bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2003: P38α suppresses tumor initiating cell phenotypes through inhibition of NFATc4 in non-small cell lung cancer
Authors: Xiao Zhi-Jie , Liu Jing , Wang Si-Qi , Gao Xu-Yuan , Tin Vicky Pui-Chi , Wong Maria Pik 
Published: August 2018

Abstract
Lung cancer development is often mediated through oxidative and inflammatory stresses caused by tobacco and environmental carcinogens, suggesting dysregulation of stress mediators might play a role during carcinogenesis. The p38 MAPK pathway is activated by multiple stress stimuli and inflammatory cytokines, and mediates a wide range of cellular processes in a context-specific manner. P38α, a member of the p38 family, is known to regulate the self-renewal and differentiation of adult lung stem cells. While p38α has been reported to mediate tumor suppressive or supportive roles in different cancers, inactivation of p38α in the lung epithelium is involved in KRASG12V induced tumorigenesis. However, whether p38α could be involved in regulating tumor initiating cells (TIC) of lung cancer remains unclear. To investigate this possibility, immunohistochemistry was first used to analyse the nuclear expression of phosphorylation-activated p38α (p-p38α) in 90 human primary lung adenocarcinomas. Results showed higher expression of p-p38α was significantly correlated with longer progression free and overall survivals, as well as a more differentiated tumor histological phenotype, indicating p38α might play a tumor suppressive role and drive tumor differentiation in lung cancer. To further address its functional role on lung TIC, p38α was suppressed by siRNA or pharmacologically inhibited by SB203580. This led to increase of the TIC subset that coexpresses ALDH and CD44 (ALDH+/CD44+-TIC), as well as up-regulated expression of the pluripotency genes SOX2, OCT4, and NANOG in lung cancer cell lines. Functionally, p38α inhibition by SB203580 promoted tumor spheres formation for two consecutive generations. NFAT is a family of transcription factors reported to regulate TIC in various cancers which are activated via de-phosphorylation leading to nuclear translocation. We hypothesize the TIC supportive function of p38α inhibition might be mediated through loss of phosphorylation and subsequent activation of NFATc4. In line with this hypothesis, we showed, using Western blot, p38α inhibition increased the expression of nuclear NFATc4. Moreover, NFATc4 knockdown led to suppressed sphere formation and pluripotency genes expression in lung cancer cell lines. Together, our results indicated p38α mediates a tumor suppressor pathway through downstream NFATc4 inactivation and TIC inhibition. The p38α -NFATc4 stress pathway might serve as a potential target for long term lung cancer treatment through TIC regulation.
Citation Format: Zhi-Jie Xiao, Jing Liu, Si-Qi Wang, Xu-Yuan Gao, Vicky Pui-Chi Tin, Maria Pik Wong. P38α suppresses tumor initiating cell phenotypes through inhibition of NFATc4 in non-small cell lung 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 2003.
Abstract 2008: Stem cell-associated proteins P63 and Bmi-1 may cooperate in maintaining cancer-initiating cell populations in squamous cell carcinomas
Authors: Ha Linan , Reilly Devin , Ponnamperuma Roshini , George Andrea , Weinberg Wendy C. 
Published: August 2018

Abstract
Overexpression of p53-related protein p63, particularly ΔNp63α, is seen in squamous cell carcinomas of the head and neck, lung, cervix and skin. We use primary murine epidermal keratinocytes as a model of human squamous epithelial cells and mimic these elevated levels using adeno- and lentiviral vectors. In previous studies, we established that ΔNp63α inhibits induction of p16ink4a and p19arf, blocks oncogene-induced senescence, and cooperates with activated v-rasHa to enhance conversion of papilloma to carcinoma in a nude mouse grafting model. We evaluated the relationship between ΔNp63α and Bmi-1, a member of the polycomb complex known to repress the INK4a/ARF gene locus, and modulated Bmi-1 expression in the presence or absence of elevated ΔNp63α to assess its impact on p16ink4a and p19arf expression. Bmi-1 protein levels correlate with those of ΔNp63α; however, higher levels of Bmi-1 block p16ink4a but not p19arf. Consistent with this, Bmi-1 is required for the binding of ΔNp63α to the p16ink4a but not the p19arf promoter. These findings may have further important implications in HNSCC as other previously published models have demonstrated that Bmi-1 is important for prevention of senescence in stem cells. Using FACS analysis and cell sorting, we are defining cell populations of keratinocytes with respect to the expression of ΔNp63α, Bmi-1, and other markers of stem cells and senescence and extending these approaches from murine to human HNSCC models with the aim of correlating these distinct patterns with cancer-initiating potential and tumor phenotype.
Citation Format: Linan Ha, Devin Reilly, Roshini Ponnamperuma, Andrea George, Wendy C. Weinberg. Stem cell-associated proteins P63 and Bmi-1 may cooperate in maintaining cancer-initiating cell populations in squamous cell carcinomas [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 2008.
Abstract 2023: RhebL1 is involved in epithelial mesenchymal transition of breast cancer cells
Authors: KIM Hyunji , LEE Changhoon 
Published: August 2018

Abstract
RhebL1 belongs to the ras superfamily of G proteins and is highly conserved across many species. However, the cellular function of RhebL1 have not yet been reported especially in breast cancer. In this study, we found that RhebL1 is highly expressed in MDA-MB-231 and SK-BR-3 breast cancer cells. By using the public microarray data sets, we found that overall and relapse free survival were decreased in breast cancer patients with high expression of RhebL1. The involvement of RhebL1 in epithelial mesenchymal transition of breast cancer cells was examined. Gene silencing of RhebL1 decreased the expression of mesenchymal markers such as N-cadherin, Vimentin, snail and slug and increased the expression of epithelial marker E-cadherin in MDA-MB-231 and SK-BR-3 breast cancer cells. In contrast, overexpression of RhebL1 increased the expression of mesenchymal markers and decreased the expression of E-cadherin in MCF7 breast cancer cells. Next, we examined the effects of RhebL1 expression on migration and invasion since migratory and invasive capabilities were strongly related to EMT. RhebL1 overexpression significantly increased the migration and invasion of MCF7 cells and gene silencing of RhebL1 reduced the migration and invasion of MDA-MB-231 and SK-BR-3 cells. Furthermore, we identify a novel RhebL1-binding protein, RBP1, which mediates the segregation of protein phosphatase 2A from Akt, leading to induced Akt phosphorylation under conditions by binding to RhebL1. The collective results indicate that RhebL1 is involved in EMT of breast cancer cells via interaction with RBP1-Akt-PP2A complex. These results suggest that RhebL1 may be a key regulator modulating metastatic breast cancer cells.
Citation Format: Hyunji KIM, Changhoon LEE. RhebL1 is involved in epithelial mesenchymal transition of breast 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 2023.
Abstract 2031: The noncanonical pathways of transforming growth factor β in ovarian carcinoma
Authors: Catane Liora Jacobs , Trope Claes G. , Davidson Ben , Reich Reuven 
Published: August 2018

Abstract
Introduction: Of all the gynecological malignancies, ovarian cancer (OC) has the highest mortality rate. This can be attributed to the late detection and acquired drug resistance. It metastasizes mainly in the serosal cavities, and produces cancerous cells dispersed in the peritoneal and pleural fluids called effusions. Transforming Growth Factor β (TGFβ) is a family of growth factors that play a significant role in cellular processes. There are three homologous isoforms of TGFβ expressed in humans: TGFβ1-3. These 3 ligands activate 3 transmembrane receptors, TβRI-III. The 3 receptors and the ligand TGF-β2 have different splice variants. TGFβ signaling induces canonical and non-canonical signaling. The Non-canonical pathways consist of a variety of different pathways, including MAP kinase, Rho-like GTPase, and phosphatidylinositol-3-kinase (PI3K)/ AKT pathways.
Aims and methods: Our first aim was to investigate the metastatic role of TGFβ receptor variants. This was accomplished through the creation of specific receptor variant knockouts (KO's) using the CRISPR/Cas9 genome editing system and subsequent metastatic tests. Next we characterized chosen non-canonical pathways and downstream effectors in the CRISPR KO's through Western Blot analysis and qPCR respectively. The Second aim of this study was to characterize the non-canonical pathways In-vivo. Using human tumor tissue samples, we examined the expression and activation of the different pathways via Western Blot analysis and checked for correlation with clinical parameters.
Results: KO cells showed significantly lower migration and invasion capabilities compared to Wild Type (WT) cells. Our results show a decrease in the activation of ERK1/2, JNK1 and JNK2 in the TβRI variant 1 KO in ES-2 cells (p=0.058, p=0.002 and p&lt;0.0001 respectively). The downstream effectors SNAIL and TWIST show significantly higher levels in the KO compared to WT cells. Of the pathways examined, p-AKT was found to be higher in post chemotherapy samples (p=0.029) and JNK1 was higher in effusions from patients with poor chemotherapy response (p=0.045). Site-related findings show that p85 (PI3K), AKT and p-AKT were highest in metastasis, medium in solid ovarian carcinoma and lowest in effusions (p&lt;0.0001, p=0.0024 and p=0.0021 respectively).
Closing statement: These findings provide new insight on the importance of TGFβ‘s role in the progression of OC, and is, as far as we know, is the first study done on the metastatic roles of the receptor variants.
Citation Format: Liora Jacobs Catane, Claes G. Trope, Ben Davidson, Reuven Reich. The noncanonical pathways of transforming growth factor β in ovarian carcinoma [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 2031.
Abstract 2032: CXCR7 promotes the migration and invasion of head and neck squamous cell carcinoma through Smad2/Akt signaling
Authors: Kim Nayoung , Kim Solbi , Ryu Hyewon , Lee Hyo Jin 
Published: August 2018

Abstract
Background: The chemokine receptor, CXCR7, has been shown to play an important role in the progression of several types of cancer. However, there have been few reports on the biological role of CXCR7 in head and neck squamous cell carcinoma (HNSCC). In this study, we investigated the functional role of CXCR7 and the underlying molecular mechanism of disease progression in HNSCC.
Methods: We characterized the expression of CXCR7 in tumor specimens from patients with HNSCC. The biological functions of CXCR7- and CXCR7-mediated signaling pathways were investigated in HNSCC cell lines with CXCR7 overexpression and treatment of SDF-1α, a major ligand of CXCR7, as well as knockdown of CXCR7.
Results: CXCR7 was differentially expressed in human HNSCC patients. High expression of CXCR7 was associated with an aggressive tumor behavior. Overexpression of CXCR7 dramatically promoted cell migration and invasion in HNSCC cells, although it was not involved in cell proliferation and colony formation. CXCR7 knockdown using siRNA in HNSCC cells recovered the cell migratory and invasive behavior of HNSCC cells. CXCR7 overexpression also induced the epithelial-mesenchymal transition. Vimentin, Slug, and Twist were increased but E-cadherin and Ep-CAM were decreased by CXCR7 expression. Akt phosphorylation and Smad2 signaling activation were induced in HNSCC cells with CXCR7 overexpression. Treatment with a PI3K inhibitor reduced Slug and Twist levels while suppression of Smad2 signaling by siRNA reduced Akt phosphorylation, as well as Slug and Twist. Furthermore, inhibition of Smad2 decreased tumor cell migration and invasion in HNSCC.
Conclusions: CXCR7 contributed to cell migration and invasion of HNSCC through the Smad2/Akt signaling axis, suggesting that CXCR7 might be a therapeutic target for the treatment of HNSCC.
Citation Format: Nayoung Kim, Solbi Kim, Hyewon Ryu, Hyo Jin Lee. CXCR7 promotes the migration and invasion of head and neck squamous cell carcinoma through Smad2/Akt signaling [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 2032.
Abstract 2040: Withaferin A inhibits epithelial-to-mesenchymal transition in non-small lung cell cancer cells via regulation of SMAD and NFkB signaling
Authors: Kyakulaga Al Hassan , Aqil Farrukh , Munagala Radha , Gupta Ramesh 
Published: August 2018

Abstract
Background: Metastasis remains the primary cause in lung cancer. Epithelial-to-mesenchyme transition (EMT) has been identified as the hallmark for metastasis in NSCLC, and is being explored for drug targeting. Aberrant signaling mechanisms for cytokines such as TGF-β1 and TNFα are known to induce EMT. In this study we demonstrate the effect and mechanisms of WFA inhibition of EMT in NSCLC cell lines.
Objective: The present study was done to determine the effect of WFA on TGF-β1 and TNFα induced EMT, migration and invasion in human NSCLC cells. Furthermore, to determine underlying the mechanisms of WFA inhibition of EMT.
Methods: Two human NSCLC cell lines (H1299 and A549) were cultured in DMEM media. To induce the EMT, cells in serum free media were challenged with TGF-β1 (5 ng/mL) or TNFα (5 ng/mL) alone or in combination. To determine the effects of WFA, cells were either pre- or co-treated with different concentrations of WFA for various time points. Western blot analysis, electrophoretic mobility shift assay (EMSA), RT-PCR and immunofluorescence staining were used to determine effects of WFA on Smad2/3 and NFkB activation. Cell adhesion, migration and invasion assays were used to assess in vitro anti-metastatic activity.
Results: Our findings indicate that the cytokines TGF-β1 and TNFα cooperate to promote the acquisition of EMT phenotype, migration and invasion of NSCLC cells in vitro. There was a marked increase in the expression of EMT transcription factors Snail, Slug, ZEB and EMT markers such as vimentin and N-cadherin. Cells treated with TGF-β1/TNFα had significantly increased migratory and invasive capacities. WFA treatment significantly inhibited the TGF-β1 induced Smad2/3 activation and TNFα-induced translocation of NFkB into the nucleus. We observed a dose and time dependent inhibition of the phosphorylation of Smad2/3 and NFkB in both cell lines. The cell adhesion, migratory and invasive capacities of both H1299 and A549 cells were greatly diminished by WFA in the presence or absence of cytokines. Conclusion: Based on the current finding, it can be concluded that WFA inhibits EMT via negative regulation of Smad2/3 and NFkB signaling in NSCLC cells.
Citation Format: Al Hassan Kyakulaga, Farrukh Aqil, Radha Munagala, Ramesh Gupta. Withaferin A inhibits epithelial-to-mesenchymal transition in non-small lung cell cancer cells via regulation of SMAD and NFkB signaling [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 2040.
Abstract 2054: Tumor endothelial cells survive under lactic acidosis
Authors: Annan Dorcas A. , Maishi Nako , Soga Tomoyoshi , Dawood Randa , Hida Yasuhiro , Hida Kyoko 
Published: August 2018

Abstract
Tumor endothelial cells (TECs) which line tumor blood vessels differ functionally, structurally and genetically from normal endothelial cells (NECs). Recent findings have furthermore shown that TECs are hyper-glycolytic, making them a significant source of lactic acid within the tumor. Similar to TECs, tumor cells are also preferably glycolytic and release large amounts of lactic acid. Consequently, TECs may be influenced by both intrinsic and tumor-derived lactic acid. However, the effects of lactic acidic on TECs have not been elucidated. Moreover, with the quest to find novel therapeutic antiangiogenic targets, it is of much essence to identify adaptive mechanisms supporting TECs under conditions of lactic acidosis. In this study, metabolomic analysis was performed in TECs and NECs. TECs had significantly higher intracellular levels of glycolytic metabolites, lactate, ATP and amino acids than NECs. Additionally, unlike NECs, TECs proliferated when exposed to conditions of lactic acidosis (20mM lactate, pH 6.9) and not under lactosis (20mM lactate, pH 7.3). This observation implied that TECs survive and sustain their growth under low pH conditions but in the presence of lactate. Furthermore, qRT -PCR analysis revealed an elevated expression of proton-coupled transporters in TECs than in NECs. The TECs were sensitive to drugs targeting some of the transporters. This indicated that proton-coupled transporters may be involved in the survival and proliferation of TECs in lactic acidosis. Next, the effects of lactic acidosis on tumor blood vessels, particularly endothelial cellular junctions was investigated. VE-cadherin expression was analysed by immunocytochemistry in endothelial cells exposed to lactosis and lactic acidosis. The VE-cadherin was more disorganized under lactic acidosis than in lactosis. Lactic acidosis may therefore contribute to the poor integrity of tumor blood vessels. More studies are on-going to elucidate the molecular effects of lactic acidosis on TECs and the role played by proton-coupled transporters in TECs survival in the tumor microenvironment. These will lead to the identification of a proton-coupled transporter as an antiangiogenic therapeutic target.
Citation Format: Dorcas A. Annan, Nako Maishi, Tomoyoshi Soga, Randa Dawood, Yasuhiro Hida, Kyoko Hida. Tumor endothelial cells survive under lactic acidosis [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 2054.
Abstract 2070: The prevalence of DICER1 pathogenic variation in cancer population databases
Authors: Kim Jung , Schultz Kris Ann P. , Hill D. Ashley A. , Stewart Douglas R. 
Published: August 2018

Abstract
DICER1 is an RNaseIII endonuclease that is crucial for processing pre-microRNA into mature microRNA. The DICER1 syndrome is a rare, autosomal dominant tumor-predisposition disorder associated with pleuropulmonary blastoma, a rare pediatric lung cancer. Somatic missense variation in “hotspot” codons in the RNaseIIIb domain (E1705, D1709, G1809, D1810, E1813) is observed in DICER1-associated tumors. Previously, we found in the general population (non-TCGA ExAC) that the prevalence of pathogenic DICER1 variation is approximately 1:10,000. In this study, we investigated the prevalence of pathogenic DICER1 variation in common adult and pediatric cancers. We examined two publicly-available cancer datasets: TCGA (adult; 32 cancer types; 9,173 exomes) and TARGET (pediatric; 3 cancer types; 236 exomes). TCGA bam files were downloaded and germline variants were called. Germline VCF files were obtained from TARGET investigators. All datasets were annotated with snpEff and ANNOVAR. Variants were binned into 4 categories: likely benign (LB), variant of unknown significance (VUS), likely pathogenic (LP), or pathogenic (P). We reviewed publicly-available pathology images for the TCGA tumors. The prevalence of DICER1 P/LP variants (in all cancers combined) was 1:834 and 1:118 in TCGA and TARGET, respectively. To reduce potential prevalence inflation, we conducted a more stringent prevalence calculation by only considering loss-of-function and hotspot variants. The prevalence of P variants was approximately 1:4586 in TCGA and 1:236 in TARGET. With these more stringent criteria, a single participant with a uterine corpus endometrial carcinoma (UCEC in TCGA) harbored a two pathogenic germline DICER1 (hotspot and splice donor) variants, and a second UCEC harbored a somatic DICER1 (hotspot) variant. In TARGET, a single participant with a neuroblastoma harbored a germline DICER1 canonical splice variant. There were no atypical or unusual features noted on pathology review of publicly-available slides from TCGA tumors. In TCGA, across many types of cancer, the prevalence of pathogenic DICER1 variation was higher compared with the general population (~1:4,600 vs. ~1:10,000), a finding driven by one cancer type (UCEC). In the smaller TARGET dataset, we observed a single pathogenic germline variant in neuroblastoma. This is the first comprehensive analysis of DICER1 pathogenic variation in large adult and pediatric cancer populations. The novel association of DICER1 variation with UCEC merits additional investigation.
Citation Format: Jung Kim, Kris Ann P. Schultz, D. Ashley A. Hill, Douglas R. Stewart. The prevalence of DICER1 pathogenic variation in cancer population databases [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 2070.