bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3550: microRNA-211 promotes aggressive melanoma growth in vivo by epigenetic modification, and contributes to BRAFV600E inhibitor resistance via ERK5 signaling
Authors: Lee Bongyong , Sahoo Anupama , Sawada Junko , Zisoulis Dimitrios G. , Marchica John , Sahoo Sanjay , Layng Fabiana I Alves De Lima , Finlay Darren , Mazar Joseph , Joshi Piyush , Komatsu Masanobu , Vuori Kristiina , Powis Garth , Jong Petrus R. de , Ray Animesh , Perera Ranjan J. 
Published: August 2019

Abstract
The microRNA miR-211 is an established participant in melanomagenesis, but controversy exists as to whether it acts as a bone fide tumor suppressor or oncogene. Here we ectopically expressed miR-211 in the BRAF v600E-mutant A375 melanoma cell line and examined its effect in xenografts in vivo. The miR-211 ectopic expression promoted aggressive tumor xenograft growth with extensive cell proliferation, and angiogenesis. ChIP-seq and single cell sequencing analysis of xenograft tissues demonstrated that aggressive tumor formation is partly associated with H3K27me3 and H3K4me3, and migration of cells from mouse tissues to tumor locus. Interrogation of xenograft transcriptomics data revealed activation of the ERK5 pathway, itself negatively regulated by miR-211 target genes, BIRC2 and DUSP6, further confirmed as direct miR-211 target genes by RNA immunopurification with RNA-seq (RIP-seq) and site-directed mutagenesis. miR-211 conferred resistance to the BRAF inhibitor vemurafenib, and MEK inhibitor cobimetinib with corresponding increases in ERK5 phosphorylation. The miR-211-ERK5 axis may represent a novel therapeutic target, but however, miR-211 is exquisitely pleiotropic in the complex in vivo tumor environment and its context must be considered carefully in diagnostic and therapeutic development.
Citation Format: Bongyong Lee, Anupama Sahoo, Junko Sawada, Dimitrios G. Zisoulis, John Marchica, Sanjay Sahoo, Fabiana I Alves De Lima Layng, Darren Finlay, Joseph Mazar, Piyush Joshi, Masanobu Komatsu, Kristiina Vuori, Garth Powis, Petrus R. de Jong, Animesh Ray, Ranjan J. Perera. microRNA-211 promotes aggressive melanoma growth in vivo by epigenetic modification, and contributes to BRAFV600E inhibitor resistance via ERK5 signaling [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 3550.
Abstract 3557: miR-181a is a key driver of genomic instability and ovarian cancer tumorigenesis through the regulation of RB1
Authors: Knarr Matthew , Kwiatkowski Lily , Nagaraj Anil , Drapkin Ronny , DiFeo Analisa 
Published: August 2019

Abstract
Epithelial ovarian cancer (EOC) is one of the deadliest gynecological cancers currently diagnosed in women with approximately 20,000 new cases and 15,000 deaths per year. Ovarian cancer can be stratified into distinct subtypes of which high-grade serous ovarian cancer (HGSOC) comprises 90% of all cases and has the highest mortality rate. Reducing the high mortality rate associated with HGSOC currently has two primary barriers: 1) most HGSOCs are diagnosed at a post-metastatic stage and 2) up to 70% of patients recur within 5 years. Both of these limitations are due to the fact that the drivers of tumor initiation are poorly understood. In order to change the status quo of the last 30 years, a new approach that focuses on understanding the origins of HGSOC is required. Our lab has recently discovered that miR-181a promotes key hallmarks of HGSOC progression in fallopian tube secretory epithelial cells (FTSECs) which are precursor cells of HGSOC. We show that enhanced expression of miR-181a in FTSECs results in increased proliferation, survival, and anchorage independent growth in vitro. Furthermore, FTSECs with miR-181a overexpression are able to form tumors in vivo whereas FTSECs that overexpress a control scramble miRNA cannot. Using cell cycle analysis, dynamic live-cell imaging, and SNP array analysis, we also found that miR-181a overexpression increases aneuploidy and genomic instability in FTSECs. We show that miR-181a promotes defects in nuclear structure, ruptures in the nuclear envelope, as well as mitotic and cytokinetic defects affecting proper chromosome segregation. A combination of global mRNA expression profiling and target prediction software identified the tumor suppressor retinoblastoma (RB1) as a target for miR-181a mediated FTSEC tumorigenesis. Using an RB1 3’UTR luciferase assay, along with stable expression of an shRNA against RB1 in FTSECs, we are able to show that miR-181a directly targets RB1 and that knockdown of RB1 phenocopies miR-181a mediated tumorigenesis. Taken together, our data shed light on a novel mechanism that promotes genomic instability and tumorigenesis in the early phases of HGSOC development. Our results suggest miR-181a as a promising early detection biomarker as well as a prognostic tool to guide patient treatment.
Citation Format: Matthew Knarr, Lily Kwiatkowski, Anil Nagaraj, Ronny Drapkin, Analisa DiFeo. miR-181a is a key driver of genomic instability and ovarian cancer tumorigenesis through the regulation of RB1 [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 3557.
Abstract 3559: A crowd-control approach for castration-resistant prostate cancer therapeutics
Authors: Shukla Girish C. 
Published: August 2019

Abstract
Castration-resistant prostate cancer (CRPC) is defined by affecting intrinsic cellular mechanisms including dysregulated androgen signaling, aerobic glycolysis (Warburg effect), epithelial-mesenchymal transition (EMT) and dysregulation of transcription factors including androgen receptor (AR) and c-Myc. Development of CRPC post Androgen-deprivation therapy is indicated by tumor microenvironment heterogeneity, compensating cellular pathways and recurrence of AR expression leading to the failure of androgen-signaling inhibitors including Enzalutamide and Abiraterone Acetate. We have discovered that miR-644a potentiates Enzalutamide efficacy both, in vitro and in vivo prostate cancer models. In depth analyses revealed that miR-644a downregulated expression of diverse tumor microenvironment regulators including c-Myc, AR, AR co-regulators and the anti-apoptosis factors Bcl-xl and Bcl-2, EMT factors ZEB1, cdk6, and Snail. Enhanced miR-644a expression also suppressed the Warburg effect by direct down-regulating c-Myc, Akt, IGF-1R and GAPDH expression. Taken together, our data demonstrate that the adjunctive miRNA expression down-regulated several oncogenesis promoting cellular pathways and functions cooperatively with Enzalutamide. We propose that a “crowd-control” approach to pacifying aggressive tumorigenesis and metastasis supporting cellular pathways by a miRNA with a wide range of gene targets is likely to potentiate the efficacy of cancer treating drugs and potentially preventing the drug-resistance.
Note: This abstract was not presented at the meeting.
Citation Format: Girish C. Shukla. A crowd-control approach for castration-resistant prostate cancer therapeutics [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 3559.
Abstract 356: Novel conditionally active biologic (CAB) antibody targeting EpCAM demonstrates anti-tumor efficacy in vivo
Authors: Chang Cathy , Frey Gerhard , Sharp Leslie , Boyle William (Bill) J. , Wang Jing , Xing Charles , Liu Haizhen , Wheeler Christina , Walls Marlena , Short Jay M. 
Published: August 2019

Abstract
Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein mediating Ca2+-independent homotypic cell-cell adhesion during cell signaling, migration, proliferation, and differentiation. EpCAM is expressed at high levels exclusively in epithelia and epithelial-derived neoplasms, making it a suitable target for many important solid tumor types and cancer stem cells. EpCam expression on normal tissues limits its utility as target for therapeutic antibodies and ADCs due to the potential effects on normal epithelial throughout the body. Conditionally Active Biologics (CAB) technology is a proprietary platform that selects antibodies that bind to target antigens in the context of diseased tissues, but not normal tissues, by taking advantage of the unique conditions in the tumor microenvironment. Using our CAB technology, we have developed CAB antibodies to EpCAM that reversibly bind to recombinant EpCAM and EpCAM expressing cells under select conditions that are present in the tumor microenvironment but not in normal tissues. In vitro and in vivo efficacy data for several anti-EpCAM antibodies and ADCs will be presented and suggest that conditionally active EpCam ADCs generated using the CAB technology will provide drug candidates that have an increased safety margin and therapeutic index in the clinic.
Citation Format: Cathy Chang, Gerhard Frey, Leslie Sharp, William (Bill) J. Boyle, Jing Wang, Charles Xing, Haizhen Liu, Christina Wheeler, Marlena Walls, Jay M. Short. Novel conditionally active biologic (CAB) antibody targeting EpCAM demonstrates anti-tumor efficacy in vivo [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 356.
Abstract 3563: Exosomal transfer of tumor-associated macrophage derived miR-6068 promote ovarian cancer progression
Authors: Baydogan Seyda , Sheng Jianting , Kahraman Nermin , Kanlikilicer Pinar , Mokhlis Hamada Ahmed , Dilmac Sayra , Wong Stephen T. C. , Ozpolat Bulent 
Published: August 2019

Abstract
Ovarian cancer, especially high-grade serous ovarian cancer (HGSOC), is the deadliest gynecological cancer with 50-70% 5-year mortality rates. Every year more than 22,000 new cases of ovarian cancer and 15,000 deaths are anticipated within the United States only. Recent clinical and experimental evidence indicates that tumor-associated macrophages (TAMs), the most abundant cells in the tumor microenvironment, play a significant role in tumor growth and progression by contributing to angiogenesis, invasion, metastasis, and drug resistance, leading to poor clinical outcomes and significantly shorter patient survival in HGSOC. More than 50% of cells in the peritoneal tumor microenvironment and malign ascites consist of TAMs in ovarian cancer (OC) patients. Especially, M2 macrophages have been shown to support tumor proliferation and promote tumor progression, angiogenesis, and drug resistance. But the mechanisms of these oncogenic effects are still not clear. The goal of our study to investigate the role of TAM-derived exosomes, which are 30-100nm microvesicles released from cells and are key factors in communication between cancer cells and the tumor microenvironment. To this end, we evaluated differentially expressed miRNAs in high-grade ovarian cancer cells (OVCAR3, OVCAR 432 and OVCAR5) after treatment with exosomes-derived from TAMs (M2 phenotype) using the Affymetrix Gene Chip miRNA 4.0 microarrays. We identified several miRNAs, including miR-6068 that we validated by qPCR and found it to be significantly upregulated in both HGSOC cells and their exosomes. We demonstrated that transfection of HGSOC cells with miR-6068 significantly increased proliferation, migration and invasion capacities of the cells in vitro, suggesting that this miR-6068 act as an oncogenic miR (oncomiR). Using in silico prediction algorithms we found that miR-6068 has binding sites on the 3’-untranslated region (3’-UTR) of PTPN4 gene encoding a phosphatase and demonstrated that it miR-6068 suppresses PTPN4 expression by Western blot and qPCR. Inhibition of PTPN4 by siRNA significantly induced cell proliferation in OC cells, suggesting that PTPN4 acts as a tumor suppressor. In conclusion, our results suggest that miR-6068 has an oncogenic role in ovarian cancer progression by targeting PTPN4 and may be a novel effective therapeutic target for ovarian cancer.
Citation Format: Seyda Baydogan, Jianting Sheng, Nermin Kahraman, Pinar Kanlikilicer, Hamada Ahmed Mokhlis, Sayra Dilmac, Stephen T. C. Wong, Bulent Ozpolat. Exosomal transfer of tumor-associated macrophage derived miR-6068 promote ovarian cancer progression [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 3563.
Abstract 3572: SNPs in lncRNA genes are associated with non small cell lung cancer in a Chinese population
Authors: Wang Ruoyang , Qian Biyun 
Published: August 2019

Abstract
Background: Recent genetic studies indicate that single nucleotide polymorphisms (SNPs) in the genes encoding non-coding RNAs are associated with lung cancer susceptibility. But the comprehensive analysis of SNPs in long non-coding RNA (lncRNA) genes has not been elucidated. Methods: Based on the previous expression microarray of lncRNAs, we genotyped 17 SNPs located in 13 selected lncRNA genes by the TaqMan method in 1294 non-small cell lung cancer (NSCLC) cases and 1729 controls. Then we followed up NSCLC patients to get the survival data, and conduct logistic regression, Kaplan-Meier method and Cox hazards regression analysis to explore the associations of SNPs with NSCLC risk and overall survival (OS). Results: We identified 4 SNPs significantly associated with NSCLC risk. For rs498238, compared with CC genotype, TT genotype could decrease the risk of NSCLC (adjusted OR=0.32, 95%CI=0.11-0.92, p=0.034). As for rs16901995, TT genotype showed significantly protective effect compared with CC genotype (adjusted OR=0.76, 95%CI=0.59-0.99, p=0.040). For rs219741 dominant model, increased risk of NSCLC was evident in younger patients (age &lt;60) compared those with wild type (adjusted OR=1.47, 95%CI=1.03-2.10, p=0.033). Rs3113503 demonstrated a controversial effect on NSCLC risk. No SNPs showed effects on overall survival of NSCL patients. Conclusion: Our findings indicated that genetic variants within lncRNA genes may predict NSCLC risk in Chinese population.
Citation Format: Ruoyang Wang, Biyun Qian. SNPs in lncRNA genes are associated with non small cell lung cancer in a Chinese population [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 3572.
Abstract 3577: A p53-responsive long noncoding RNA GUARDIN is essential for genome integrity
Authors: Jin Lei , Hu Wang Lai , Xu An , Wang Yu Fang , Thorne Rick F. , Zhang Xu Dong , Wu Mian 
Published: August 2019

Abstract
The list of long non-coding RNAs (lncRNAs) involved in the p53 pathway of the DNA damage response is rapidly expanding, but whether lncRNAs have a role in maintaining the de novo structure of DNA is unknown. Here, we demonstrate that the p53-responsive lncRNA GUARDIN is important for maintaining genomic integrity under steady-state conditions and after exposure to exogenous genotoxic stress. GUARDIN is necessary for preventing chromosome end-to-end fusion through maintaining the expression of telomeric repeat-binding factor 2 (TRF2) by sequestering microRNA-23a. Moreover, GUARDIN also sustains breast cancer 1 (BRCA1) stability by acting as an RNA scaffold to facilitate the heterodimerization of BRCA1 and BRCA1-associated RING domain protein 1 (BARD1). As such, GUARDIN silencing triggered apoptosis and senescence, enhanced cytotoxicity of additional genotoxic stress and inhibited cancer xenograft growth. Thus, GUARDIN may constitute a target for cancer treatment.
Citation Format: Lei Jin, Wang Lai Hu, An Xu, Yu Fang Wang, Rick F. Thorne, Xu Dong Zhang, Mian Wu. A p53-responsive long noncoding RNA GUARDIN is essential for genome integrity [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 3577.
Abstract 3581: LncRNA THAP9-AS1 promotes pancreatic cancer growth via sponging miR-484 and interacting with YAP to enhance YAP activity
Authors: Li Nan , Yang Guohua , He Zhimin , Liu Wanqing , Liu Haiying , Zheng Guopei 
Published: August 2019

Abstract
This study was supported by grants from the National Natural Science Foundation of China (No. 81872197, 81672616, 81401989 and 81602016); Guangdong Natural Science Funds for Distinguished Young Scholars (No.2016A030306003); Guangdong Special Support Program (No.2017TQ04R809); Science and Technology Program of Guangzhou (No.201710010100 and 201804010001).
Abnormal expression of long non-coding RNAs (lncRNAs) has been observed in various cancer types, providing probability to exploit new diagnostic markers, prognostic factors and therapeutic targets in cancer treatment. Our analysis showed lncRNA THAP9-AS1 was highly overexpressed in pancreatic cancer. Here, we aimed to investigate the roles and mechanisms of THAP9-AS1 in pancreatic cancer. We confirmed the overexpression of lncRNA THAP9-AS1 in pancreatic cancer and validated the no protein-coding potential. THAP9-AS1 promotes pancreatic cancer cells growth in vitro and in vivo. Mechanically, THAP9-AS1 exerts its effects via enhancing YAP signaling. Ectopic YAP expression disrupts the effects of THAP9-AS1 knockdown. Inversely, YAP knockdown overcomes the effects of THAP9-AS1 overexpression. THAP9-AS1acts as a competing endogenous RNA for miR-484, leading to YAP upregulation. Moreover, THAP9-AS1 binds YAP protein and inhibits the phosphorylation mediated inactivation of YAP by LATS1. Reciprocally, YAP/TEAD1 complex promotes THAP9-AS1 transcription to form a feed-forward circuit. Importantly, THAP9-AS1 level positively correlates with YAP expression in pancreatic cancer tissues. THAP9-AS1 and YAP overexpression predicts a poor outcome of pancreatic cancer patients. Our findings indicate that THAP9-AS1 plays an important role in pancreatic cancer growth via enhancing YAP signaling at two aspects. THAP9-AS1/YAP axis may serve as a potential biomarker and therapeutic target for pancreatic cancer treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Nan Li, Guohua Yang, Zhimin He, Wanqing Liu, Haiying Liu, Guopei Zheng. LncRNA THAP9-AS1 promotes pancreatic cancer growth via sponging miR-484 and interacting with YAP to enhance YAP activity [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 3581.
Abstract 3584: Role of long noncoding RNA LINC00461 in EGFR-TKIs resistant non-small cell lung cancer
Authors: Lee Ji Yun , Luu Thi-Thu-Trang , Bach Duc-Hiep , Hu Ruoci , Kim Donghwa , Lee Sang Kook 
Published: August 2019

Abstract
Chemo-resistance is one of the major factors limiting the therapeutic efficacy and prognosis of non-small cell lung cancer (NSCLC) patients, especially with patients who harbor epidermal growth factor receptor (EGFR)-activating mutations. Accumulating evidence suggests that aberrant expression of long noncoding RNAs (lncRNAs) is in part associated with carcinogenesis. Therefore, we tried to identify lncRNAs and their potential target genes in drug-resistant NSCLC. We evaluated lncRNAs with drug-resistant NSCLC using microarray data and in vitro assays. W found that lots of lncRNAs were differentially expressed between the drug-resistant NSCLC cells (HCC827-gef) and its parental (HCC827) cells. Among them, LINC00461 was found to be up-regulated lncRNAs, and highly correlated with the drug resistance. Taken together, the present study provides the expression profiles of chemo-resistant lncRNAs and identifies LINC00461 as a potential biomarker associated with EGFR-TKI resistance in non-small cell lung cancer cells.
This work was supported by a National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MEST) (NRF-2016M3A9B6903499).
Citation Format: Ji Yun Lee, Thi-Thu-Trang Luu, Duc-Hiep Bach, Ruoci Hu, Donghwa Kim, Sang Kook Lee. Role of long noncoding RNA LINC00461 in EGFR-TKIs resistant non-small cell lung 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 3584.
Abstract 3588: Identification of a potent, orally bioavailable and selective MCT4 Inhibitor for the treatment of solid Warburg tumors
Authors: Hambruch Nina , Herkert Barbara , Gege Christian , Mallinger Aurelie , Fabian Johannes , Kinzel Olaf , Wang Yansong , Fink Gero , Albers Michael , Funk Anette , Bittman-Waetzig Annika , Fleckenstein Tilly , Braun Floriane , Kremoser Claus 
Published: August 2019

Abstract
A key metabolic alteration in tumor cells is an elevated glycolysis rate, resulting in the production of increased amounts of protons and lactate leading to lactic acidosis within the tumor microenvironment. The tumor-promoting effects of lactic acidosis are versatile, ranging from stimulation of proliferation, angiogenesis and metastasis to the reshaping of the tumor immune environment to a tumor-permissive phenotype. In tumors lactate is transported across the plasma membrane by the monocarboxylate transporters 1 and 4 (MCT 1/4) in symport with a proton. While MCT1 is expressed almost ubiquitously at low levels, MCT4 expression is regulated by hypoxia-inducible factor 1α (Hif1α), the central player in the cellular response to hypoxia. Thus, MCT4 is present in hypoxic, highly glycolytic cells. Given their central role in prevention of intracellular acidification and lactate transport, MCTs appear to be indispensable for glycolytic tumor growth. Since MCT4 has the strongest implication on the development and aggressiveness of diverse cancer types it has emerged as a new target for the treatment of solid tumors.
We have identified MCT4 specific inhibitors structurally based on an internal compound library using cell-based lactate export assays. A subsequent extensive medicinal chemistry program was able to significantly improve activity and selectivity of the primary structures. Cellular target engagement was verified by cell-based assays like cellular thermal shift assay (CETSA). These efforts resulted in the identification of highly potent, orally bioavailable and selective MCT4 inhibitors (MCT4 IC50 &lt; 20nM; MCT1 IC50 &gt; 100µM) with good physicochemical properties and beneficial pharmacokinetics in mouse.
In vivo efficacy and tumor lactate modulation were evaluated in NCI-H358 xenograft and MC38 syngeneic mouse models. Thereby we explore the potential of our MCT4 inhibitor to act as a single anti-cancer agent or to synergize with other established therapies like angiogenesis inhibitors or cancer immunotherapeutics.
Citation Format: Nina Hambruch, Barbara Herkert, Christian Gege, Aurelie Mallinger, Johannes Fabian, Olaf Kinzel, Yansong Wang, Gero Fink, Michael Albers, Anette Funk, Annika Bittman-Waetzig, Tilly Fleckenstein, Floriane Braun, Claus Kremoser. Identification of a potent, orally bioavailable and selective MCT4 Inhibitor for the treatment of solid Warburg tumors [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 3588.