler, SMARCA1 or SMARCA2, by shRNAs in cancer cell lines promoted their growth.
These results showed that epigenetic and genetic alterations of chromatin remodelers are induced at an early stage of carcinogenesis (Takeshima et al., Cancer Letters, in press).
Citation Format: Hideyuki Takeshima, Tohru Niwa, Takamasa Takahashi, Takayuki Ando, Hirokazu Taniguchi, Hitoshi Katai, Toshiro Sugiyama, Toshikazu Ushijima. Chromatin remodelers are frequently disrupted by epigenetic and genetic alterations at an early stage of carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1048. doi:10.1158/1538-7445.AM2015-1048
Abstract 1054: Aberrant TET1 methylation closely associated with CpG island methylator phenotype in colorectal cancer
Authors: Ichimura Norihisa , Shinjo Keiko , Ohka Fumiharu , Katsushima Keisuke , Hatanaka Akira , Tojo Masayuki , Shimizu Yasuhiro , Yamamoto Eiichiro , Suzuki Hiromu , Kondo Yutaka 
Published: August 2015

Abstract
Inactivation of methylcytosine dioxygenase, ten-eleven translocation (TET) is known to be associated with aberrant DNA methylation in cancers. Tumors with a CpG island methylator phenotype (CIMP), a distinct subgroup with extensive DNA methylation, show characteristic features in the case of colorectal cancer (CRC). The relationship between TET inactivation and CIMP in CRCs is not well understood. The expression level of TET family genes was compared between CIMP-positive (CIMP-P) and CIMP-negative (CIMP-N) CRCs. Furthermore, DNA methylation profiling, including assessment of the TET1 gene, was assessed in CRCs, as well as colon polyps. The TET1 was silenced by DNA methylation in a subset of CRCs as well as cell lines, expression of which was reactivated by demethylating agent. TET1 methylation was more frequent in CIMP-P (24/55, 44%) than CIMP-N (3/113, 3%, P&lt;0.0001) CRCs. This trend was also observed in colon polyps (CIMP-P, 18/40, 45%; CIMP-N, 2/24, 8%; P = 0.002), suggesting that TET1 methylation is an early event in CIMP tumorigenesis. TET1 methylation was significantly associated with BRAF mutation but not with hMLH1 methylation in the CIMP-P CRCs. CRCs with TET1 methylation have a significantly greater number of DNA methylated genes and less pathological metastasis compared to those without TET1 methylation (P = 0.007 and P = 0.045, respectively). Our data suggest that TET1 methylation may contribute to the establishment of a unique pathway in respect to CIMP-mediated tumorigenesis, which may be incidental to hMLH1 methylation. In addition, our findings provide evidence that TET1 methylation may be a good biomarker for the prediction of metastasis in CRC.
Citation Format: Norihisa Ichimura, Keiko Shinjo, Fumiharu Ohka, Keisuke Katsushima, Akira Hatanaka, Masayuki Tojo, Yasuhiro Shimizu, Eiichiro Yamamoto, Hiromu Suzuki, Yutaka Kondo. Aberrant TET1 methylation closely associated with CpG island methylator phenotype in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1054. doi:10.1158/1538-7445.AM2015-1054
Abstract 1059: Analysis of promoter methylation levels of COX2 gene in Turkish patients with head and neck cancer
Authors: Demokan Semra , Ozkoklesen Cansu , Yalniz Zubeyde , Enver Necati , Ulusan Murat , Dalay Nejat 
Published: August 2015

Abstract
Purpose: Methylation of CpG islands in the promoter regions of genes plays an important role in head and neck carcinogenesis. Overexpression of COX2 gene was recorded in various types of cancer in literature. In addition, the promoter region of the COX2 gene displayed high methylation in normal colorectal tissue and normal gastric tissue samples. On the other hand, it has recently been reported in two different gastrointestinal cancer studies, that low expression of COX2 was observed in some colorectal/gastric cancers and hypermethylation/related transcriptional silencing of COX2 gene is common in colorectal cancer. There is no study investigating the COX2 methylation status on head and neck cancer (HNC) in the literature. In our study we evaluated the COX2 gene promoter methylation in patients with HNC.
Experimental Design: Methylation of the COX2 was investigated by bisulfite modification/methylation-specific polymerase chain reaction in tumors and matched normal tissue samples from 99 Turkish patients with HNC.
Results: The promoter region of the COX2 was methylated in 53.5% and 65.6% of the primary tumors and the corresponding normal tissue samples, respectively [p = 0.082, χ2 = 3.02, OR(95%CI) = 0.602 (0.34-1.06)]. Considering the methylation levels observed in our previous studies, and published data on different cancer types, methylation levels &lt;10% were considered unmethylated, whereas levels between 10% to 25% and 25% to 100% were classified as moderate and high methylation, respectively. Based on this information, methylation ratio was observed less than 10% in 46.5% and 34.3% of tumor and normal samples, respectively. The moderate methylation levels (10-25%) were found in 23.2% of the tumors and 7.1% of the adjacent normal tissues. High methylation levels (&gt;25%) were 30.3% and 58.6% in the tumor and normal tissues, respectively (p = 0.00006, χ2 = 19.24). The results were similar when a subgroup of 60 patients with larynx cancer from this cohort, were analyzed separately (p = 0.0006, χ2 = 14.87).
Conclusions: Methylation may play an important role in HNC carcinogenesis. Although we found that there was no significant association between the methylation levels of tumor and adjacent normal tissues, high methylation levels of the COX2 gene were observed (&gt;25%) in normal matched tissues when compared to the levels in HNC tumors.
Citation Format: Semra Demokan, Cansu Ozkoklesen, Zubeyde Yalniz, Necati Enver, Murat Ulusan, Nejat Dalay. Analysis of promoter methylation levels of COX2 gene in Turkish patients with head and neck cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1059. doi:10.1158/1538-7445.AM2015-1059
Abstract 1060: Epigenome-wide DNA methylation profiling of lung tumors from asbestos-exposed patients
Authors: Kettunen Eeva M. , Hernandez-Vargas Hector , Cros Marie-Pierre , Durand Geoffroy , Le Calvez-Kelm Florence , Wolff Henrik , Salmenkivi Kaisa , Anttila Sisko L. , Herceg Zdenko , Husgafvel-Pursiainen Kirsti 
Published: August 2015

Abstract
Introduction and objectives.
Epigenetic modifications such as changes in DNA methylation have been shown as response to many toxic exposures. However, not much is known about the role of epigenetics in human lung carcinogenesis associated with asbestos exposure. Here, we explored the epigenome-wide DNA methylation (DNA methylome) patterns in lung tumors focused on asbestos-exposed and non-exposed patients who were mostly smokers. We sought to investigate whether methylation markers in lung cancer associate with exposure (asbestos, tobacco smoke) and clinico-pathological features.
Study design, subjects, and methods.
The DNA methylome was examined by Illumina Infinium 450K HumanMethylation technology covering more than 450 000 CpG sites. Validation experiments were done by pyrosequencing. DNA methylation was studied in lung tumors and normal lung as matched pairs obtained from 28 patients from lung surgery in Helsinki during years 1988-1996. Detailed data on the patients’ work and smoking histories, pulmonary fiber counts (14 asbestos-exposed and 14 non-exposed), and clinical data were available. As controls, normal lung specimens from patients with non-malignant lung disease were studied for genome-wide DNA methylation.
Results.
DNA methylation profiles differed in relation to sample type, tumor histology and exposure status. We identified more than 10.000 methylation variable positions (MVPs) that differed (adjusted P &lt; 0.05) between lung tumors and matched normal lung. Differential methylation in 14 MVPs were significantly associated with asbestos exposure in lung tumor tissue whereas more than 100 MVPs were suggested as smoking-related. Differential methylation of genes such as those involved in cell stress and inflammation, cellular energy and lipid metabolism, and protein degradation processes were observed in lung tumors.
Conclusions.
Our analysis suggests that methylation profiles were globally affected in lung tumors in comparison to matched normal lung. We also found associations to asbestos exposure and tobacco smoking, suggesting a role for these exposures in modification of DNA methylome profiles.
Citation Format: Eeva M. Kettunen, Hector Hernandez-Vargas, Marie-Pierre Cros, Geoffroy Durand, Florence Le Calvez-Kelm, Henrik Wolff, Kaisa Salmenkivi, Sisko L. Anttila, Zdenko Herceg, Kirsti Husgafvel-Pursiainen. Epigenome-wide DNA methylation profiling of lung tumors from asbestos-exposed patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1060. doi:10.1158/1538-7445.AM2015-1060
Abstract 1064: RASSF10 suppresses colorectal cancer growth by activating p53 signaling and sensitizes colorectal cancer cell to docetaxel
Authors: Guo Jing , Yang Yage , Yang Yunsheng , Linghu Enqiang , Zhan Qimin , Brock Malcolm V. , Herman James G. , Zhang Bingyong , Guo Mingzhou 
Published: August 2015

Abstract
RASSF10 has previously been reported to be frequently methylated in a number of malignancies. To understand the importance of RASSF10 inactivation in colorectal carcinogenesis, eight colorectal cancer cell lines, 89 cases of primary colorectal cancer and 5 cases of normal colorectal mucosa were examined. Methylation specific PCR, western blot, siRNA, gene expression array and xenograft mice were employed. The expression of RASSF10 was was regulated by promoter regional methylation in colorectal cancer cells. RASSF10 was methylated in 60.7% (54/89) of primary colorectal cancers and was positively associated with tumor stage (p&lt;0.05) and metastasis (p&lt;0.05). Restoration of RASSF10 led to inhibition of colorectal cancer cell proliferation in vitro and in vivo and increased apoptosis. Gene expression arrays discovered RASSF10 inhibition of MDM2 expression as a mediator of these effects, which was confirmed with RT- PCR and western blot. RASSF10 was shown to activate P53 signaling in RKO and HCT116 cells after UV exposure, and sensitized these cells to docetaxel. In conclusion, our study demonstrates RASSF10 is frequently methylated in human colorectal cancer leading to loss of expression. RASSF10 normally suppresses human colorectal cancer growth by activating P53 signaling in colorectal cancer, and restored expression sensitizes colorectal cancer to docetaxel.
Citation Format: Jing Guo, Yage Yang, Yunsheng Yang, Enqiang Linghu, Qimin Zhan, Malcolm V. Brock, James G. Herman, Bingyong Zhang, Mingzhou Guo. RASSF10 suppresses colorectal cancer growth by activating p53 signaling and sensitizes colorectal cancer cell to docetaxel. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1064. doi:10.1158/1538-7445.AM2015-1064
Abstract 1068: Correlation of DNA methylation pattern between peripheral blood cell and normal breast tissue
Authors: Guo Xingyi , Shu Xiao-Ou , Li Chun , Long Jirong , Li Bingshan , Gao Yu-Tang , Zheng Wei , Cai Qiuyin 
Published: August 2015

Abstract
Aberrant DNA methylation in peripheral blood cells (PBCs) may be a potential noninvasive biomarker for breast cancer risk. Whether methylations at CpG sites in PBCs can serve as proxies in normal breast tissues are unknown. We evaluated the correlation of DNA methylation between PBC DNA and breast cancer adjacent normal tissue using data and samples from the Shanghai Breast Cancer Study. Genome-wide DNA methylation profiles in PBCs and matched tumor adjacent normal tissues from 31 breast cancer patients were assayed using Illumina HumanMethylation450 BeadChip, which includes &gt;485,000 CpG sites and covers 99% of RefSeq genes with multiple probes per gene. After quality control filtering, a total of 432,513 CpG sites were retained for analysis. We evaluated the association of methylation for each CpG site between DNA samples for PBCs and normal breast tissue using Spearman's rank correlation (r). The overall median correlation (r) is 0.35. A total of 99,928 (23.1%) and 18,290 (4.2%) of CpG sites had a high correlation between PBC DNA and normal breast tissue DNA with r &gt; 0.50 and r &gt; 0.75, respectively. Interestingly, we found that the correlation was negatively associated with both methylation levels (mean) and inter-person variability (standard deviation) in normal breast tissues (ρ = -0.14 and -0.19; P &lt; 2.2 x10-16 for both). In 926 previously reported methylation quantitative trait loci, the correlations between PBCs and normal breast tissue were significantly higher (median r = 0.42) than the remaining loci (median r = 0.34) (Wilcoxon test, P &lt; 2.2 x10-16), suggesting that methylation variations controlled by genetic variations exhibited a robust correlation between PBC and normal breast tissue DNA. In summary, our results suggest that the methylation status of CpG sites with large inter-person variations or genetically-controlled variations in PBC DNA correlate well with those in normal breast tissue. This supports the conduct of a genome-wide methylation study for breast cancer using PBC DNA.
Citation Format: Xingyi Guo, Xiao-Ou Shu, Chun Li, Jirong Long, Bingshan Li, Yu-Tang Gao, Wei Zheng, Qiuyin Cai. Correlation of DNA methylation pattern between peripheral blood cell and normal breast tissue. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1068. doi:10.1158/1538-7445.AM2015-1068