bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1986: IRAK1 augments cancer stemness and drug resistance via the AP-1/AKR1B10 signaling cascade in hepatocellular carcinoma
Authors: Cheng Bowie Yik Ling , Leung Doris Hoi Wing , Lau Eunice Yuen Ting , Ng Irene Oi Lin , Lee Kin Wah 
Published: August 2018

Abstract
Frequent relapse and drug resistance can be attributed to the existence of tumor-initiating cells (T-ICs) within the tumor bulk. From transcriptome sequencing of 16 pairs of clinical HCC samples, we found that Interleukin-1 receptor-associated kinase 1 (IRAK1) in the TLR/IRAK pathway was significantly upregulated in hepatocellular carcinoma (HCC). IRAK1 overexpression in HCC was further confirmed at the mRNA and protein levels and correlated with advanced tumor stages and poor patents survival. Interestingly, IRAK4, an upstream regulator of IRAK1, was also found to be consistently upregulated. We demonstrated that IRAK1 regulates liver T-IC properties, including self-renewal, tumorigenicity and liver T-IC marker expression. IRAK1 inhibition sensitized the HCC cells to doxorubicin and sorafenib treatment in vitro through the suppression of the apoptotic cascade. Pharmacological inhibition of IRAK1 with a specific IRAK1/4 kinase inhibitor consistently suppressed liver T-IC populations. Through RNA sequencing analysis by comparing gene expression profiles between IRAK1-knockdown and control cells, we identified Aldo-Keto Reductase Family 1 Member 10 (AKR1B10) as a novel downstream target of IRAK1. Clinically, AKR1B10 was found to be overexpressed in HCC, which was significantly correlated with IRAK1 expression. Functional analysis demonstrated that knockdown of AKR1B10 negated the IRAK1-induced T-IC functions via modulation of the AP-1 complex. Using an HCC xenograft model, we found that an IRAK1/4 inhibitor in combination with sorafenib synergistically suppressed the tumor growth. In conclusion, targeting the IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway may be a potential therapeutic strategy against HCC.
Citation Format: Bowie Yik Ling Cheng, Doris Hoi Wing Leung, Eunice Yuen Ting Lau, Irene Oi Lin Ng, Kin Wah Lee. IRAK1 augments cancer stemness and drug resistance via the AP-1/AKR1B10 signaling cascade in hepatocellular 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 1986.
Abstract 2007: A novel CRISPR/Cas9 reporter system to monitor TNBC cancer stem cells in real time
Authors: Truchan Nathan A. , Buschhaus Johanna , Brooks Michael , Halabu Andre , Guo Hongwei , Yuan Hebao , Luker Kathryn , Wicha Max , Sun Duxin , Burnett Joseph P. 
Published: August 2018

Abstract
Increasing evidence suggests that breast cancers arise from so-called cancer stem cells (CSC), which, consistent with their normal adult counterpart, are uniquely capable of long term self-renewal and differentiation into all bulk cancer cell types that exhibit unique epigenetic states within a tumor. While FACS has been instrumental to isolating these cells and quantifying efficacy of CSC targeted drugs in vitro and in vivo, having to remove cells from their native environment is an inherent limitation, thereby only providing a snapshot of information with each experiment. In order to directly visualize CSC dynamics in real time the CRISPR/Cas9 system was used to precisely knockin mCherry directly downstream of the final exon of ALDH1A3 in SUM149 triple-negative breast cancer cells. With regard to CSC properties, ALDH1A3 high cells were shown to be dramatically correlated with the ALDEFLUOR assay and functionally, increased ammosphere and tumor formation in vitro and in vivo. Strikingly, a single ALDH1A3 high cell was capable of reconstituting the entire heterogeneity of the parental cell line. With the ability to directly visualize CSCs we sought to utilize live cell imaging to observe population changes in response to varying therapeutics. As evident by mCherry fluorescence intensity we confirm previous findings that suggest conventional chemotherapeutics such as docetaxel enrich for CSCs while the natural product sulforpahane reduces the population. Taken together, we believe our mCherry reporter cells could be adapted to rapidly screen for novel inhibitors of CSCs in triple-negative breast cancers.
Citation Format: Nathan A. Truchan, Johanna Buschhaus, Michael Brooks, Andre Halabu, Hongwei Guo, Hebao Yuan, Kathryn Luker, Max Wicha, Duxin Sun, Joseph P. Burnett. A novel CRISPR/Cas9 reporter system to monitor TNBC cancer stem cells in real time [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 2007.
Abstract 2016: Potential role of polo-like kinase 1 in epithelial-mesenchymal transition in melanoma
Authors: Chhabra Gagan , Singh Chandra K. , Ndiaye Mary A. , Ahmad Nihal 
Published: August 2018

Abstract
Mammalian polo-like kinase 1 (Plk1), an important serine/threonine kinase, has been shown to be a critical regulator of mitosis and cytokinesis. A number of studies, including those from our laboratory, have shown that Plk1 is significantly overexpressed in several cancers, including melanoma. Plk1 has also been linked with poor disease prognosis in cancer patients. A limited number of recent studies have suggested that Plk1 may be involved in epithelial-mesenchymal transition (EMT) in different cancers. However, the role of Plk1 in EMT process in melanoma has not been studied. Indeed, EMT plays a driving role in the acquisition of cancer metastasis and an important hallmark of EMT is downregulation of epithelial marker E-cadherin, and upregulation of mesenchymal marker, N-cadherin. In this study, we investigated whether the kinase activity of Plk1 plays a role in EMT process by modulating EMT markers in melanoma cells. To determine this, we performed western blots, RT-qPCR, cell migration and cell invasion assays using A375 melanoma cells stably transfected with plasmids for wild-type (WT) Plk1 overexpression, constitutively active Plk1 (T210D) and kinase-inactive (K82R) Plk1, as well as shRNA-mediated Plk1 knockdown. We observed that overexpression of WT Plk1 upregulated the mesenchymal markers N-cadherin, Vimentin, and Fibronectin, and downregulated the epithelial marker E-cadherin. We also found that the modulation in EMT markers by Plk1 in melanoma cells was associated with the upregulation of transcription factors Snail and Zeb1. Interestingly, downregulation of endogenous Plk1 by specific shRNA resulted in a downregulation of N-cadherin, Vimentin, Fibronectin, Snail and Zeb1. Further, when we assessed the EMT-related molecular changes in A375 melanoma cells containing constitutively active and kinase-inactive Plk1, the cells containing constitutively active Plk1 showed a significant decrease in epithelial marker as well as marked increases in mesenchymal markers. However, the cells containing kinase-inactive Plk1 showed the opposite trend. Moreover, A375 melanoma cells containing constitutively active Plk1 showed higher migration and invasion potential, whereas cells containing kinase-inactive Plk1 showed limited cell migration and invasion. Overall, these results suggest that Plk1 is involved in the EMT process and its kinase activity is important for EMT-related changes in melanoma cells. Further studies are in progress to determine the cause-and-effect molecular mechanisms of Plk1 mediated EMT regulation.
Citation Format: Gagan Chhabra, Chandra K. Singh, Mary A. Ndiaye, Nihal Ahmad. Potential role of polo-like kinase 1 in epithelial-mesenchymal transition in melanoma [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 2016.
Abstract 2027: P62/IMP2 promotes metastasis in hepatocellular carcinoma (HCC) by regulating EMT in different signaling pathway
Authors: Xing Mengtao , Shi Jianxiang , Li Jitian , Chen Beibei , Francia Giulio , Zhang Jianying 
Published: August 2018

Abstract
Insulin- like growth factor 2 mRNA binding proteins (IMPs) Family contains three members: IMP1, IMP2 and IMP3. IMPs are oncofetal proteins, expressed during embryogenesis and lost in most tissues in adults. Overexpressed IMPs have been reported in various types of cancers. They share similar protein structure in mammals and have similar functions: to bind specific mRNAs, stabilize and extend their half-life. IMP2 was first reported as a tumor-associated antigen in HCC. However, only a few research was done on what a role of p62/IMP2 plays on HCC progression.
Previous studies show that IMP2 is overexpressed in HCC tissues and in several human HCC cell lines. Western blotting was performed for different HCC cells has a relatively low expression in SNU449 and higher expression in HepG2 and Hep3b. Stable IMP2 overexpression SNU449 cell line was made by IMP2 cDNA plasmid transfection; stable IMP2 knockout Hep3b and HepG2 cell lines was made by IMP2 Crispr-Cas9 KO plasmid transfection. Wound healing assay has shown that overexpression of p62/IMP2 can significantly enhance cell migration ability in SNU449 cells. On the contrary, the depletion of p62/IMP2 can reduce the migration ability in HepG2 and Hep3b cells (p&lt;0.05). Furthermore, we analyzed HCC gene expression data from TCGA. Median count of IMP2 was used to separate HCC expression data into high and low IMP2 expression group to conduct differential gene expression analysis. Gene Ontology over-representation analysis shows differentially expressed genes (adjusted p&lt;0.05) mainly enriched in membrane part and plasma membrane. The expression of several genes involved in EMT regulation such as CTNNB1, SMAD2, SNAI2, AKT2 shows significant difference (adjust p&lt;0.05). Western blotting assay was performed to show whether IMP2 is involved in EMT regulation. Wnt/beta-catenin pathway and TGF-beta/SMAD pathway were both activated and further upregulated SNAIL, which is an E-cadherin inhibitor. Western blotting results showed that E-cadherin was inhibited in IMP2 overexpressed SNU449 cells, which is supportive to our hypothesis.
Citation Format: Mengtao Xing, Jianxiang Shi, Jitian Li, Beibei Chen, Giulio Francia, Jianying Zhang. P62/IMP2 promotes metastasis in hepatocellular carcinoma (HCC) by regulating EMT in different signaling pathway [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 2027.
Abstract 2029: Notch signaling inhibitor increases E-selectin/ligand interactions and alters cell migration of mesenchymal-like breast cancer cells
Authors: Showalter Christian A. , Burdick Monica M. 
Published: August 2018

Abstract
Activation of Notch signaling has been shown to promote cell migration properties and hematogenous metastasis by inducing a dramatic phenotypic change in breast cancer cells via the epithelial-to-mesenchymal transition (EMT). In response to these findings, Notch signaling inhibitors are being explored as therapeutics to prevent EMT in cancers. However, research examining the effects of Notch inhibitors on the activity of sialofucosylated ligands used by circulating tumor cells to adhere to vascular endothelial E-selectin during metastasis is lacking. To advance knowledge in this area, our study investigated the use of an indirect Notch signaling inhibitor (DAPT) on modifying E-selectin ligand activity of breast cancer cell lines by shear flow adhesion assays performed at physiological bone marrow shear stress. DAPT exposure to mesenchymal-like MDA-MB-231 and MDA-MB-468 (induced to the mesenchymal-like state by exogenous epidermal growth factor) breast cancer cells increased E-selectin ligand activity. Furthermore, mesenchymal-like MDA-MB-468 cells after DAPT exposure demonstrated E-selectin ligand activity similar to that of epithelial-like MDA-MB-468 cells. This supports the hypothesis by our group that epithelial-like and mesenchymal-like phenotypes determine activity of functional E-selectin ligands in breast cancer cells, as we have previously shown that epithelial cells display high E-selectin ligand activity while mesenchymal cells display little or no ligand activity. Cell migration ability was assessed using wound closure assays. Mesenchymal-like MDA-MB-468 cells exposed to DAPT exhibited decreased migration compared to mesenchymal-like MDA-MB-468 cells exposed to the DMSO diluent control, whereas mesenchymal-like MDA-MB-231 cells demonstrated no difference in migration compared to DMSO exposed cells. Altogether, our results suggest Notch inhibitors may both increase fluid-shear resistant adhesion and alter migration ability of mesenchymal-like breast cancer cells, and that factors present in the blood might impact the metastatic potential of cancer cells via regulating cellular phenotypes.
Citation Format: Christian A. Showalter, Monica M. Burdick. Notch signaling inhibitor increases E-selectin/ligand interactions and alters cell migration of mesenchymal-like 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 2029.
Abstract 2036: Alternative activation of TGFβ signaling pathways in breast cancer tumors with different subtype is related to a differential expression of transcription factors that induce EMT
Authors: Ortega-Hernández Victoria , Fernandez Wanda , Carvallo Pilar 
Published: August 2018

Abstract
Breast cancer is the leading cause of cancer death among women worldwide being distant metastases the main cause of disease. Patients with triple negative breast cancer tumors develop distant metastases earlier compared to luminal tumors. Epithelial-mesenchymal transition (EMT) induced by TGFβ signaling pathways, is the main mechanism to promote metastasis through the expression of the transcription factors TWIST, SNAIL, SLUG and ZEB1. Expression of EMT transcription factors has been studied in cancer cell lines however studies in breast cancer tumors with different subtype have not been reported. In addition, the molecular mechanism that induce EMT program is not known yet. In this study we evaluated the expression of the four transcription factors as well as the state of TGFβ/SMAD, ERK/MAPK and PI3K/AKT pathways in breast cancer cell lines HCC1937 (triple negative) and T47D (luminal) after TGFβ treatment. The same analysis was done by immunohistochemistry in 100 breast cancer tumors with different subtype. After TGFβ treatment T47D showed activation of ERK/MAPK and PI3K/AKT pathways and expression of only two transcription factors: SNAIL and SLUG. HCC1937 cells showed activation of TGFβ/SMAD and ERK/MAPK pathways and expression of TWIST, SLUG and ZEB1 but not SNAIL. Similar results were observed in breast cancer tumors, being TGFβ/SMAD pathway active in the majority of triple negative tumors, whereas an active state of PI3K/AKT was observed in luminal tumors. Active ERK/MAPK pathway was observed in both triple negative and luminal tumors. In relation to expression of transcription factors triple negative tumors with an active state of the TGFβ/SMAD pathway showed expression of transcription factors TWIST, SNAIL and SLUG, whereas those tumors with an active state of ERK/MAPK pathway showed only ZEB1 expression. Luminal tumors with an active PI3K/AKT pathway frequently showed ZEB1 expression. Our results showed that expression of a specific EMT transcription factor induced by TGFβ is related to the tumor subtype and depends on the activated signaling pathway. These results suggest different mechanisms of EMT induction by TGFβ in relation to breast cancer tumor subtype.
Citation Format: Victoria Ortega-Hernández, Wanda Fernandez, Pilar Carvallo. Alternative activation of TGFβ signaling pathways in breast cancer tumors with different subtype is related to a differential expression of transcription factors that induce EMT [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 2036.
Abstract 2052: A novel PHD2/VHL- mediated regulation of YAP1 and its role in vascular mimicry and tumor angiogenesis
Authors: Singhal Namrata Bora , Saha Biswarup , Chellappan Srikumar 
Published: August 2018

Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer related death worldwide. In this study, we show that transcriptional co-activator YAP1, the oncogenic component of the Hippo pathway, may contribute to the progression of NSCLC by supporting tumor angiogenesis and vascular mimicry of cancer stem-like cells (CSCs). NSCLC CSCs were found to have higher mRNA expression of VEGF receptor II (KDR) and Angiopoietin-2 (AngPT-2); depletion of YAP1 inhibited the promoter activity as well as the mRNA expression of VEGF, KDR and AngPT-2, with a corresponding reduction in vascular mimicry as well as tumor growth in a mouse xenograft studies. These results suggest a possible mechanism by which YAP1 regulates tumor angiogenesis.
A role for YAP1 in tumor angiogenesis was further supported by the finding that NSCLC cells grown in hypoxic conditions showed higher levels of YAP1. There was little to no changes in the canonical Hippo pathway proteins like LATS1/2, MST1/2, SAV and MOB as well as in the expression of TAZ, an orthologue of YAP1. Elevated YAP1 was found to associate with HIF1α under hypoxic conditions and enhance its transcriptional activity; YAP1 could increase HIF1α-mediated induction of the VEGF promoter confirmed by chromatin immunoprecipitations and transient transfection assays. Elevated levels of YAP1 and HIF1α interaction was detected in lung tumor tissues compared to normal lung tissue, as detected by proximity ligation assay (PLA), suggesting that the higher association of YAP1 with HIF1α and resulting transcriptional activity might have contributed to tumor growth.
An examination of the underlying mechanism by which YAP1 levels are elevated under hypoxic conditions revealed a novel regulation of YAP1 protein by prolyl hydroxylase PHD2 and E3 ubiquitin ligase VHL, which are mainly known to regulate HIF1α under normoxia. PHD2 was found to hydroxylate proline residue(s) of YAP1 between aa 284 to aa 289 as seen by mutational studies. YAP1 was found to directly associate with PHD2 as well as with VHL. Depletion of PHD2 or treatment with DMOG, an inhibitor of prolyl hydroxylases, reduced YAP1 association with VHL ligase. This further elevated YAP1 levels in the nucleus. Interestingly, disruption of the YAP1-PHD2 interaction using a domain specific peptide enhanced the angiogenic tubule formation by endothelial cells. Our data therefore identifies a novel non-canonical pathway of regulation of YAP1 that supports angiogenesis and tumor growth.
Citation Format: Namrata Bora Singhal, Biswarup Saha, Srikumar Chellappan. A novel PHD2/VHL- mediated regulation of YAP1 and its role in vascular mimicry and tumor angiogenesis [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 2052.
Abstract 2059: Alcohol enhances estrogen-responsive breast cancer neovascularization
Authors: Cruz Natalie C. , Maniyar Rachana , Suriano Robert 
Published: August 2018

Abstract
The pleiotropic effects of estrogen in breast cancer development have been observed at both the initiation and progression phases. Interestingly, alcohol, as a dietary component, has been observed to possess estrogenic activity, but the synergistic interaction between alcohol and estrogen and its cellular targets remains undefined. Our previous study identified neovascularization as a cellular target of estrogen that was mediated by the mobilization of bone marrow-derived endothelial progenitor cells (BM-EPCs) and their subsequent incorporation within the tumor mass. The present study was undertaken to define the synergistic interaction between estrogen and alcohol using a cell culture model. To examine the effects of both estrogen and alcohol on breast cancer progression, we developed an in vitro model using the murine mammary tumor cell line, TG1-1, and the murine endothelial cell line, SVEC4-10. Neovascularization was assayed by the tubulogenesis and scratch wound assays as well as quantitating the expression of various provasculogenic markers. Conditioned media, generated by culturing the murine mammary cancer cell line, TG1-1, in estrogen and ethanol, was observed to enhance tubule formation and migration of the murine endothelial cell line, SVEC4-10. In addition, the TG1-1 conditioned media enhanced the prosurvival MAP kinase-signaling pathway in SVEC4-10 cells. Presumably, the observed enhancement of both endothelial cell tubulogenesis and migration is in part attributed to provasculogenic proteins secreted by TG1-1 cells. In order to address this, Western blot analysis using TG1-1 cell lysates indicated an increase in VEGF, MMP-9, and eNOS expression in presence of alcohol and estrogen. As a whole, our data suggest that both estrogen and alcohol function to enhance expression of key provasculogenic molecules in breast cancer cells, which in turn modulates the morphologic, migratory, and survival properties of endothelial cells.
Citation Format: Natalie C. Cruz, Rachana Maniyar, Robert Suriano. Alcohol enhances estrogen-responsive breast cancer neovascularization [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 2059.
Abstract 2061: Genipin inhibits invasion and migration of colon cancer cells by suppression of HIF1α accumulation and VEGF expression
Authors: Lee Dae-Hee , Oh Sang-Choul , Lee Suk-young , Kim Hong Jun 
Published: August 2018

Abstract
Expression of hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) is known to play an important role in cancer progression in various cancer cell lines. Although genipin, a constituent of Gardenia fruit, has shown to have anti-tumor activity, its role in suppression of HIF-1 protein and downstream genes has yet to be clarified. We examined the effect of genipin on intracellular level of HIF-1α and extracellular level of VEGF proteins using colon cancer cell line HCT116. We observed genipin suppressed accumulation of HIF-1α under hypoxia in various cancer cell lines including HCT116. We found out suppressed accumulation of HIF-1α occurred through modulation of protein degradation. Genipin was also observed to suppress expression of VEGF and invasion of colon cancer cells through blocking of the ERK signaling pathway. Taken together, our results provide a new insight into the potential role of genipin in suppressing cancer progression of colon cancer cells.
Citation Format: Dae-Hee Lee, Sang-Choul Oh, Suk-young Lee, Hong Jun Kim. Genipin inhibits invasion and migration of colon cancer cells by suppression of HIF1α accumulation and VEGF expression [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 2061.