bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5249: The transcriptional regulation of CCND1 by miR-15a-5p in the nucleus of colorectal carcinoma cell lines
Authors: Liu Zhenzhen , Bai Xue , Li Chunyan 
Published: August 2019

Abstract
Although miRNAs are important post-transcriptional regulators of gene expression in cytoplasm, more and more evidences demonstrate that miRNAs also have nuclear functions. The majority of miRNAs are present in both the cytoplasm and the nucleus. The canonical function of translational repression in cytoplasm is well studied, but the functions of nuclear miRNAs are currently not well understood. From previous studies, we found that miR-15a-5p (miR-15a for short) can be detected in the nucleus of the colon cancer cell line. By transfected miR-15a labelled with biotin, we validated that miR-15a could bind to DNA (especially dsDNA) in the nucleus of colorectal carcinoma cell line HCT116. To find the targets of miR-15a in the nucleus, we scanned the promoter region of the potential targets which were predicted by Targetscan, miRWalk, and miRDB. The promoter of CCND1 has one region that is complementary to miR-15a. By integrating the RNA-seq data and miRNA-Seq data from NCI60 cell line panel and TCGA (The Cancer Genome Atlas), we found that CCND1 was negatively regulated by miR-15a in colorectal cancer. To confirm that miR-15a regulates CCND1’s transcription in the nucleus, we constructed the promoter of CCND1 and a luciferase reporter into one plasmid, then site-specific mutation was introduced into the potential binding site of miR-15a in the promoter of CCND1. The luciferase assay demonstrated that the mutation in the binding site decreased the expression of CCND1, which validate that miR-15a may regulate the expression of CCND1 by binding to the promoter of CCND1 in the nucleus. The next step, we will further study the function of nuclear miR-15a distinct from the canonical paradigm in carcinogenesis.
Note: This abstract was not presented at the meeting.
Citation Format: Zhenzhen Liu, Xue Bai, Chunyan Li. The transcriptional regulation of CCND1 by miR-15a-5p in the nucleus of colorectal carcinoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5249.
Abstract 5254: CARMIL3 promotes tumor progression in triple negative breast cancer: A possible novel biomarker
Authors: Lee Jeeyeon , Baek Dong Won , Lee Soo Jung , Jeong Jae-Hwan , Lee In Hee , Jung Jin Hyang , Park Ho Yong , Chae Yee Soo , Kang Jieun 
Published: August 2019

Abstract
Purpose: CARMIL3 (LRRC16B, capping protein regulator and myosin 1 linker 3) was previously identified as a novel oncofetal-like gene. It influences cell proliferation, cell cycle control and transformation, possibly mediated by cyclin B1. This study aimed to investigate the function of CARMIL3 in triple negative breast cancer (TNBC) cells and tissues.
Methods: CARMIL3 mRNA was measured using a qRT-PCR in breast cancer cells (MDA-MB-231, MCF7, SK-BR3 and T-47D) and tissues from 20 patients with TNBC. The effects of CARMIL3 on cell proliferation, migration, and invasion were determined using MTT, wound healing, and Matrigel Transwell assays.
Results: Results showed that, the CARMIL3 mRNA expressions were significantly increased in breast cancer cell lines, especially in triple negative breast cancer cell lines (MDA-MB-231 and MDA-MB-468) when compared to normal breast epithelial cells (MCF10A). Downregulation of CARMIL3 inhibited the cell proliferation, migration and invasion of MDA-MB-231. Furthermore, high CARMIL3 mRNA expression was found in 20 TNBC specimens than normal controls (p&lt;0.0001).
Conclusions: In conclusion, CARMIL3 expression in TNBC affects cancer progression, which suggests that CARMIL3 can be a new biomarker for patients with TNBC.
Citation Format: Jeeyeon Lee, Dong Won Baek, Soo Jung Lee, Jae-Hwan Jeong, In Hee Lee, Jin Hyang Jung, Ho Yong Park, Yee Soo Chae, Jieun Kang. CARMIL3 promotes tumor progression in triple negative breast cancer: A possible novel biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5254.
Abstract 5256: Molecular signatures associated with obesity-related tumor growth in breast cancer women
Authors: Prada Diddier , Arriaga-Canon Cristian , Diaz-Chavez Jose , Cortes Carlo , Andonegui-Elguera Marco , Perez-Collado Pedro , Muniz Rodolfo , Cantu-de-Leon David , Cabrera-Galeana Paula , Bargallo Enrique , Herrera Luis , Penaloza Fernando 
Published: August 2019

Abstract
Obesity has been widely associated with chronic diseases, including cancer. Obesity increases the risk of developing several types of cancer, both in women and men, especially breast cancer in postmenopausal women. However, the role of obesity after tumors is established and its potential mechanisms are unknown. Our study aims to determine the molecular signatures associated with obesity-related tumor growth in a cohort of breast cancer patients from a country with an obesity epidemic. We evaluated a cohort of patients with breast cancer (n=151) at diagnosis, including patients in all clinical stages and 78% of them showed overweight or obesity. We determined the role of body mass index (BMI) on clinical characteristics and, using RNA-seq analyses in biopsy samples at diagnosis, we determined potential genes associated. We found a positive correlation between BMI and tumor size at diagnosis (r = 0.147, p-value = 0.006) and age (r=0.116, p-value=0.03). Lower BMI was observed when the number of positive nodes increased (p-value = 0.015). In a random subset from these patients (n=12) and using robust linear models, we determined that 10 genes (GPRC5B, SLITRK6, KRT23, VTCN1, TNFRSF12, PTP4A2, BACE2, EPH8, CYP21A1P, and TMEM52) were positively associated with BMI. CSTA and IGKV1-16 showed a negative association with BMI. Gene ontology analyses revealed that VTCN1 and PTP4A3 were linked to increased proliferation and tumor progression. CSTA, a protease inhibitor, was also associated with poor prognosis. Our study suggested a deleterious effect of obesity on breast cancer patients, which could be caused by changes in cell expression on key genes in tumor cells.
Citation Format: Diddier Prada, Cristian Arriaga-Canon, Jose Diaz-Chavez, Carlo Cortes, Marco Andonegui-Elguera, Pedro Perez-Collado, Rodolfo Muniz, David Cantu-de-Leon, Paula Cabrera-Galeana, Enrique Bargallo, Luis Herrera, Fernando Penaloza. Molecular signatures associated with obesity-related tumor growth in breast cancer women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5256.
Abstract 5259: Fatty acid oxidation represents a metabolic vulnerability in glioblastoma in nutrient-deprived conditions
Authors: Kant Shiva , Dayalan Antony , Kesarwani Pravin , Chinnaiyan Prakash 
Published: August 2019

Abstract
Glioblastoma represents an aggressive, primary brain tumor with limited treatment options. We performed an integrative, cross-platform analysis coupling global metabolomics and gene expression profiling in &gt;100 patient-derived gliomas to begin to understand the diverse metabolic programs driving the aggressive phenotype of this malignancy. Alterations in fatty acid β-oxidation (FAO) emerged as a key metabolic node differentiating glioblastoma from low-grade astrocytoma, as demonstrated by an accumulation of acylcarnitines. Metabolic heterogeneity was observed within glioblastoma that could further define tumors as FAO ‘high’ and ‘low’. Integrative analyses identified these metabolic subtypes to be enriched with mesenchymal (MES) and proneural (PN) glioblastoma subtypes, respectively. These findings were metabolomically and functionally recapitulated in molecular subtype-specific preclinical models. Analysis of gene expression profiles from these lines uncovered an orchestrated transcriptional program designed to promote fatty acid uptake, activation, and mitochondrial oxidation. Studies designed to determine the biologic consequence of enhanced FAO in glioblastoma only identified a role in glucose-deprived conditions, where it served as a vital, alternate source for ATP synthesis. Based on these findings, we tested the hypothesis that dual targeting of glycolysis and FAO would elicit energetic stress-mediated cell death in glioblastoma. Accordingly, the glycolysis inhibitor 2DG and the FAO inhibitor etomoxir only demonstrated anti-proliferative activity in MES glioblastoma cell lines when used as single agents in vitro, while the combination resulted in robust, necroptosis-mediated cell death. Synergistic anti-tumor activity was observed following combined glycolysis and FAO inhibition when extended in vivo in an orthotopic model. Collectively, our findings suggest FAO provides metabolic plasticity in MES glioblastoma, allowing these cells to adapt to nutrient-deprived microenvironments. Combinatorial strategies designed to inhibit glycolysis and FAO represents an attractive therapeutic approach in glioblastoma.
Citation Format: Shiva Kant, Antony Dayalan, Pravin Kesarwani, Prakash Chinnaiyan. Fatty acid oxidation represents a metabolic vulnerability in glioblastoma in nutrient-deprived conditions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5259.
Abstract 5262: Lipidomic profiling of neuroblastoma cells after treatment with novel withalongolide A 4, 19, 27-triacetate (WGA-TA)
Authors: Subramanian Chitra , Thekkelnaycke Rajendiran , Soni Tanu , Opipari Valerie P. , Timmermann Barbara N. , Cohen Mark S. 
Published: August 2019

Abstract
Introduction: Neuroblastoma (NB) is a pediatric solid tumor that affects approximately 700 children every year in the United States. Despite advances in treatment, the cure rate for high risk advanced NB having N-myc amplification has a poor response of 40-50%. Standard of care treatment for high risk NB patient consists of surgery, intensive chemotherapy and radiotherapy. Recently, we and others have shown that withanolide treatment of NB induce apoptosis of NB cells, through several mechanism including lipid oxidation, down regulation of N-myc and suppression of Akt/mTOR/NF-κB activation. Therefore, we hypothesized that mass spectrometric analysis of untargeted lipidomic profiling after treatment of NB cells with withanolide WGA-TA will identify novel prognostic and diagnostic biomarkers of NB.
Methods: Validated neuroblastoma cell lines IMR32 (N-myc amplified) and SH-EP (N-myc non-amplified) were grown in 2D culture in appropriate growth medium. Lipids were extracted from cells using modified Bligh and Dyer method. Lipidomic profiling was carried out using LC MS/MS. Principal component analysis (PCA) was used to identify differentially regulated metabolites.
Results: Principal component analysis of NB cell lines and WGA-TA treatment showed complete separation of samples as well as internal controls. Initial analysis of lipid profiling of IMR32 and SH-EP cells showed differential regulation of several lipids. N-myc non-amplified SH-EP cells have upregulation of phospholipids such as phosphocholine (PC), phosphor ethanol amine (PE), sphingomyelin (SM) and free fatty acid, whereas glycerol lipid diacyl glycerol (DG) is down regulated in SH-EP cells compared to IMR32 cells. Treatment of IMR32 cells with WGA-TA led to up regulation of phospho lipids such as PC, phosphoserine (PS), SM, Lyso PE, free fatty acids just like N-myc non-amplified cells. But, triglycerides (TG) were up regulated after treatment with WGA-TA in both IMR32 and SH-EP cells.
Conclusions: WGA-TA treatment of N-myc amplified cells led to upregulation of phospholipids similar to that of N-myc non-amplified cells indicating that CDP-Choline pathway lipids might play an important role in NB. Further analysis is needed to unravel the link between N-myc and lipid metabolism in NB.
Citation Format: Chitra Subramanian, Rajendiran Thekkelnaycke, Tanu Soni, Valerie P. Opipari, Barbara N. Timmermann, Mark S. Cohen. Lipidomic profiling of neuroblastoma cells after treatment with novel withalongolide A 4, 19, 27-triacetate (WGA-TA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5262.
Abstract 5275: Cancer specific caloric restriction using novel small molecule improves the therapeutic regime for triple negative breast cancer
Authors: Tailor Dhanir , Resendez Angel , Kumar Vineet , Going Catherine , Pitteri Sharon , Malhotra Sanjay 
Published: August 2019

Abstract
Hyperglycemic and hyper insulin condition are the signature symptoms for type two diabetes which is the most favorable condition for the development of cancer. Women having a type two diabetes has 20-27% high risk to develop breast cancer including triple negative breast cancer (TNBC). Microenvironment including hyperglycemic, hyper insulin condition leads to the therapy resistance. According to ‘Warburg’s effect’ cancer cells consume a high amount of glucose in comparison to normal cells via aerobic glycolysis process. To take care of this condition currently, several clinical studies are going on for the combination therapy of type 2 diabetes and chemotherapy drugs together including erlotinib and metformin. The major drawback of this kind of type 2 diabetes drugs is that they won't affect cancer cells under hyperglycemic and hyper insulin conditions. These drugs including metformin work via AMP-activated protein kinase (AMPK) activation to switch aerobic glycolysis to oxidative phosphorylation. We have developed a novel AMPK activator (SU-18) who selectively induces an oxidative phosphorylation in TNBC cells and glycolysis in normal cells. We found that SU-18 induces G2/M phase arrest, mitochondrial stress and apoptosis in TNBC cells as same as metformin but at 1000 fold less concentration. It selectively reduces the glucose consumption, lactate and ATP production in TNBC cells where normal cells act opposite to this. SU-18 activity is through AMPK activation which got abolished in presence of AMPK inhibitor (Compound c). During mouse xenograft studies, it inhibits the tumor growth and progression. It also improves the blood glucose level in hyperglycemic mice. Comparative studies with metformin suggest that SU-18 works irrespective of hyperglycemia and insulin conditions, whereas metformin, is ineffective in this condition. FDG-PET scan analysis also supported to our in vitro glucose consumption data that treatment with SU-18 reduces the FDG accumulation in tumor cells. This study advocates the clinical candidature of SU-18 for TNBC patients.
Citation Format: Dhanir Tailor, Angel Resendez, Vineet Kumar, Catherine Going, Sharon Pitteri, Sanjay Malhotra. Cancer specific caloric restriction using novel small molecule improves the therapeutic regime for triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5275.
Abstract 5284: Hypoxia promote self-renewal in pancreatic cancer by modulating L-2-Hydroxyglutarate level
Authors: Gupta Vineet K. , Sharma Nikita , Kesh Kousik , Hadad Roey , Dudeja Vikas , Saluja Ashok , Banerjee Sulagna 
Published: August 2019

Abstract
Pancreatic cancer cells undergo extensive metabolic reprogramming to fulfil the demands of metabolic nutrients to fuel their rapid proliferation. This results in abnormal accumulation of various metabolites which causes both metabolic and nonmetabolic dysregulation and potential transformation to malignancy and therefore termed as “oncometabolites”. Hypoxia is a major hallmark of pancreatic tumors which associated with increase in self-renewal. The present study investigates the role of Hypoxia mediated altered oncometabolite in regulating self-renewal in pancreatic cancer. GC-mass spectrometric analysis of pancreatic cancer cells under hypoxia showed significant accumulation of 2-hydroxyglutarate (2-HG) both in cells and culture supernatant. Further analysis of hypoxic cells showed selective accumulation L- enantiomer form. Self-renewal requires critical balance between stemness and differentiation. Present study showed for the first time that L-2-HG regulates self-renewal by increasing expression of genes associated with stemness (Sox-2, CD133) and by decreasing expression of differentiation genes (PdX-1, HB9, NKX6.1). Further analysis showed that L-2-HG mediated epigenetic changes regulates these self-renewal gens in pancreatic cancer. Our results indicated that hypoxia mediated metabolic changes results in accumulation of L-2-HG which upregulate self-renewal by shifting critical balance of gene expression towards stemness in pancreatic cancer which contribute to chemoresistance and metastasis in Pancreatic cancer.
Citation Format: Vineet K. Gupta, Nikita Sharma, Kousik Kesh, Roey Hadad, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee. Hypoxia promote self-renewal in pancreatic cancer by modulating L-2-Hydroxyglutarate level [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5284.
Abstract 5289: Gain-of-function mutant p53 predisposes head and neck keratinocytes and squamous cell carcinoma cells to replicative stress and genomic instability through minichromosome maintenance complex component 5
Authors: Zhao Mei , Wang Tianxiao , Zhen Chen , Wang Jing , Pickering Curtis R. , Chen Junjie , Myers Jeffrey N. , Zhou Ge 
Published: August 2019

Abstract
As the guardian of genome, p53 plays important roles in maintaining the genome integrity, and TP53 mutations thereby often lead to genomic instability in cancers. In addition to the loss-of-function, many TP53 mutations can lead to the gain-of-functions (GOF) that often promote tumor development and tumor progression. As an effort to identify the mechanisms involved in mutant p53 GOF activities in head and neck squamous cell carcinoma (HNSCC), we performed an unbiased proteomic screen to identify the mutant p53 G245D interactome in HNSCC cells by immunoprecipitation, and quantitative proteomics using stable isotope labeling with amino acids in cell culture and liquid chromatography coupled with tandem mass spectrometry. Our results identified that MCM5, a member of replication licensing heterohexameric origin recognition complex minichromosome maintenance 2-7 (MCM2-7), interacts with mutant p53s, which suggests a possible role of mutant p53 in regulation of DNA replication. Consistent with this, we show that overexpression of mutant p53 in p53-depelted oral keratinocytes and HNSCC cells predisposes cells susceptibility to replication stress by inhibiting the dormant origin firing, leading to increased chromosomal instability (CIN) under replication stress. Moreover, by overexpressing and downregulating MCM5, we demonstrate that MCM5 modulates GOF mutant p53-mediated susceptibility to replication stress and CIN. Given the importance of MCM2-7 in replication licensing, initiation, and elongation, our discovery of the relationship between mutant p53 and MCM5 suggests that the MCM2-7 complex is one of the key downstream effectors, through which GOF mutant p53s regulate DNA replication and genomic instability in HNSCC.
Citation Format: Mei Zhao, Tianxiao Wang, Chen Zhen, Jing Wang, Curtis R. Pickering, Junjie Chen, Jeffrey N. Myers, Ge Zhou. Gain-of-function mutant p53 predisposes head and neck keratinocytes and squamous cell carcinoma cells to replicative stress and genomic instability through minichromosome maintenance complex component 5 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5289.
Abstract 5293: Celf2 suppresses non-small cell lung carcinoma growth by inhibiting the prex2-pten interaction
Authors: Yeung Yiu To , Fan Suyu , Lu Bingbing , Li Xiang , Bode Ann M. , Dong Zigang 
Published: August 2019

Abstract
The phosphoinositide 3-kinase (PI3-K)/Akt signaling pathway is important in the regulation of cell proliferation through its production of phosphatidylinositol 3,4,5-triphosphate (PIP3). Activation of this pathway is frequently observed in human cancers, including non-small cell lung cancer. The PI3- K/Akt pathway is negatively regulated by the dual-specificity phosphatase and tensin homolog (PTEN) protein. PTEN acts as a direct antagonist of PI3-K by dephosphorylating PIP3. Studies showed that PTEN phosphatase activity is inhibited by PREX2, a guanine nucleotide exchanger factor (GEF). Multiple studies revealed that CELF2, an RNA binding protein, cooperates synergistically with PTEN as a tumor suppressor in many cancers. However, the underlying mechanism as to how CELF2 enhances PTEN activity remains unclear. Here, we report that CELF2 interacts with PREX2 and reduces the association of PREX2 with PTEN. Consistent with this observation, PTEN phosphatase activity is upregulated with CELF2 overexpression and overexpression of CELF2 represses both Akt phosphorylation and cell proliferation only in the presence of PTEN. CELF2 gene delivery significantly inhibited PDX tumor growth. We analyzed 87 paired clinical lung adenocarcinoma samples and results showed that CELF2 protein expression is down-regulated in tumor tissues and associated with poor prognosis. Analysis of TCGA datasets showed that CELF2 expression is also associated with shorter patient survival time in many cancers. Overall, our work suggests that CELF2 plays a novel role in PI3-K signaling by antagonizing the oncogenic effect of PREX2.
Citation Format: Yiu To Yeung, Suyu Fan, Bingbing Lu, Xiang Li, Ann M. Bode, Zigang Dong. Celf2 suppresses non-small cell lung carcinoma growth by inhibiting the prex2-pten interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5293.