bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1029: Receptor-interacting protein kinase 1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy
Authors: Yan Xu Guang , Luan Qi , Jin Lei , Jiang Chen Chen , Tay Kwang Hong , Lai Fritz , Liu Xiao Ying , Liu Yi Lun , Guo Su Tang , Tseng Hsin-Yi , Zhang Xu Dong 
Published: August 2015

Abstract
Although receptor-interacting protein kinase 1 (RIP1) is emerging as a critical determinant of cell fate in response to cellular stress resulting from activation of death receptors and DNA damage, its potential role in response of cells to endoplasmic reticulum (ER) stress remains undefined. Here we report that RIP1 functions as an important pro-survival mechanism in melanoma cells undergoing ER stress through activation of autophagy. While pharmacological induction of ER stress upregulated RIP1 and triggered autophagy in melanoma cells resistant to ER stress-induced apoptosis, knockdown of RIP1 inhibited autophagy and rendered the cells sensitive to killing by ER stress, recapitulating the effect of inhibition of autophagy. Consistently, overexpression of RIP1 enhanced induction of autophagy and conferred resistance of melanoma cells to killing by ER stress. Activation of JNK, which phosphorylated the BH3-only protein Bim leading to its dissociation from Beclin-1, was involved in ER stress-induced, RIP1-mediated activation of autophagy in melanoma cells. On the other hand, activation of the transcription factor heat shock factor protein 1 (HSF1) downstream of the IRE1/XBP1 axis of the unfolded protein response was responsible for the increase in RIP1 in melanoma cells undergoing ER stress. Collectively, these results identify upregulation of RIP1 as an important adaptive mechanism of melanoma cells to ER stress by protecting against cell death through activation of autophagy, and suggest that targeting the autophagy-activating mechanism of RIP1 may be a useful strategy to enhance sensitivity of melanoma cells to therapeutic agents that induce ER stress.
Citation Format: Xu Guang Yan, Qi Luan, Lei Jin, Chen Chen Jiang, Kwang Hong Tay, Fritz Lai, Xiao Ying Liu, Yi Lun Liu, Su Tang Guo, Hsin-Yi Tseng, Xu Dong Zhang. Receptor-interacting protein kinase 1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy. [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 1029. doi:10.1158/1538-7445.AM2015-1029
Abstract 1032: The acetylcholine signaling pathway: A novel molecular target for lung cancers
Authors: Brown Kathleen C. , Lau Jamie K. , Perry Haley E. , Thornhill Brent A. , Stevenson Cathryn D. , Rollyson William D. , Stover Cody A. , Jones Dennie V. , Pulliam Joseph F. , Dasgupta Piyali 
Published: August 2015

Abstract
Cigarette smoking is a major risk factor for all types of lung cancers. Nicotine, the addictive component of cigarettes, accelerates the growth and angiogenesis of human lung cancers. The biological activity of nicotine is mediated by nicotinic acetylcholine receptors (nAChRs). The endogenous ligand of nAChRs is acetylcholine (ACh). We show that both human SCLCs and NSCLCs contain all proteins of the acetylcholine signaling pathway, namely nAChRs, choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), choline transporter (ChT1) and acetylcholinesterase (AChE). ACh functions as an autocrine growth factor for human lung cancer cells. Lung adenocarcinoma (LAC), squamous cell carcinoma (SCC-L) and invasive mucinous adenocarcinoma (IMA) express a diverse array of nAChRs. In addition, normal human lung cells also express nAChRs and other ACh signaling proteins. Nicotine amplifies the ACh signaling loop in human lung cancer cells. It increases the levels of alpha7-nAChR subunit in human SCC-Ls. The alpha7-nAChR is responsible for the proliferative and pro-angiogenic activity of nicotine in lung cancer. The level of alpha7-nAChR was analyzed in human SCC-L samples isolated from patients. It was found that the level of alpha7-nAChR in SCC-L patients (who are heavy smokers) was much higher than that of moderate smoker suffering from SCC-Ls. Nicotine was also found to elevate the levels of ChAT and VAChT in human lung cancers. The acetylcholine signaling pathway may be a useful molecular target for the diagnosis and therapy of human lung cancers in smokers. Our results are also relevant to lung cancer patients who are exposed to nicotine via secondhand smoke, nicotine patches, gums or electronic cigarettes.
Citation Format: Kathleen C. Brown, Jamie K. Lau, Haley E. Perry, Brent A. Thornhill, Cathryn D. Stevenson, William D. Rollyson, Cody A. Stover, Dennie V. Jones, Joseph F. Pulliam, Piyali Dasgupta. The acetylcholine signaling pathway: A novel molecular target for lung cancers. [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 1032. doi:10.1158/1538-7445.AM2015-1032
Abstract 1039: Leucine-rich α2 glycoprotein modulates the effect of TGFβ1 on the growth of lewis lung carcinoma cells
Authors: Takemoto Norihiko , Serada Satoshi , Fujimoto Minoru , Inohara Hidenori , Naka Tetsuji 
Published: August 2015

Abstract
Background:
Leucine-rich α2 glycoprotein (LRG) is an approximately 50 kDa serum glycoprotein. It has been reported that the expression levels of LRG were elevated in the sera and tissues in several cancers. While it has been demonstrated that LRG modulated TGFβ1 signaling in endothelial cells and resulted in the promotion of pathogenic angiogenesis, the precise function of LRG in cancer remains unclear. The aim of this study was to investigate the role of LRG on the cellular response by TGFβ1 in Lewis lung carcinoma (LLC) cells.
Methods:
Parental LLC, mLRG-overexpressing LLC or control vector transfected LLC cells were subcutaneously transplanted into LRG knockout (KO) or Wild-type (WT) C57BL/6J mice and tumor growth was monitored. Cell proliferation treated with TGFβ1 was evaluated by WST-8 assay. Caspase activity was measured with Caspase-GloTM assay kit, protein expression levels were analyzed by western blotting and gene expression was analyzed with quantitative real-time PCR. LLC tumor growth were monitored in LRG KO or WT mice treated with TGFβRI inhibitor (SB431542) or vehicle. Apoptosis of LLC tumor was evaluated by TUNEL staining.
Result:
In LRG KO mice, LLC tumor growth was significantly increased compared with that in WT mice. In contrast, overexpression of mLRG significantly inhibited the growth of LLC tumors in WT mice. Treatment of TGFβ1 inhibited the proliferation of LLC cells in vitro. Addition of TGFβ1 strongly inhibited the proliferation of mLRG-overexpressing LLC cells than control vector LLC cells by induction of apoptosis. By TGFβ1 stimulation, induction of apoptosis via activation of smad2 and downstream signaling pathway was significantly increased in mLRG overexpressing LLC compared with control LLC cells in vitro. Treatment of TGFβRI inhibitor significantly enhanced growth and inhibited apoptosis of LLC tumor in WT mice compared with LRG KO mice.
Conclusion:
We found that LRG promoted TGFβ1-induced apoptosis in LLC, in vitro and in vivo. LRG is involved in the enhancement of TGFβ1-smad signal transduction.
Citation Format: Norihiko Takemoto, Satoshi Serada, Minoru Fujimoto, Hidenori Inohara, Tetsuji Naka. Leucine-rich α2 glycoprotein modulates the effect of TGFβ1 on the growth of lewis lung carcinoma 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 1039. doi:10.1158/1538-7445.AM2015-1039
Abstract 1046: The role of NF-kB activation in the immortalization of nasopharyngeal epithelial cells
Authors: Tsao George Sai-Wah , Zhu Dan Dan , Zhang Jun , Deng Wen 
Published: August 2015

Abstract
NF-κB is a key regulator of inflammatory response and is frequently activated in human cancers including nasopharyngeal carcinoma (NPC), which is closely associated with Epstein-Barr virus (EBV) infection and a common cancer in Southern China including Hong Kong. However, it is well-established that EBV infection alone is not sufficient for NPC development. Other genetic alterations in host cells and the interaction between EBV infection and host cell microenvironment are required for NPC development. Our group has been involved in illustrating molecular events underlying the immortalization of nasopharyngeal epithelial (NPE) cells. Molecular changes which facilitate immortalization may represent early genetic events in human carcinogenesis. We found that the activation of NF-κB was a common feature in telomerase-immortalized NPE cell lines. We further showed that canonical NF-κB activation pathway was involved in the immortalization of NPE cells. The activation of NF-κB was essential for the proliferation of the immortalized NPE cells because suppression of NF-κB activity could selectively inhibit the proliferation of immortalized but not primary NPE cells. The upregulation of c-Myc and Bmi-1, known to promote cell proliferation, were associated with NF-κB activation in the immortalized NPE cell lines. Interestingly, mTOR was found to be the upstream activator of NF-κB. We further showed that EGFR/Erk(1/2) pathway was the upstream regulator of mTOR/NF-κB pathway, revealing the pathway of EGFR/Erk(1/2)/mTOR/NF-κB for NF-κB activation in telomerase-immortalized NPE cells. Elucidation of specific pathway leading to NF-κB activation in immortalized NPE cells may open up opportunity for early intervention to suppress or prevent NPC development.
Citation Format: George Sai-Wah Tsao, Dan Dan Zhu, Jun Zhang, Wen Deng. The role of NF-kB activation in the immortalization of nasopharyngeal epithelial 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 1046. doi:10.1158/1538-7445.AM2015-1046
Abstract 105: A rational approach for the discovery of inhibitors of NSD2 for the treatment of cancer
Authors: Fromond Claudia , Espanel Xavier , Soudé Anne , Chene Laurent , Masson Philippe , Boubia Benaïssa , Montalbetti Christian , Broqua Pierre 
Published: August 2015

Abstract
Multiple myeloma (MM) is a plasma cell malignancy which accounts for approximately 10% of hematologic malignancies. Despite the introduction of new therapeutic agents, MM remains incurable and nearly all patients ultimately relapse. About 20% of MM are due to a chromosomal translocation t(4;14) leading to overexpression of the NSD2 histone methyltransferase. NSD2 catalyzes dimethylation of lysine 36 on histone H3 (H3K36me2) and is associated with transcriptionally active regions. Several studies have shown that in MM harboring the translocation t(4;14), oncogenic programming is dependent on the methyltransferase activity of NSD2. In addition, the NSD2 overactivity is also observed in prostate and lung cancers. Thus, NSD2 is a potential target for cancers, for which no selective drug is available to date.
Using the AlphaLisa™ technology, we screened 240,000 compounds coming from our proprietary library. The assay is based on the detection of H3K36me2 on nucleosome by a specific antibody. False positives hits were removed by a technological counterscreen, and compounds with redox activity were excluded. This strategy allowed us to identify about 200 compounds. To focus on the most interesting ones, an orthogonal counterscreen based on 3H SAM incorporation is being completed. In parallel to the biochemical screening, we are developing secondary cellular assays based on the H3K36me2 methylation and proliferation to further confirm hit activity. To our knowledge, no NSD2 inhibitor have been identified to date despite several screening effort performed by other groups. Our library has already produced new chemical starting points for other KMTs, and we believe that our hits could be promising starting points to generate potent and selective NSD2 inhibitors.
Citation Format: Claudia Fromond, Xavier Espanel, Anne Soudé, Laurent Chene, Philippe Masson, Benaïssa Boubia, Christian Montalbetti, Pierre Broqua. A rational approach for the discovery of inhibitors of NSD2 for the treatment of 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 105. doi:10.1158/1538-7445.AM2015-105
Abstract 1050: Effects of 5-hydroxymethylcytosine epigenetic modification on G-quadruplex and i-motif structure and stability within the VEGF promoter
Authors: Morgan Rhianna , Wadkins Randy , Brooks Tracy 
Published: August 2015

Abstract
CpG islands are prone to epigenetic cytosine modification via methylation (5mC) or 5-hydroxymethylation (5hmC). Although their potential sequences and regions for occurrence in G/C-rich DNA overlap, throughout the genome 5mC and 5hmC, and 5mC and G-quadruplex (G4) and i-motif (iM) structures, are found to not be co-existent. Moreover, in some regions of DNA, 5hmCs and G4/iM forming regions have high potential to form in concurrence. However, minimal research has been done examining the effect of 5hmC incorporation into G4 and iMs in order to determine the effect of cytosine modification on non-B-DNA structures. These higher order secondary DNA formations have been described within the VEGF promoter and have great potential to silence its transcription and prevent subsequent angiogenesis. In addition, there are three cytosines in the promoter on both the guanine- and the cytosine-rich strands found in CpG sequences that have the potential for 5mhC modification. Therefore, the current study was undertaken to examine the whether there is an effect of 5hmC incorporation into G4 loops and iM stems on structure formation and stabilization. Significant changes in structure or stability in buffers with varying pH’s, cationic strength, and molecular crowding conditions were examined by circular dichroism and confirmed by UV-monitored melting. Electromobility shift assays differentiated inter- and intra-molecular structures, further identifying the number of isoforms. Notable changes in G4 dynamics were seen with two of the three loop modifications, which decreased overall stability and increased intermolecular structures. Much less marked effects were discovered for the iM structures. Ongoing studies examining the role of G4 and iM 5hmC incorporation in regulation by endogenous proteins are part of a global effort to best understand the physiological conditions regulating G4 and iM stability and function. These VEGF promoter higher order structures are promising therapeutic targets for anti-angiogenic therapy, and a comprehensive understanding of the physiological principles governing their formation will best inform future drug discovery efforts.
Brooks Lab startup funds, R15, University of Mississippi School of Pharmacy
Citation Format: Rhianna Morgan, Randy Wadkins, Tracy Brooks. Effects of 5-hydroxymethylcytosine epigenetic modification on G-quadruplex and i-motif structure and stability within the VEGF promoter. [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 1050. doi:10.1158/1538-7445.AM2015-1050
Abstract 1055: Genome-wide DNA methylation analysis in precancerous conditions associated with hepatitis B virus and hepatitis C virus infection
Authors: Arai Eri , Tian Ying , Gotoh Masahiro , Takahashi Yoriko , Ojima Hidenori , Kosuge Tomoo , Kanai Yae 
Published: August 2015

Abstract
The aim of this study is to reveal the significance of DNA methylation alterations in precancerous conditions associated with hepatitis virus infection. Genome-wide DNA methylation analysis using Infinium HumanMethylation450 BeadChip (Illumina) has been performed in 36 specimens of normal liver tissue obtained from patients without hepatocellular carcinomas (HCCs), 12 and 24 specimens of noncancerous liver tissues obtained from hepatitis B virus (HBV) infection-positive and hepatitis C virus (HCV) infection-positive patients with HCCs, respectively, and 24 samples of HCC themselves. On 21,106 CpG sites, alterations of DNA methylation levels were already evident in tissue specimens showing chronic hepatitis and liver cirrhosis, which are considered to be precancerous conditions, compared to normal liver tissues, and were inherited by HCC themselves. Unsupervised hierarchical clustering analysis based on DNA methylation levels at the 21,106CpG sites appropriately classified tissue specimens into normal, precancerous and cancerous clusters, indicating that DNA methylation alterations may participate continuously in hepatocarcinogenesis from the precancerous stage until cancers have become established. The incidence of DNA methylation alterations was higher at the precancerous stage of HCV-positive patients than that of HBV-positive patients. The incidence of DNA methylation alterations that actually occurred at the chronic hepatitis and liver cirrhosis stages but were restored in HCC themselves, which may be associated with inflammation or fibrosis, but may not participate in carcinogenesis itself, was at the almost equal levels regardless of probe annotations or hepatitis viruses. Many Infinium probes showing DNA methylation alterations participating continuously in multistage hepatocarcinogenesis were shared between HBV-positive and HCV-positive patients: only a small number of probes showed HBV-positive patient-specific DNA methylation alterations. On the other hand, DNA hypermethylation on regions around the transcription start sites was especially frequent during carcinogenesis in HCV-positive patients. We now intend to make the carcinogenetic risk estimation based on DNA methylation profiles at the precancerous stage clinically practical using liver biopsy specimens obtained prior to interferon therapy from patients who are followed up because of chronic liver diseases.
Citation Format: Eri Arai, Ying Tian, Masahiro Gotoh, Yoriko Takahashi, Hidenori Ojima, Tomoo Kosuge, Yae Kanai. Genome-wide DNA methylation analysis in precancerous conditions associated with hepatitis B virus and hepatitis C virus infection. [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 1055. doi:10.1158/1538-7445.AM2015-1055
Abstract 1062: Hypermethylation of BARHL2 gene is useful as a molecular marker in early stage of gastric cancer
Authors: Watanabe Yoshiyuki , Oikawa Ritsuko , Yamamoto Hiroyuki , Itoh Fumio 
Published: August 2015

Abstract
Aim: Although minimal invasive treatment is accepted for gastric cancer, we still do not have any appropriate risk markers to detect residual neoplasia and recurrence. We previously reported that aberrant DNA methylation is an early and frequent process in gastric carcinogenesis and could be useful for detection of neoplasia. Our goal is to find some candidate genes as a treatment marker using genome wide DNA methylation analysis for early gastric cancer (EGC). Methods and Results: We studied Methylated CpG Island Amplification Microarray (MCAM) analysis using 12 gastric washes (each 6 before (Pre) and after (Post) endoscopic treatment in same patients). One of them is BARHL2. We examined the DNA methylation status of BARHL2 in a validation set consisting of 128 washes samples (Pre, 64: Post, 64) at EGC. We next identified functional studies about BARHL2 as a putative tumor suppressor gene. Treating GCa cells that lacked BARHL2 expression with a methyltransferase inhibitor, 5-aza-2′-deoxycytidine, restored the gene's expression. Introduction of exogenous BARHL2 into silenced cells suppressed colony formation. Moreover, BARHL2 showed significantly differential methylation between before and after treatment in EGC patient (BARHL2, p&lt;0.0001). Discussion: Our data suggest that silencing of BARHL2 occurs frequently in EGC and may play a key role in development and progression of the disease.
Citation Format: Yoshiyuki Watanabe, Ritsuko Oikawa, Hiroyuki Yamamoto, Fumio Itoh. Hypermethylation of BARHL2 gene is useful as a molecular marker in early stage of gastric 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 1062. doi:10.1158/1538-7445.AM2015-1062
Abstract 1065: RASSF- 1A methylation in squamous cell carcinoma of the lower lip using pyrosequencing technique
Authors: Kaminagakura Estela , Coutinho-Camillo Cláudia , Strieder Luciana , Perez Danyel , Soares Fernando , Oliveira Kátia , Kowalski Luiz Paulo 
Published: August 2015

Abstract
Background: Chronic exposure to UVB radiation can cause hypermethylation and silencing of the tumor suppressor gene RASSF-1A. The protein encoded by this gene has multiple important functions in cell cycle control. Objective: to investigate the clinical significance of the methylation profile of RASSF-1A and of its protein expression in lower lip squamous cell carcinoma (SCC). Methods: The demographic and clinical-pathological data of 87 patients with a confirmed diagnosis were collected from the medical records. DNA was extracted from paraffin-embedded tissue samples and treated with sodium bisulfite. 2ug of treated and intact DNA was submitted to PCR amplification using a specific primer targeting the RASSF-1A promoter segments 1 and 2. RASSF1A methylation was investigated by pyrosequencing; the complementary strand was synthesized automatically and the signal emitted during the reaction was detected with a camera and transformed into peaks on a pyrogram. Results: Lower lip SCC was more frequent in men than women, with a proportion of 2.4:1. The mean patient age was 63.3 years. Lymph node involvement was absent (N0) in 73 (83.1%) of cases and present (N+) in 14 (16.1%). In group N0, most patients (n = 49, 67.1%) were in an early clinical stage (CS I and II). Analysis of the methylation of RASSF1A_01 was possible in 29 of the SCC cases. Hypermethylation was observed in 15 (51.7%) cases, one (3.4%) of them being associated with metastasis to regional lymph nodes. Analysis of RASSF1A_02 was possible in 20 cases and hypermethylation was observed in only 9 (45.0%). No significant correlation was found between the clinical-pathological parameters (age, gender, clinical stage) and aberrant methylation of the promoter region studied (p&gt;0.05). Conclusions: Hypermethylation of the two RASSF-1A segments studied was observed in approximately 50% of SCC cases, but was not correlated to clinicopathologic parameters.
Citation Format: Estela Kaminagakura, Cláudia Coutinho-Camillo, Luciana Strieder, Danyel Perez, Fernando Soares, Kátia Oliveira, Luiz Paulo Kowalski. RASSF- 1A methylation in squamous cell carcinoma of the lower lip using pyrosequencing technique. [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 1065. doi:10.1158/1538-7445.AM2015-1065