bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3998: Integrative molecular analysis uncovers key molecules and signaling pathways regulated by RKIP in gastrointestinal stromal tumors (GISTs)
Authors: Campanella Nathália C. , Melendez Matias , Leal Leticia Ferro , Evangelista Adriane Feijo , Faça Vitor Marcel , Reis Rui Manuel 
Published: August 2018

Abstract
Introduction: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor on the gastrointestinal tract, and are characterized by hotspot mutations in KIT and PDGFRA genes, which are predictive of imatinib-based therapy response. We showed previously that RKIP, a metastasis suppressor gene, is lost in about 17% of GIST, and it was associated with an adverse outcome. RKIP is plays a pivotal role in several signaling pathways, namely MAPK, NF-κβ, and GSK3β however a multidimensional integrative analysis to uncover its biological impact was never done in cancer and in particular in GIST.
Experimental procedures: We established a RKIP knockout GIST cell line (GIST-T1 KO) by CRISPR/Cas9 system. The differential gene and microRNA expression profile between GIST-T1 RKIP-KO and GIST-T1 negative control cells were assessed using the NanoString nCounter® technology and the nCounter® PanCancer Pathways and nCounter® miRNA Expression assays (NanoString Technologies). All procedures including sample preparation (100 ng of RNA), hybridization, detection and scanning were performed according to manufacture's instructions (NanoString Technologies). In a second step, we performed a global proteomic analysis using the Acquity UPLC M-Class chromatography system (Waters Co) linked to the mass spectrometer Synapt G2-Si (Waters Co). The protein
identification and quantification were performed in Progenesis QI for Proteomics (Waters Co) software.
Results: The nCounter gene expression analysis showed 56 genes differentially expressed: 18 downregulated and 38 upregulated genes in RKIP KO cells. The altered genes are especially involved in PI3k-AKT, MAPK and Ras signaling pathways. The global proteomic characterization showed 50 proteins differentially expressed: 5 were downregulated and 44 upregulated proteins in RKIP KO cells. In microRNA expression profile analysis we found 133 downregulated microRNAs in RKIP KO cells. Taking together, these findings uncover new molecules that are going to screen in a cohort of GIST patients.
Conclusion: For the first time, using a multidimensional integrative analysis we identified driver candidates and pathways, which will contribute the uncovered the biological role of RKIP in cancer.
Citation Format: Nathália C. Campanella, Matias Melendez, Leticia Ferro Leal, Adriane Feijo Evangelista, Vitor Marcel Faça, Rui Manuel Reis. Integrative molecular analysis uncovers key molecules and signaling pathways regulated by RKIP in gastrointestinal stromal tumors (GISTs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3998.
Abstract 40: The role of pressure-driven flow in invasion and chemoresistance of cancer cells in an engineered breast tumor model
Authors: Simi Allison K. , Kourouklis Andreas P. , Piotrowski-Daspit Alexandra S. , Tien Joe , Nelson Celeste M. 
Published: August 2018

Abstract
Collapsed blood or lymphatic vessels in the tumor microenvironment often cause fluid buildup, leading to heterogeneous flow throughout the tissue. Here, we used a three-dimensional (3D) engineered tumor model to investigate how fluid flow specifically influences invasion and chemoresistance of breast cancer cells. To mimic breast tumors, we cultured aggregates of MDA-MB-231 human breast cancer cells embedded in 3D collagen channels. Collagen channels were flanked on the ends by two media reservoirs. By changing the relative heights of media in the reservoirs, we controlled the pressure-induced flow experienced by the tumor cell aggregate. We found that the direction of flow through the collagen channel determined the invasive phenotype of the engineered tumor. These analyses will be repeated with the addition of chemotherapy drugs taxol or 5-fluorouracil in the media to determine the effect of fluid flow on chemotherapeutic response. Our engineered tumor model provides insight into how physical forces influence the invasive phenotype of cancer cells.
Citation Format: Allison K. Simi, Andreas P. Kourouklis, Alexandra S. Piotrowski-Daspit, Joe Tien, Celeste M. Nelson. The role of pressure-driven flow in invasion and chemoresistance of cancer cells in an engineered breast tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 40.
Abstract 400: Noncanonical role of SEC23B in thyroid carcinogenesis: Anemia gene meets cancer
Authors: Yehia Lamis , Ni Ying , Jindal Supriya , Abbas Ata , Komar Anton A. , Eng Charis 
Published: August 2018

Abstract
Hereditary cancer syndromes serve as powerful models to uncover cancer-relevant genes. Cowden syndrome (CS), typically caused by germline PTEN mutations, is a heritable cancer syndrome with high risks of breast and thyroid cancers. However, there is a growing subset of CS without PTEN mutations. By exome sequencing cum family-studies, we identified heterozygous SEC23B variants in CS-associated and apparently sporadic thyroid cancer. Functional characterization revealed mutant CS-associated SEC23B led to endoplasmic reticulum (ER)-stress-mediated cell-colony formation and survival, growth and invasion, reflecting major hallmarks of cancer.
Classically, SEC23B is a component of coat protein complex II (COPII) vesicles that transport secretory proteins from the ER to the Golgi apparatus. Germline homozygous or compound heterozygous loss-of-function SEC23B mutations cause Congenital Dyserythropoietic Anemia Type II (CDA II), resulting in decreased SEC23B levels. Intriguingly, our in vitro data does not recapitulate the CDA II-like decreased SEC23B protein expression, suggesting possible change-of-function effects in a cancer context. Here, we show mutant SEC23B exists within nucleoli, besides classical distribution at the ER/Golgi. This occurs in the absence of nucleolar localization of other COPII protein components and does not compromise canonical secretory function. Global transcriptomic and polysome profiling analyses reveal increased expression of ribosomal protein and translation-related genes, accompanied by enhanced translational capacity in mutant cells in response to ER stress. We also show mutant SEC23B directly binds to Upstream Binding Transcription Factor (UBF), concomitantly with increased UBF binding at the ribosomal DNA (rDNA) promoter region with ER stress. Unbiased proteomic analyses further show SEC23B, both wildtype and mutant, can interact with proteins in the ER stress and EIF2 signaling pathways. We validate through immunoprecipitation the binding interaction between SEC23B and UBA52, with notably increased binding with mutant SEC23B. UBA52 is ribosomal protein RPL40, known to regulate selective translation of stress-related transcripts, protein synthesis, and the cell cycle. Knockdown of SEC23B in vitro resulted in a concomitant decrease in protein levels of UBA52, further supporting that SEC23B and UBA52 are potentially co-regulated. All in all, our data suggest that SEC23B has non-canonical COPII-independent function, particularly within the ribosome biogenesis pathway, that may contribute to the pathogenesis of cancer-predisposition.
Citation Format: Lamis Yehia, Ying Ni, Supriya Jindal, Ata Abbas, Anton A. Komar, Charis Eng. Noncanonical role of SEC23B in thyroid carcinogenesis: Anemia gene meets cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 400.
Abstract 4002: EGR1 downregulation by miR-377-3p mediated lung tumorgenesis following benzo[a]pyrene exposure
Authors: Ke Xinxin , Shen Jing , Shao Jimin , Qi Hongyan 
Published: August 2018

Abstract
Polycyclic aromatic hydrocarbons (PAHs), especially Benzo[a]pyrene (B[a]P), contained in cigarette smoke and air pollution, belong to a category of important carcinogens for lung cancer. B[a]p exerts its carcinogenic function by causing mutations, cytotoxicity and inhibiting DNA synthesis. However, the early molecular events and related mechanisms of B[a]P-induced cell transformation and tumor initiation remains unclear. In this study, we showed that EGR1 was significantly downregulated during human bronchial epithelial BEAS-2B cell transformation and mice lung carcinogenesis after B[a]P and its active form B[a]PDE exposures, respectively. Using RNA-seq to screening and using qRT-PCR, western-blot and immunohistochemistry for validation. In contrast, overexpression of EGR1 inhibited the cell malignant transformation upon B[a]PDE exposure. Furthermore, miR377-3p was strongly increased by B[a]PDE/B[a]P in vitro and in vivo. And luciferase reporter assays showed that the exposure-induced miR377-3p was crucial for inhibition of EGR1 by targeting its 3'-UTR. Importantly, miR-377-3p antagomir reversed the effect of EGR1 downregulation in the cell malignant transformation and tumor initiation models. The target genes of EGR1, ANKRD1 and ATF3, which could be involved in B[a]P-induced lung tumorgenesis, were also analyzed in cell and mice model, respectively. Finally, the B[a]P exposure-induced molecular changes were examined by immunohistochemistry in clinical lung cancer tissues and evaluated with TCGA data. Taken together, the results demonstrated that Benzo[a]pyrene exposure may induce lung tumorgenesis through miR-377-3p mediated reduction of EGR1 expression, suggesting an important role of the tumor suppressor EGR1 in PAH-induced lung carcinogenesis.
Keywords: EGR1, miR-377-3p, malignant transformation, lung tumorgenesis, gene regulation
Citation Format: Xinxin Ke, Jing Shen, Jimin Shao, Hongyan Qi. EGR1 downregulation by miR-377-3p mediated lung tumorgenesis following benzo[a]pyrene exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4002.
Abstract 4006: Serine protease PRSS8 suppresses colorectal carcinogenesis and metastasis
Authors: Bao Yonghua , Guo Yongchen , Yang Yiqiong , Wei Xiaonan , Zhu Xiangdong , Zhang Wei , Yang Wancai 
Published: August 2018

Abstract
PRSS8 is a serine protease and has important physiological and pathophysiological functions, but its roles in cancer initiation and progression are unclear. In this study, a conditional knockout mouse model of Prss8 fl/fl,p-Villin-Cre+ mice were developed and thoroughly characterized at the ages of 3, 6 and 9 months. Intestinal epithelial cell proliferation, migration, and differentiation, were determined. The approaches of gain- and loss of expression of PRSS8 in human colon cancer cells were performed to evaluate anti-cancer and anti-metastasis in vitro and in nude mice by mouse subcutaneous injection, tail vein injection and intra-spleen transplantation. Gene profile and gene set enrichment analysis and mechanistic studies were conducted in vitro and in human colorectal cancer tissues. Results: Genetic deficiency of the Prss8 gene caused spontaneous formation of colitis and inflamed rectum at the early age, but caused intestinal tumors and lymph node metastasis at late age, which was linked to increased intestinal cell proliferation and migration, but decreased cell differentiation. Increased PRSS8 expression showed inhibition of cancer cell growth and metastasis in nude mice, and inhibited migration, invasion, colony formation and tumor sphere formation in vitro, but reduced expression of PRSS8 facilitated malignancies. Mechanistic studies revealed that PRSS8 targets Wnt/β-catenin, epithelial-mesenchymal-transition, and stem cell signaling pathways, which was supported by the results from the Cancer Genome Atlas, and were validated in human colorectal cancers. Conclusion: PRSS8 is a novel tumor suppressor that plays critical roles in the suppression of carcinogenesis and metastasis via targeting Wnt/β-catenin, EMT and stem cell signaling pathway.
Citation Format: Yonghua Bao, Yongchen Guo, Yiqiong Yang, Xiaonan Wei, Xiangdong Zhu, Wei Zhang, Wancai Yang. Serine protease PRSS8 suppresses colorectal carcinogenesis and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4006.
Abstract 4014: APOBEC3B promotes hepatocarcinogenesis and metastasis through novel deaminase-independent activity
Authors: Ng Irene O L , Ma Wei , Ho Daniel WH , Sze Karen MF , Tsui Yue M. , Chan Lo K. , Lee Joyce MF 
Published: August 2018

Abstract
APOBEC3B (A3B), a cytidine deaminase, is known to play important roles in creating de novo genomic C-to-T mutations in cancers and contribute to induction of genomic instability. In this study, we evaluated the roles of A3B in the progression and metastasis of human hepatocellular carcinoma (HCC). Using whole-transcriptome and whole-exome sequencing and quantitative real-time PCR, we found that A3B was overexpressed in human HCCs and A3B expression was significantly correlated with the proportion of genomic C-to-A and G-to-T mutations. Upon clinicopathological correlation, higher A3B expression was associated with more aggressive tumor behavior. Wild-type A3B (wt-A3B) overexpression in HCC cells promoted cell proliferation, and cell migratory and invasive abilities in vitro, and tumorigenicity and metastasis in vivo. On the other hand, knockdown of A3B suppressed cell proliferation, migratory and invasive abilities of HCC cells with high endogenous A3B level. However, to our surprise, overexpression of A3B deaminase-dead double mutant (E68A/E255Q) led to similar results as wt-A3B in HCC both in vitro and in vivo. Furthermore, overexpression of wt-A3B and mutant A3B both enhanced cell cycle progression in HCC cells. Altogether, our data demonstrated a novel deaminase-independent role of A3B in contributing to HCC tumorigenesis and metastasis.
Citation Format: Irene O L Ng, Wei Ma, Daniel WH Ho, Karen MF Sze, Yue M. Tsui, Lo K. Chan, Joyce MF Lee. APOBEC3B promotes hepatocarcinogenesis and metastasis through novel deaminase-independent activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4014.
Abstract 4017: Inhibition of mutagenicity of PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine)by Chinese medicinal herbs Scutellaria barbata and Oldenlandia diffusa
Authors: Alva Rayford , Wong Brian Yuen Yau , Tanner John , Wan Yanlingxue , Uppala Padma Tadi , Hayes Ryan 
Published: August 2018

Abstract
Scutellaria barbata (SB) and Oldenlandia diffusa (OD) have been used in traditional Chinese medicine for treating liver, lung and rectal tumors. Recent research revealed that these two herbs were included in most of the herbal cancer treatment formulas in Taiwan hospitals. We previously showed that SB and OD inhibited mutagenesis, DNA binding and metabolism of aflatoxin B1 (AFB1) and benzo(a)pyrene (BaP) bioactivated by Aroclor 1254-induced rat S9. PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) is produced from high cooking temperature of creatine, sugars, and amino acids. It was demonstrated positive result in the Ames mutagenicity test. PhIP is one of the most abundant heterocyclic amines (HCAs) in cooked meat and has been announced as "reasonably anticipated to be a human carcinogen" by the U.S. Department of Health and Human Services National Toxicology Program. Cancer of the prostate, breast, lung, esophagus, stomach, and colorectum may be related to high intake and high exposure to PhIP. In this study, the effects of aqueous extracts of SB and OD on PhIP-induced mutagenesis using Salmonella typhimurium TA98 as the bacterial tester strain and rat liver 9000 x g supernatant (S9) as the metabolic activation system were assessed. Our results showed that SB and OD significantly inhibited the mutagenicity of PhIP (both 0.1 and 1µg/plate) bioactivated by S9 (800 mg/plate) in a dose-response fashion (p&lt; 0.05). The percent inhibition of revertants formation of these two herbs against 0.1µg/plate of PhIP were 45%, 77%, and 87% for SB (1.5, 3, and 6 mg/plate) and 21%, 80%, and 95% for OD (1.5, 3, and 6 mg/plate), while the percent inhibition against 1 µg/plate of PhIP were similar to that of the 0.1 µg/plate (45%, 80%, 90% for SB and 44%, 81%, 93% for OD, respectively). There was a slight additive inhibition effect of the herbs in combination (SB + OD) at higher concentrations (60%, 85%, and 90%) against both concentrations of PhIP. These results suggested that OD and SB contain antimutagenic phytochemicals towards PhIP-induced mutagenicity. Further study of their modulation effects on metabolism and DNA binding of PhIP is warranted to reveal the potential anti-mutagenicity mechanism and their chemopreventive property against PhIP and potentially against other HCAs.
Citation Format: Rayford Alva, Brian Yuen Yau Wong, John Tanner, Yanlingxue Wan, Padma Tadi Uppala, Ryan Hayes. Inhibition of mutagenicity of PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine)by Chinese medicinal herbs Scutellaria barbata and Oldenlandia diffusa [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4017.
Abstract 4021: The evaluation of carcinogenicity evidence of dibenzanthracenes
Authors: Tsai Feng , Hsieh Jennifer C. , Osborne Gwendolyn , Sandy Martha 
Published: August 2018

Abstract
Dibenzanthracenes (DBAs) are identified as carcinogens and are on the California Proposition 65 list. DBAs are five-ring polycyclic aromatic hydrocarbons (PAHs). This chemical group consists of three isomers: DB[a,c]A, DB[a,h]A, and DB[a,j]A. DBAs are products of the incomplete combustion or pyrolysis of organic matter and can be formed during high temperature cooking. They are air pollutants present in engine exhaust, tobacco and marijuana smoke, and may also contaminate soil and water. DB[a,h]A is a well-studied International Agency for Research on Cancer (IARC) Group 2A carcinogen, whereas fewer studies relevant to carcinogenicity have been conducted with DB[a,c]A and DB[a,j]A. Carcinogenicity evidence from multiple data streams was integrated in the hazard identification of this chemical group. These data streams include animal cancer bioassays, mechanistic studies and other relevant data, including high-throughput studies (e.g., ToxCast), toxicogenomic studies, and information from quantitative structure-activity relationship (QSAR) models. Structure activity comparisons across the three DBAs and related carcinogenic PAHs served to bridge the data gaps for the two less studied isomers. The results of our analyses showed that each of the DBAs share similar biological activities in animals: all induce tumors in mice, are mouse skin tumor initiators, form DNA adducts, are genotoxic, and form metabolites that are also genotoxic and initiators of mouse skin tumors. All three DBAs activate the aryl hydrocarbon receptor (AhR) in reporter gene assays, and DB[a,h]A and DB[a,c]A have been shown to bind to the AhR. In addition to strong evidence of genotoxicity, other carcinogenic mechanisms are likely also operative, including receptor activation (e.g., AhR), immune suppression, altered cell proliferation, apoptosis, and cell cycle regulation. There are strong structure-activity similarities among the DBAs and several carcinogenic 4-, 5- and 6-ring PAHs, including benzo[a]pyrene and dibenzo[a,h]pyrene. In addition, DB[a,c]A and DB[a,j]A were predicted to be mutagenic and carcinogenic in several QSAR models, including VEGA, Lazar and OECD QSAR Toolbox. Integration of the evidence from these multiple data streams resulted in the identification of the DBAs as a chemical group as carcinogens.
Citation Format: Feng Tsai, Jennifer C. Hsieh, Gwendolyn Osborne, Martha Sandy. The evaluation of carcinogenicity evidence of dibenzanthracenes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4021.
Abstract 4027: Fibroblast growth factor 2 (FGF2) is associated with the development of resistance to pemetrexed in lung cancer cells
Authors: Miura Kentaro , Ito Ken-ichi , Oba Takaaki , Iesato Asumi 
Published: August 2018

Abstract
Pemetrexed (MTA) is a folate antimetabolite used for treatment of non-small cell lung cancer and plural mesothelioma. Although several molecules such as thymidylate synthase (TS) or ATP-binding cassette transporter 11 (ABCC11) have been reported to be involved in the mechanisms of resistance to MTA, precise mechanisms underlying resistance to MTA remains unknown. To elucidate the mechanisms of resistance to MTA in lung cancer, we established MTA resistant clones in PC9 and H1993 lung adenocarcinoma cell lines (PC9-MTA, H1993-MTA). Then, gene expression profiles were compared between PC9 and PC9-MTA cells by using microarray analyses, and several genes including fibroblast growth factor 2 (FGF2) were identified. Elevated expression of FGF2 in PC9-MTA cells and H1993-MTA cells were confirmed by western blot analyses. Knockdown of FGF2 by siRNA partially restored the sensitivity to MTA both in PC9-MTA and H1993-MTA cells. In addition, anti-FGFR1 inhibitor (PD173074) restored MTA sensitivity particularly in PC9-MTA cells. On the other hand, the expression of TS was increased in PC9-MTA and H1993-MTA cells, and the inhibition of TS with the TS-targeting siRNA restored the sensitivity to MTA. However, with regard to the expression of FGF2 and TS, the inhibition of FGF2 did not modify the expression of TS, and vise versa. Furthermore, a simultaneous inhibition of FGF2 and TS by siRNAs in the MTA-resistant cells restored MTA sensitivity to approximately the level observed for the parental cell lines. With regard to the factors related to the signal transduction pathway, the phosphorylation of Erk and Akt in H1993-MTA cells was decreased compared with those in the parental cells. When H1993-MTA cells were treated with FGF2-targeting siRNA or anti-FGFR1 inhibitor, the increase of phosphorylation of ERK and AKT were induced. These data indicated the possibility that both FGF2 and TS could confer MTA resistance in the lung cancer cell lines in an independent manner, and that modification of signal transduction through FGF2-FGFR1 pathway might be involved in the development of MTA resistance in lung cancer cells.
Citation Format: Kentaro Miura, Ken-ichi Ito, Takaaki Oba, Asumi Iesato. Fibroblast growth factor 2 (FGF2) is associated with the development of resistance to pemetrexed in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4027.