bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5149: EZH2 as a novel therapeutic target in melanoma treatment
Authors: Tiffen Jessamy , Gunatilake Dilini , Gallagher Stuart , Gowrishankar Kavitha , Hersey Peter 
Published: May 2015

Abstract
Histone modifications are increasingly being recognized as an important epigenetic mechanism that governs chromatin structure and gene expression. EZH2 is the catalytic subunit of the polycomb repesssive complex 2 (PRC2), responsible for tri-methylation of lysine 27 residues on type 3 histones (H3K27Me3) that leads to gene silencing. EZH2 is found to be over-expressed in many different types of cancers, where it is postulated to abnormally repress tumor suppressor genes. Activating mutations described within the catalytic SET domain of EZH2 at codon 646 confer its oncogenic activity, as identified in approximately 3% of melanomas.
We sought to assess whether direct inhibition of EZH2's methyltransferase activity is a suitable strategy for melanoma treatment. This was tested using a small molecule inhibitor known as GSK126, a potent, highly selective drug that competes with S-adenosyl-methionine substrate. We found that both mutant and non-mutant EZH2 melanoma cell lines over-express EZH2 compared to primary cells, via western blot and that levels of H3K27 methylation were reduced following drug treatment. GSK126 significantly decreased proliferation and reduced the percentage of cells in the G1 phase of the cell cycle, most likely attributed to a G2 arrest. Flow cytometery also revealed an increased sub-G1 population, indicative of drug induced apoptosis. This was confirmed by Annexin-V staining. Growth inhibition by GSK126 was particularly effective in melanoma cells harboring EZH2 activating mutations and had little effect on primary cells that displayed low levels of EZH2.
Expression arrays and chromatin immunoprecipitation are being used to determine which PCR2 target genes are being de-repressed and to decipher the mechanisms of GSK126 growth inhibition. Collectively our initial data indicate that EZH2 represents a promising gene target for therapeutic intervention in melanoma in vitro and that in vivo studies are warranted.
Citation Format: Jessamy Tiffen, Dilini Gunatilake, Stuart Gallagher, Kavitha Gowrishankar, Peter Hersey. EZH2 as a novel therapeutic target in melanoma treatment. [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 5149. doi:10.1158/1538-7445.AM2014-5149
Abstract 515: G12 overexpression in hepatocellular carcinoma promotes epithelial-mesenchymal transition through microRNAs deregulation
Authors: Kim Sang Geon , Yang Yoon Mee , Kim Tae Hyun , Lee Chan Gyu , An Jihyun , Kim Sung Hoon , Lee Chang H. , Hwang Sejin , Lee Seung Jin , Kim Kang M. 
Published: May 2015

Abstract
Hepatocellular carcinoma (HCC) has a poor prognosis due to its aggressive nature. Ligand activation of G-protein coupled receptor with enhanced G-protein activity may contribute to tumorigenesis and tumor progression in microenvironments. Here, we report the overexpression of Gα12 in HCC and its effect on deregulation of microRNAs in association with epithelial-mesenchymal transition. Gα12 expression levels were higher in human HCC than surrounding normal tissue. Array analyses using Huh7 cells stably transfected with an active mutant of Gα12 (Gα12QL) enabled us to extract down-regulated microRNAs. Of them, decreases of miR-200b/a, -192 and -215 contributed to ZEB induction through the up-regulation of MDM2. Transfection with miR-200b, -192 or miR-215 mimic antagonized HCC cell migration and invasion facilitated by Gα12QL. In tumor xenograft studies, sustained knockdown of Gα12 decreased the overall growth rate and average volume of tumors derived from SK-Hep1, a mesenchymal liver tumor cell line. In human HCC samples, levels of the identified microRNAs were all decreased, and correlated with the induction of mesenchymal markers. Moreover, decreases of the miRNAs discriminated microvascular invasion versus non-microvascular invasion of HCC. Conclusion: Increase of Gα12 in HCC deregulates a set of miRNAs promoting epithelial-mesenchymal transition of HCC and may be responsible for tumor microvascular invasion, implying that Gα12 signaling and the downstream mediators may be utilized as therapeutic targets and/or prognostic markers.
Citation Format: Sang Geon Kim, Yoon Mee Yang, Tae Hyun Kim, Chan Gyu Lee, Jihyun An, Sung Hoon Kim, Chang Ho Lee, Sejin Hwang, Seung Jin Lee, Kang Mo Kim. G12 overexpression in hepatocellular carcinoma promotes epithelial-mesenchymal transition through microRNAs deregulation. [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 515. doi:10.1158/1538-7445.AM2014-515
Abstract 516: Detection of human satellite RNA in the serum of high-risk patients of pancreatic cancer
Authors: Kishikawa Takahiro , Otsuka Motoyuki , Yoshikawa Takeshi , Ohno Motoko , Koike Kazuhiko 
Published: May 2015

Abstract
Introduction: Most satellite repeats in pericentmeric heterochromatin are epigenetically silenced and rarely transcribed into RNAs. However, in some pathological conditions, satellite RNA are transcribed and may deregulate cellular homeostasis. Recently, human satellite repeat II (HSATII) RNA were reported to be highly and specifically detected in human pancreatic cancers. However, precise localization of HSATII RNA expression in pancreatic cancer tissues and the time-course of its expression during carcinogenesis are unknown, mainly due to the technical difficulties to detect repetitive RNA sequences, which are difficult to amplify by PCR-based method. In this study, we determined the precise localization of HSATII RNA expression in pancreatic carcinoma tissues and developed a new method to detect HSATII RNA from the patient serum.
Methods: 1) Highly sensitive and specific custom-made locked nucleic acid-modified oligonucleotide probes were synthesized to detect HSATII RNA expression by Northern blotting and RNA in situ hybridization. Resected tissues containing pancreatic carcinoma lesions and those adjacent lesions in the same section from individual patients were used to determine the precise localization of HSATII RNA expression, along with tissue arrays. 2) Total RNAs were extracted from the serum of pancreatic cancer, intraductal papillary mucinous neoplasm (IPMN), and non-cancerous patients. Custom-made biotinylated RNA probes for HSATII RNA were hybridized with the patient RNA. Paired RNA was collected, and visualized by applying modified RNA protection method.
Results: 1) While no HSATII RNA expression was detected in pancreatic tissues without carcinoma, it was expressed in almost all pancreatic carcinoma tissues. Interestingly, the expression levels were clearly higher in non-cancerous lesions adjacent to carcinoma rather than in cancerous lesions themselves. 2) HSATII RNA was detected from 200 µl of the serum of pancreatic cancer and IPMN patients, whereas not detected from non-cancer patients.
Conclusion: HSATII RNA is highly expressed in the tissues surrounding human pancreatic cancerous lesions. This non-coding RNA could be detected in the serum of pancreatic cancer patients as well as patients with pre-cancerous lesions. These results may facilitate the development of novel methods to determine high-risk patients of pancreatic cancer.
Citation Format: Takahiro Kishikawa, Motoyuki Otsuka, Takeshi Yoshikawa, Motoko Ohno, Kazuhiko Koike. Detection of human satellite RNA in the serum of high-risk patients of pancreatic 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 516. doi:10.1158/1538-7445.AM2014-516
Abstract 5166: Characterization of somatic mutation spectrum in gastric cancer cases from Hispanic populations
Authors: Prieto Rodrigo , Lott Paul , Sahasrabudhe Ruta , Bohorquez Mabel , Castro Jorge , Mateus Gilbert , Echeverry Magdalena , Carmona Luis G. Carvajal 
Published: May 2015

Abstract
Gastric cancer is the second leading cause of cancer related deaths worldwide. Identification of gastric cancer drivers and somatic changes are essential to understand the molecular basis of tumorigenesis and to develop better preventive and therapeutic strategies. Till date, the large-scale initiatives to characterize somatic changes have been largely limited to Caucasian and Asian populations. This approach is likely to miss potential driver mutations that can be unique to other populations. Therefore, identification of somatic changes in cancers from multi-ethnic populations is essential to advance our understanding of tumor biology as well to bridge the gap in heath-care disparities. Hispanics are the largest and fastest growing minority in the USA and gastric cancer is a significant health care concern in this population. To understand molecular signatures of somatic alterations in gastric cancer in Hispanic population, we performed exome sequencing of 36 tumor samples and matched normal mucosa from gastric cancer patients from Colombia. In addition, we also performed microsatellite instability (MSI) testing and determined Epstein Barr virus and Helicobacter Pylori infection status for these samples. Our preliminary analysis of exome sequencing data by a locally developed pipeline indicates that the frequency of known cancer drivers in our study population in different than that has been reported previously and a subset of these cancers are following unique genetic pathways. In summary, our sequencing efforts in gastric cancer cases from Hispanic population are likely to identify novel cancer drivers and can help to further our understanding of molecular basis of this tumor type.
Citation Format: Rodrigo Prieto, Paul Lott, Ruta Sahasrabudhe, Mabel Bohorquez, Jorge Castro, Gilbert Mateus, Magdalena Echeverry, Luis G. Carvajal Carmona. Characterization of somatic mutation spectrum in gastric cancer cases from Hispanic populations. [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 5166. doi:10.1158/1538-7445.AM2014-5166
Abstract 5168: Gastric adenocarcinomas show pervasive loss of heterozygosity and enrichment for “STOP” genes in regions of hemizygous deletion
Authors: Cutcutache Ioana , Wu Alice Yingting , McPherson John R. , Lei Zhengdeng , Deng Niantao , Wong Wai Keong , Soo Khee Chee , Chan Weng Hoong , Ooi London Lucien , Welsch Roy E. , Tan Patrick , Rozen Steven G. 
Published: May 2015

Abstract
Purpose: Gastric cancer, the second leading cause of cancer death worldwide, has been little studied compared with other cancers that impose similar burdens on public health. Our goal is to assess loss of heterozygosity (LOH) and hemizygous deletion across a large series of gastric adenocarcinomas using the most sensitive and comprehensive method currently available.
Experimental design: We used high-density single-nucleotide-polymorphism microarrays that assay genotype and copy number at 906,600 sites and analyzed the results to determine patterns of LOH and hemizygous deletion in 77 gastric adenocarcinomas. We investigated whether “STOP” genes - genes that tend to impede proliferation - are associated with hemizygous deletion. We also analyzed the extent to which hemizygous deletion affected CYCLOPS (Copy number alterations Yielding Cancer Liabilities Owing to Partial losS) genes - genes that may be attractive targets for therapeutic inhibition when hemizygously deleted.
Results: We found that LOH is pervasive: on average 27% of each tumor genome is subject to LOH, and &gt; 98% of single nucleotide polymorphisms assayed were subject to LOH in at least 10% of tumors. Furthermore, 26% of LOH was due to hemizygous deletion, and STOP genes were significantly associated with regions of frequent hemizygous deletion; on average, 61 STOP genes were hemizygously deleted per tumor. Furthermore, on average, 4.65 CYCLOPS genes were hemizygously deleted per tumor, and 54.5% of the tumors had at least one CYCLOPS gene deleted.
Conclusions: These findings suggest that hemizygous deletion of anti-proliferative STOP genes contributes substantially to gastric carcinogenesis. Furthermore, the presence of several hemizygously deleted CYLOPS genes in some tumors suggests potential therapeutic targets in these tumors.
Citation Format: Ioana Cutcutache, Alice Yingting Wu, John R. McPherson, Zhengdeng Lei, Niantao Deng, Wai Keong Wong, Khee Chee Soo, Weng Hoong Chan, London Lucien Ooi, Roy E. Welsch, Patrick Tan, Steven G. Rozen. Gastric adenocarcinomas show pervasive loss of heterozygosity and enrichment for “STOP” genes in regions of hemizygous deletion. [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 5168. doi:10.1158/1538-7445.AM2014-5168
Abstract 5180: Profiling signaling pathways in chronic lymphocytic leukemia using reverse phase protein array
Authors: Noonepalle Satish Kumar R. , Shull Austin , Awan Farrukh T. , Pei Leah , Ding Zhiyong , Shi Huidong 
Published: May 2015

Abstract
Chronic lymphocytic leukemia (CLL), the most common adult leukemia remains incurable despite advancements in treatment regimens over the past decades. B-cell receptor (BCR) mediated signaling is well recognized for its central role in the pathogenesis of CLL. Small molecular inhibitors targeting BCR signaling pathway and its downstream PI3K/AKT pathway are currently investigated in clinical trials because of their ability to induce apoptosis or block protein interactions in CLL cells. However, variability in pathological conditions and genetic aberrations render these small molecule inhibitors not equally effective in all CLL patients and highlights the need for individualized treatment options. In this pilot study, we analyzed differential protein expression of 18 CLL patient and 6 normal B-cell samples using reverse phase protein array (RPPA). RPPA enables us to study the proteome as well as phospho-proteome of CLL samples. When probed with 167 monoclonal antibodies RPPA revealed distinct protein expression patterns between CLL and normal B-cells. RPPA data was analyzed by unsupervised hierarchical clustering and CLL patient samples were clearly separated from normal B-cell samples. Proteins of BCR and downstream PI3K/AKT pathway such as SYK, LCK, PDK1, AKT, RICTOR, mTOR, TSC1, TSC2 and p70S6K were all upregulated in CLL samples. Harvesting the full potential of RPPA to study phosphorylation changes, we observed an increase in PI3K pathway activating signals such as PDK1-pS241, p70S6K-pT389, 4EBP1-pS65 and 4EBP1-pT70 suggesting a cell proliferative mechanism. There was also decrease in inhibitory signals such as RICTOR-pT1135. Pro-apoptotic factors BID, BAX, Caspase 7-cleaved and ANXA1 were poorly expressed in CLL samples compared to normal B-cells suggesting a defect in apoptosis mechanism is predominant in CLL samples. As previously reported, we have seen overexpression of anti-apoptotic factor BCL2. BIM isoforms, BIM-EL and BIM-L were overexpressed in CLL compared to normal samples; however the ratio of BIM-EL to BIM-L was higher in normal B cells compared to CLL cells. For the first time, we generated a comprehensive BCR protein and phospho-protein expression profiles in primary CLL samples. Our results reveal novel anti-apoptosis and cell proliferative mechanisms in CLL and potentially identified new therapeutic targets in CLL.
Citation Format: Satish Kumar R. Noonepalle, Austin Shull, Farrukh T. Awan, Leah Pei, Zhiyong Ding, Huidong Shi. Profiling signaling pathways in chronic lymphocytic leukemia using reverse phase protein array. [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 5180. doi:10.1158/1538-7445.AM2014-5180
Abstract 5181: Genomic and transcriptomic somatic alterations of hepatocellular carcinoma in non-cirrhotic livers
Authors: Griffith Obi L. , Lin Yiing , Griffith Malachi , Hundal Jasreet , Regier Allison , Fulton Robert , Brunt Elizabeth M. , Wilson Richard K. , Chapman William , Mardis Elaine R. 
Published: May 2015

Abstract
Background: In 2014, it is estimated that there will be over 30,000 new cases of hepatocellular carcinoma (HCC) and an estimated 20,000 subjects will die of this disease in the U.S. alone. Risk factors include chronic HBV/HCV infections, cirrhosis, alcohol abuse, diabetes, and fatty liver disease. However, an important subset of HCC occurs in the absence of any such risk factors. We surveyed the genomic and transcriptomic landscape of this subset of HCC.
Methods: We performed whole genome and transcriptome sequencing of 30 matched tumor and non-tumor liver samples from resections performed at Washington University School of Medicine. Somatic variants identified in this discovery set were extended to a set of 89 additional cases by custom capture sequencing for a total of 119 HCCs profiled. All data were processed through The Genome Institute's Genome Modeling System (GMS) to analyze for viral integrations, SNVs, Indels, CNVs, fusions, SVs, expression and differential expression.
Results: We report here for the first time the unique landscape of somatic alterations of HCC arising in non-cirrhotic liver. We detected and validated over 3,010 SNVs and indels in coding regions and 2,390 fusion transcripts, as well as extensive copy number and expression changes. We identified a single undiagnosed HBV case with viral integration occurring at the TERT promoter. We also confirmed recent reports of a recurrent TERT promoter mutation (G1295228A) occurring in at least 56% of cases. Additional recurrent mutations were observed in previously reported genes such as CTNNB1, TP53, AXIN1, and ARID1A, along with an increased frequency of RB1 loss, novel recurrent mutations of APOB, fusions in NR1H4, and other alterations. These molecular features were tested for association with clinical variables and outcome. Pathway analysis of recurrently altered genes suggests that, in the absence of external factors, genomic aberrations in basic liver metabolism genes may promote malignant transformation to HCC.
Citation Format: Obi L. Griffith, Yiing Lin, Malachi Griffith, Jasreet Hundal, Allison Regier, Robert Fulton, Elizabeth M. Brunt, Richard K. Wilson, William Chapman, Elaine R. Mardis. Genomic and transcriptomic somatic alterations of hepatocellular carcinoma in non-cirrhotic livers. [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 5181. doi:10.1158/1538-7445.AM2014-5181
Abstract 5184: Distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers revealed by whole exome sequencing
Authors: Ong Choon Kiat , Chan-on Waraporn , Nairismagi Maarja-Liisa , Lim Weng Khong , Dima Simona , Pairojkul Chawalit , Sithithaworn Paiboon , Popescu Irinel , Rozen Steve , Tan Patrick , Teh Bin Tean 
Published: May 2015

Abstract
Cholangiocarcinoma, the second most common liver cancer, is known to be caused by different etiologies such as liver fluke infection, choledochal cyst and primary sclerosing cholangitis. Thus, this cancer provides a good model to study the impact of different carcinogenic exposures on the specific patterns of somatic mutations in human tumors. To address this issue, we profiled 209 cholangiocarcinomas (CCAs) from Asia and Europe, including 108 cases caused by liver fluke Opisthorchis viverrini (O. viverrini)-infection and 101 cases due to non-O. viverrini etiologies. Whole-exome (N = 15) and prevalence screening (N = 194) revealed recurrent somatic mutations in BAP1 and ARID1A, neither of which has been previously reported to be mutated in CCA. Comparisons between intrahepatic O. viverrini and non-O. viverrini CCAs demonstrated statistically significant different mutation patterns: BAP1 and IDH1/2 were more frequently mutated in non-O. viverrini CCAs, while TP53 displayed the reciprocal pattern. Functional studies demonstrated tumor suppressive roles of BAP1 and ARID1A, establishing the role of chromatin modulators in CCA pathogenesis. These findings indicate that different causative etiologies may induce distinct somatic alterations even within the same tumor type.
Citation Format: Choon Kiat Ong, Waraporn Chan-on, Maarja-Liisa Nairismagi, Weng Khong Lim, Simona Dima, Chawalit Pairojkul, Paiboon Sithithaworn, Irinel Popescu, Steve Rozen, Patrick Tan, Bin Tean Teh. Distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers revealed by whole exome sequencing. [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 5184. doi:10.1158/1538-7445.AM2014-5184
Abstract 519: MicroRNA-31 is upregulated by EGF through C/EBPβ signaling cascade in HNSCC
Authors: Lu Wen Cheng , Lin Shu Chun , Chang Kuo Wei , Tu Hsi Feng 
Published: May 2015

Abstract
MicroRNA-31 (miR-31) was reported as an important oncomir in head and neck squamous cell carcinoma (HNSCC) by targeting FIH gene and activating the hypoxia pathway. Epidermal growth factor receptor (EGFR) was also found up-regulated in 80% of HNSCC. The interplay between miR-31 expression and EGFR signaling in HNSCC attract our attention and is worthy elucidating. In this study, we identified the up-regulation of miR-31, miR-181b and miR-222 in OSCC cells following EGF treatment and subsequent analysis showed that EGF treatment up-regulated miR-31 via the AKT signaling pathway and this phenomenon could be counteracted by curcumin, a natural compound with anti-neoplastic activity. EGF treatment and associated AKT activation up-regulated C/EBPβ expression, which was also attenuated by curcumin. Expression of miR-31 could be up-regulated by exogenous C/EBPβ and this was correlated with decreased FIH expression. Moreover, the up-regulation of miR-31 induced by EGF was abrogated by knockdown of C/EBPβ expression. In human HNSCC tissues the significant correlation between expressions of EGFR, C/EBPβ and miR-31 was also detected. This study demonstrated a novel scenario that the up-regulation of miR-31 in HNSCC could be a consequence of EGFR activation, which are mediated by both AKT and C/EBPβ signaling.
Citation Format: Wen Cheng Lu, Shu Chun Lin, Kuo Wei Chang, Hsi Feng Tu. MicroRNA-31 is upregulated by EGF through C/EBPβ signaling cascade in HNSCC. [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 519. doi:10.1158/1538-7445.AM2014-519