bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 241: Contribution of female breast cancer predisposition SNPs to risk of male breast cancer
Authors: Orr Nick , Jones Michael , Maguire Sarah , Swerdlow Anthony 
Published: August 2018

Abstract
Genome-wide association studies have identified more than 170 loci that confer susceptibility to breast cancer. Male breast cancer accounts for approximately 1% off all newly diagnosed cases of breast cancer and several reports have implicated germline genetic factors as significant in the aetiology of the disease. Inherited germline mutations in the BRCA2 gene are thought to account for up to 10% of cases. Here we demonstrate that there are substantial overlaps between polygenic susceptibility to male and female breast cancer and that a subset of shared predisposition loci confer significantly larger risk effects in males than in females. Men in the highest quintile of the distribution of risk allele count have a 2.7-fold (2.17-3.30) increased risk of breast cancer compared to those in the lowest quintile. Furthermore, comparisons of the risk allele distributions in male and female cases suggests that the overall impact of genetic predisposition to breast cancer may be greater in a susceptible minority of males from the general population than in females.
Citation Format: Nick Orr, Michael Jones, Sarah Maguire, Anthony Swerdlow. Contribution of female breast cancer predisposition SNPs to risk of male breast 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 241.
Abstract 2412: The nuclear homeoprotein NKX3.1, has a novel function in the mitochondria in regulation of prostate cancer initiation
Authors: Dutta Aditya , Abate-Shen Cory 
Published: August 2018

Abstract
An emerging hallmark of cancer is reprograming of energy metabolism, in which mitochondrial plasticity plays a central role. Mitochondrial plasticity, particularly in response to oxidative stress, is coordinately orchestrated by both mitochondrial- and nuclear-encoded genes. Recent reports highlight the association of mitochondrial dysfunction and prostate cancer, one of the leading causes of cancer and cancer-related death for men. One of the earliest events in prostate cancer etiology is loss of functional NKX3.1, a homeoprotein that is known to play essential roles in prostate differentiation and prostate cancer by regulation of nuclear-encoded genes. We now show that in response to oxidative stress, NKX3.1 is localized to the mitochondria where it directly protects against reactive oxygen species (ROS). NKX3.1 regulates mitochondrial function by directly binding to the D-loop (mitochondrial DNA control region) to specifically regulate mitochondrial genes coding for the electron transport chain. Moreover, we show that aberrant NKX3.1 function in the mitochondria leads to enhanced reactive oxygen species and DNA damage, both of which are reversed by metformin, a biguanide class of anti-diabetic drug that targets the mitochondrial electron transport chain. This uncovers the potential for metformin administration to individuals with NKX3.1 loss as a precision prevention approach against prostate cancer initiation. These observations highlight novel functions for homeoproteins as direct regulators of mitochondrial DNA, and demonstrate the critical role of the mitochondrial stress response in enabling prostate cancer initiation with potential novel therapeutic implications. &gt;
Citation Format: Aditya Dutta, Cory Abate-Shen. The nuclear homeoprotein NKX3.1, has a novel function in the mitochondria in regulation of prostate cancer initiation [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 2412.
Abstract 2418: PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis
Authors: Liu Fabao , Ma Fengfei , Wang Yuyuan , Hao Ling , Zeng Hao , Jia Chenxi , Wang Yidan , Liu Peng , Ong Irene M. , Li Baobin , Chen Guojun , Jiang Jiaoyang , Gong Shaoqin , Li Lingjun , Xu Wei 
Published: August 2018

Abstract
Metabolic reprogramming is a hallmark of cancer. Herein we discover that the key glycolytic enzyme pyruvate kinase M2 isoform (PKM2), but not the related isoform PKM1, is methylated by co-activator-associated arginine methyltransferase 1 (CARM1). PKM2 methylation reversibly shifts the balance of metabolism from oxidative phosphorylation to aerobic glycolysis in breast cancer cells. Oxidative phosphorylation depends on mitochondrial calcium concentration, which becomes critical for cancer cell survival when PKM2 methylation is blocked. By interacting with and suppressing the expression of inositol-1,4,5-trisphosphate receptors (InsP3Rs), methylated PKM2 inhibits the influx of calcium from the endoplasmic reticulum to mitochondria. Inhibiting PKM2 methylation with a competitive peptide delivered by nanoparticles perturbs the metabolic energy balance in cancer cells, leading to a decrease in cell proliferation, migration and metastasis. Collectively, the CARM1-PKM2 axis serves as a metabolic reprogramming mechanism in tumorigenesis, and inhibiting PKM2 methylation generates metabolic vulnerability to InsP3R-dependent mitochondrial functions
Citation Format: Fabao Liu, Fengfei Ma, Yuyuan Wang, Ling Hao, Hao Zeng, Chenxi Jia, Yidan Wang, Peng Liu, Irene M. Ong, Baobin Li, Guojun Chen, Jiaoyang Jiang, Shaoqin Gong, Lingjun Li, Wei Xu. PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis [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 2418.
Abstract 2420: Skp2-mediated stabilization of MTH1 promotes survival of melanoma cells upon oxidative stress
Authors: Jin Lei , Wang Jiayu , Liu Guangzhi , Wilmott James S. , Yan Xu Guang , Thorne Rick F. , Scolyer Richard A. , Zhang Xu Dong 
Published: August 2018

Abstract
MTH1 helps prevent misincorporation of ROS-damaged dNTPs into genomic DNA, however, there is little understanding of how MTH1 itself is regulated. Here we report that MTH1 is regulated by polyubiquitination mediated by the E3 ligase Skp2. In melanoma cells, MTH1 was upregulated commonly mainly due to its improved stability caused by K63-linked polyubiquitination. While Skp2 along with other components of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex were physically associated with MTH1, blocking the SCF function ablated MTH1 ubiquitination and expression. Conversely, overexpressing Skp2 elevated levels of MTH1 associated with an increase in its K63-linked ubiquitination. In melanoma cell lines and patient specimens, we observed a positive correlation of Skp2 and MTH1 expression. Mechanistic investigations showed that Skp2 limited DNA damage and apoptosis triggered by oxidative stress and that MAPK upregulated Skp2 and MTH1 to render cells more resistant to such stress. Collectively, our findings identify Skp2-mediated K63-linked polyubiquitination as a critical regulatory mechanism responsible for MTH1 upregulation in melanoma, with potential implications to target the MAPK/Skp2/MTH1 pathway to improve its treatment.
Citation Format: Lei Jin, Jiayu Wang, Guangzhi Liu, James S. Wilmott, Xu Guang Yan, Rick F. Thorne, Richard A. Scolyer, Xu Dong Zhang. Skp2-mediated stabilization of MTH1 promotes survival of melanoma cells upon oxidative stress [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 2420.
Abstract 2435: ST6Gal-I sialylation potentiates hypoxia adaptation by enhancing HIF-1a signaling
Authors: Jones Robert B. , Dorsett Kaitlyn A. , Hjelmeland Anita B. , Bellis Susan L. 
Published: August 2018

Abstract
Aberrant surface glycosylation is a well-known hallmark of a tumor cell, however the functional role of glycans in cancer cell biology remains unclear. Tumor cells frequently display an increase in surface α2-6 sialylation, a modification added to N-glycosylated proteins by the ST6Gal-I sialyltransferase. ST6Gal-I sialylates a select cohort of surface receptors, which correspondingly modulates receptor-induced intracellular signaling cascades. Emerging evidence suggests that ST6Gal-I-mediated sialylation promotes the survival of tumor cells exposed to a variety of cell stressors. In the current study we identify a new function for ST6Gal-I in protecting against hypoxic stress. In response to low oxygen tension, the hypoxia inducible factor, HIF-1α, becomes stabilized in tumor cells. In turn, HIF-1α stimulates the transcription of genes important for cell survival. To interrogate a role for ST6Gal-I in hypoxic response, we evaluated HIF-1α accumulation in ovarian and pancreatic cancer cells with ST6Gal-I overexpression or knockdown. We find that ST6Gal-I activity augments HIF-1α accumulation in cells treated with chemical hypoxia mimetics (DFO and DMOG), or alternatively grown in a hypoxic environment. Furthermore, hypoxic cells with high ST6Gal-I expression have increased mRNA levels of HIF-1α transcriptional targets including the glucose transporters, GLUT1 GLUT3, and the glycolytic enzyme, PDHK1. Interestingly, cells with high ST6Gal-I expression also have an increased pool of HIF-1α mRNA, suggesting that ST6Gal-I may influence the biosynthesis of HIF-1α. Finally, cells grown in hypoxia for several weeks display an enrichment in ST6Gal-I expression, consistent with the concept that ST6Gal-I acts as a pro-survival factor. Taken together, these findings highlight a novel, glycosylation-dependent mechanism that facilitates tumor cell adaptation to a hypoxic milieu.
Citation Format: Robert B. Jones, Kaitlyn A. Dorsett, Anita B. Hjelmeland, Susan L. Bellis. ST6Gal-I sialylation potentiates hypoxia adaptation by enhancing HIF-1a 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 2435.
Abstract 2442: Detection of tissue hypoxia with EF5
Authors: Su Kevin , Noble Amy , Asbrock Nick , Koch Cameron , Chu Vi 
Published: August 2018

Abstract
Hypoxia, a condition of oxygen deprivation, is a salient feature of the tumor microenvironment. Hypoxia tumors are frequently resistant to conventional cancer therapies and are correlated with increased migratory and metastatic behavior. A number of detection modalities exist for the detection of hypoxia; however, only EF5 (2-[2-nitro-1H-imidazol-1-yl]-N-(2,2,3,3,3-pentafluoropropyl) acetamide) provides detailed information on the distribution of hypoxia in tissues at both the physiologic and pathologic levels. EF5 is a compound that, when injected into animal tissues, selectively binds to hypoxic cells and forms adducts. These adducts are detected by a mouse monoclonal antibody, clone ELK3-51, conjugated to fluorescent dyes including Cyanine 3, Alexa Fluor 488 and Cyanine 5. The use of EF5 and its specific fluorescent monoclonal antibody to selectively detect regions of hypoxia in mouse tissues is described. BALB/c mice between 7 to 10 weeks old and weighing between 18 to 30 g were used in the study. Mouse #1 was not treated with EF5 and its spleen was harvested as a negative control. Mouse #2 was injected with 10 mM EF5 (typically 1% of animal weight in mL) and allowed to run aerobically for 4 hours before euthanization. Mouse #3 was injected with EF5, euthanized after 10 minutes and kept warm at 37°C for 40 minutes to mimic the anaerobic hypoxic condition before the spleen was harvested (hypoxic control). Examination of spleen samples indicated highly specific binding of the EF5 adducts only in the anaerobic hypoxic mouse spleen. The use of EF5 with fluorescent conjugated antibodies provides a sensitive and quantitative method for the detection and measurement of tissue hypoxia in animal and human tumor tissues and cells.
Citation Format: Kevin Su, Amy Noble, Nick Asbrock, Cameron Koch, Vi Chu. Detection of tissue hypoxia with EF5 [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 2442.
Abstract 2450: The importance of a family of long noncoding RNAs from the Y chromosome in radiotherapy and chemotherapy response of male non-small cell lung cancer
Authors: Brownmiller Tayvia , Barr Jamie , Harold Abby , Bey Erik , Martinez Ivan 
Published: August 2018

Abstract
Lung cancer is the number one cause of cancer-related deaths in the United States. The 5-year overall survival rate for patients with non-small cell lung cancer (NSCLC) stands at 18%, with women having a twice better overall survival rate than men. Currently, there is no solid evidence to explain the disparity between gender survival rates. The protein coding genes of the X and Y chromosomes have been relatively well characterized, and previous studies have implicated phenomena such as the dysregulation of X inactivation and the loss of the Y chromosome in a number of cancers. However, the regions of these chromosomes responsible for producing noncoding RNAs (ncRNAs) are not well understood. One such class of ncRNAs are long noncoding RNAs (lncRNAs), which are primarily classified as larger than 200 nucleotides and carry out functions in nearly every cellular process via a variety of mechanisms. In this study, we have identified a novel family of Y chromosome-linked lncRNAs that we hypothesize play a role in NSCLC cell survival. Our preliminary data show a time- and dose-dependent response in expression of the Y chromosome lncRNA family after radiation in radiosensitive NSCLC cell lines but not in radioresistant NSCLC cell lines, and we see a similar trend in response to cisplatin. Additionally, upon knockdown of this family in a sensitive cell line using two different shRNAs, we immediately observed an increase in proliferation of the knockdown cells when compared to shCtrl as well as increased cell viability and resistance to apoptosis in response to radiation, and increased resistance to cisplatin. We plan to further characterize these lncRNAs using methods such as qRT-PCR, virtual Northern blotting, traditional Northern blotting, direct RNA sequencing, cellular fractionation, and fluorescent in situ hybridization and determine their function by shRNA knockdown and subsequent assays to measure cellular processes in response to radiation and chemotherapy. The Identification of a male-specific component of lung cancer would fill a knowledge gap that could provide potential therapeutic targets and new prognostic factors, thereby improving the response rate of men with NSCLC.
Citation Format: Tayvia Brownmiller, Jamie Barr, Abby Harold, Erik Bey, Ivan Martinez. The importance of a family of long noncoding RNAs from the Y chromosome in radiotherapy and chemotherapy response of male 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 2450.
Abstract 2454: Identification of a novel lncRNA family that is required for efficient cellular transformation by Bcr-Abl oncogene
Authors: Chen Jilong , Wang Xuefei 
Published: August 2018

Abstract
Human genome transcribes abundant long noncoding RNAs (lncRNAs) that are defined as the transcripts longer than 200 nt without protein-coding capacity. Recently, lncRNAs are being continuously recognized as critical regulators for various biological processes. Aberrant expression of lncRNAs has been shown to be a cornerstone in diverse human diseases and cancer development. Chronic myeloid leukemia (CML) is a hematological malignancy associated with a reciprocal translocation between chromosome 9 and 22 that generates the chimeric Bcr-Abl oncogene. About 10% of acute lymphoblastic leukemia (ALL) patients also contain Bcr-Abl oncogene. However, the functional relevance of lncRNAs in Bcr-Abl-mediated leukemia remains obscure. In this study, we perform a comprehensive analysis of lncRNAs in Bcr-Abl-positive K562 cells using a microarray of cDNAs encoding lncRNAs. This analysis revealed 987 upregulated lncRNAs and 1479 downregulated lncRNAs in response to treatment with imatinib, a Bcr-Abl inhibitor. Importantly, we identified a conserved, imatinib-inducible lncRNA (IIR) family, named lncRNA-IIR37. Upregulation of lncRNA-IIR37 has been detected in both human and mouse Abl-transformed cell lines after imatinib treatment. Interestingly, lncRNA-IIR37 levels are significantly lower in leukemic cells derived from Bcr-Abl-positive ALL patients than those in normal control group. Furthermore, altering lncRNA-IIR37 expression remarkably affects survival of Abl-transformed leukemic cells, and tumorigensis induced by leukemic cells in xenograft mouse model. Knockdown of lncRNA-IIR37 in transgenic mice significantly promotes Bcr-Abl-mediated primary bone marrow transformation. These results indicate that lncRNA-IIR37 functions as a suppressor gene in Bcr-Abl-induced tumorigenesis. In addition, we demonstrated that lncRNA-IIR37 directly bound and affected the phosphorylation of STAT5 to regulate leukemic cell survival. Together, our observations suggest that lncRNA-IIR37 is critically involved in Bcr-Abl-mediated leukemogenesis. These results provide novel insights into complicated mechanisms underlying cellular transformation by Bcr-Abl oncogene.
Citation Format: Jilong Chen, Xuefei Wang. Identification of a novel lncRNA family that is required for efficient cellular transformation by Bcr-Abl oncogene [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 2454.
Abstract 2470: Identification of long noncoding RNAs regulated by ZEB1 and epithelial-mesenchymal transition in lung cancer cells
Authors: Kim Jeong Seon , Ahn Young-Ho 
Published: August 2018

Abstract
Long non-coding RNA (lncRNA) are known to have various physiological and pathological functions. Some lncRNAs also show differential expression between cancer and normal tissues and play important roles in cancer development. In this study, we tried to identify novel lncRNAs that regulate epithelial-mesenchymal transition (EMT), invasion, tumorigenesis, and metastasis of lung cancer cells. We performed an NGS-based RNA sequencing analysis in murine lung cancer cells overexpressing ZEB1, an EMT-inducing transcription factor. ZEB1 overexpression changed the expression of total 194 lncRNAs: increased 80 and decreased 114 lncRNAs (fold change≥2, p≤0.01). We then selected 32 lncRNAs with high basal levels and confirmed their differential expression by qRT-PCR. In addition, we measured their expression changes after ZEB1-knockout in mesenchymal-like cells, TGFβ-treatment in epithelial-like cells, and ZEB1-overexpression in human lung cancer cells. Through these experiments, we found several lncRNAs regulated by ZEB1 or EMT in lung cancer cells. Expressions of these lncRNAs showed correlation with that of ZEB1 in human lung adenocarcinoma TCGA data. Further investigation will unveil the effects of these lncRNAs on EMT, cancer development, and metastasis of lung cancer cells.
Citation Format: Jeong Seon Kim, Young-Ho Ahn. Identification of long noncoding RNAs regulated by ZEB1 and epithelial-mesenchymal transition in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2470.
Abstract 2473: Association of functional genetic variants of long noncoding RNA HOTAIR with oral cancer susceptibility
Authors: Yang Shun-Fa , Su Shih-Chi , Lin Chiao-Wen 
Published: August 2018

Abstract
Genetic and acquired factors are thought to be interrelated and imperative to estimate the risk and prognosis of oral squamous cell carcinoma (OSCC). Polymorphisms in the HOX transcript antisense intergenic RNA (HOTAIR) have been recently linked to the predisposition to diverse malignancies. In the present study, we aimed to evaluate the influences of HOTAIR gene polymorphisms, combined with environmental triggers on the susceptibility to oral tumorigenesis. Four single-nucleotide polymorphisms (SNPs) of the HOTAIR gene, rs920778, rs1899663, rs4759314, and rs12427129 were tested in 1200 normal controls and 907 OSCC patients. We detected a significant association of rs1899663 with the risk of OSCC (AOR, 2.227; 95% CI, 1.197-4.146; p=0.012) after adjustment for three potential confounders, smoking, betel nut chewing, and alcohol consumption. In the further analyses where habitual exposure to each of three environmental factors was individually excluded, we found that, in addition to rs1899663, non-betel nut users who carried the polymorphic allele of rs920778 were more prone to develop OSCC than were those homozygous for wild-type allele (TC: OR, 1.472; 95% CI, 1.069-2.029; p=0.018; TC+CC: OR, 1.448; 95% CI, 1.060-1.977; p=0.020). This genetic association was not seen while comparing subjects who do not smoke or consume alcohol between the case and control cohort. Moreover, as exploring the relationship between HOTAIR gene polymorphisms and clinical status of only OSCC patients who were non-betel nut chewers, besides the association with the advanced clinical stage, rs920778 and rs4759314 were correlated with the development of large-size tumors (OR, 1.891; 95% CI, 1.027-3.484; p=0.04) and increased lymph node metastasis (OR, 4.140; 95% CI, 1.785-9.602; p=0.001), respectively. Further functional assessments link rs920778 to the regulation of HOTAIR expression and epigenetic status. Our results reveal an interactive effect of HOTAIR gene polymorphisms and betel nut chewing on the development and progression of oral cancer.
Citation Format: Shun-Fa Yang, Shih-Chi Su, Chiao-Wen Lin. Association of functional genetic variants of long noncoding RNA HOTAIR with oral cancer susceptibility [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 2473.