bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-034: MicroRNA-224 down-regulates Glycine N-methyltransferase gene expression in hepatocellular carcinoma
Authors: Hung Jung Hsien 
Published: July 2017

Abstract
Glycine N-methyltransferase (GNMT) is a tumor suppressor and frequently down-regulated in hepatocellular carcinoma (HCC). However, the mechanism is not fully understood. MicroRNAs are gene regulators and play important roles in tumorigenesis. In this study, we used both miRWalk and miRTar programs to search for microRNAs that may target at GNMT. Among several candidates, we found that microRNA-224 (miR-224) can bind to the GNMT transcript of the coding region. In addition, mutation of miR-224 seed sequences prevented its binding and subsequently repression activity in the reporter assay. The GNMT-MT plasmid containing GNMT mRNA with miR-224 seed sequence silent mutation can escape the suppression of miR-224 in HEK293T cells. Both exogenous and endogenous GNMT expression were suppressed by miR-224, while miR-224 inhibitors enhanced GNMT expression. In addition, miR-224 counteracts the effects of GNMT on the reduction of cell proliferation and tumor growth. We further demonstrated a significant inverse correlation of miR-224 and GNMT mRNA levels in HCC samples. In conclusion, miR-224 is the first reported miRNA that directly targets the GNMT mRNA coding sequence and plays an important role in GNMT suppression during hepatocarcinogenesis.
Citation Format: Jung Hsien Hung. MicroRNA-224 down-regulates Glycine N-methyltransferase gene expression in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-034. doi:10.1158/1538-7445.AM2017-LB-034
Abstract LB-036: Citrullinome analysis identifies the role of PADI4 in regulating RNA processing and tumor immunogenicity
Authors: Tanikawa Chizu , Matsuda Koichi 
Published: July 2017

Abstract
Recent proteome analyses have provided a comprehensive overview of various posttranscriptional modifications (PTM); however, PTMs involving protein citrullination remain unclear. Thus, we performed a proteomic analysis of citrullinated proteins and identified more than 100 PADI4 substrates, the majority of which are related to RNA processing and protein translation. Citrullination of RBMX (RNA binding motif protein, X-linked) inhibited the interaction with other hnRNP family members. RNA sequence analyses revealed altered splicing patterns in more than 300 genes in bone marrow cells in Padi4-/- mice. Approximately one-fifth of the PADI4 substrates contained an RG/RGG motif, and citrullination by PADI4 competitively inhibited the methylation of the RGG motif in FET proteins (EWS and TAF15). In addition, PADI4-mediated citrullination inhibited the aggregation of TAF15 proteins, which is a frequently-observed feature in neurodegenerative diseases, such as ALS. An antibody against citrullinated RGG motifs was observed in 11.5% (27 among 234) of serum samples from patients with HCV-related hepatocellular carcinoma, and female patients with high serum antibody exhibited poor prognosis. Our findings imply that PADI4-mediated citrullination plays a key role in RNA processing, protein aggregation and tumor immunogenicity, and suggest that PADI4 activation has potential therapeutic implications for neurodegenerative disease and cancer immunotherapy.
Citation Format: Chizu Tanikawa, Koichi Matsuda. Citrullinome analysis identifies the role of PADI4 in regulating RNA processing and tumor immunogenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-036. doi:10.1158/1538-7445.AM2017-LB-036
Abstract LB-057: The expression level and prognostic value of PD-L1 and PD-1 in cervical carcinoma patients
Authors: Bao Yongxing , Zhang Songan , Niyazi Huerdidan , Tuluwengjiang Gulixian , Zhang Lei , Zhang Yang , Su Weipeng 
Published: July 2017

Abstract
Cervical cancer is one of the most common gynecologic malignant tumors that threaten the health of women. Recently some researches have found that radiotherapy combined with anti-PD-1/PD-L1 drugs might improve anti-tumor efficacy. But there is few report about this issue on cervical cancer field. In order to testify the possibility and feasibility in cervical cancer patients, we collected 70 tissue samples of cervical squamous cell carcinoma and 70 tissue samples of cervical benign lesion, of which 24 cases of the cervical squamous cell carcinoma had matched peripheral blood samples, compared to 30 cases with matched peripheral blood samples of benign lesions. We used immunohistochemistry to detect the expression of PD-L1 in the tissues and flow cytometry to detect the proportion of CD4+PD-1+ and CD8+PD-1+ subsets in peripheral blood. Then Log-rank and COX regression were used to analyze the relationship among survival time, expression of PD-L1 and proportion of PD-1+ T cells. The results indicated that the proportion of CD4+PD-1+ T cells and CD8+PD-1+ T cells in peripheral blood positively correlated with the expression of PD-L1 in tissue samples of cervical squamous cell carcinoma patients (R2=0.734, P=0.000; R2=0.66, P=0.000), while there were less correlation in cervical benign patients (R2=0.138, P=0.043; R2=0.174, P=0.022). There were significantly differences in the proportion of CD8+PD-1+T cells and PD-L1+ tissue cells between cervical cancer group and cervical benign disease group (P=0.000, P=0.002). With the increase of tumor stage, the percentage of CD4+PD-1+ T cells and CD8+PD-1+ T cells increased correspondingly. With the increase of tumor diameter and stage, the expression of PD-L1 in tumor tissue also increased. The patients with small proportion of CD4+PD-1+ T cells and low expression of PD-L1 seemed to have longer survival time. Multivariate analysis showed that the PFS time was affected by the expression of PD-L1(B=1.844, P=0.019). Taken together, the cervical squamous cell cancer patients had more CD4+PD-1+ T cells in peripheral blood and PD-L1+ cells in tissues, which correlated to the grading of tumor and associated with prognosis.
Note: This abstract was not presented at the meeting.
Citation Format: Yongxing Bao, Songan Zhang, Huerdidan Niyazi, Gulixian Tuluwengjiang, Lei Zhang, Yang Zhang, Weipeng Su. The expression level and prognostic value of PD-L1 and PD-1 in cervical carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-057. doi:10.1158/1538-7445.AM2017-LB-057
Abstract LB-079: Expression of evolutionarily novel genes in tumors
Authors: Kozlov Andrei , Krukovskaya Larisa , Samusik Nikolai , Makashov Andrei , Matyunina Ekaterina , Karnaukhova Julia , Kurbatova Tamara , Emelyanov Alexander 
Published: July 2017

Abstract
Several genes with dual specificity - evolutionarily novel and expressed specifically or predominantly in tumors (OTP, ESRG, PVT1, ELFN1-AS1, HHLA1, DCD, SPRR1A, PBOV1 and others), have been described in our lab. We suggested to call such genes Tumor Specifically Expressed, Evolutionarily Novel (TSEEN) genes.
We also described the evolutionary novelty of the whole classes of genes expressed predominantly in tumors, e.g. CT-X genes and genes of noncoding tumor specifically expressed RNAs.
We studied the phylogenetic distribution of the orthologs of genes expressed in tumors and found that different functional gene classes have different evolutionary novelty. Some of them are enriched with evolutionarily novel genes. We showed that phylogenetic distribution curves of oncogenes, tumor suppressor genes and differentiation genes almost coincide, i.e. their evolution proceeds in a parallel manner.
Using zebrafish transgenic inducible tumor model we discovered that some human genes which determine progressive traits originated in fishes and were first expressed in fish tumors.
Our data and the data published by other authors suggest that genes originated by gene duplication; from endogenous retroviruses; by exon shuffling; and de novo are expressed in tumors, sometimes with high tumor specificity.
The expression of evolutionarily novel genes in tumors may be a novel biological phenomenon with important evolutionary role.
Citation Format: Andrei Kozlov, Larisa Krukovskaya, Nikolai Samusik, Andrei Makashov, Ekaterina Matyunina, Julia Karnaukhova, Tamara Kurbatova, Alexander Emelyanov. Expression of evolutionarily novel genes in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-079. doi:10.1158/1538-7445.AM2017-LB-079
Abstract LB-102: Landscape analysis of the initial data release from AACR Project GENIE
Authors: Cerami Ethan , Baras Alexander S. , Guinney Justin , Lepisto Eva , Pugh Trevor J. , Schultz Nikolaus , Stricker Thomas , Sweeney Shawn M. , Veer Laura J. van't , Meijer Gerrit A. , Andre Fabrice , Velculescu Victor E. , Shaw Kenna R. , Levy Mia A. , Bedard Philippe L. , Rollins Barrett J. , Sawyers Charles L. ,   on behalf of the AACR Project GENIE Consortium
Published: July 2017

Abstract
AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) is a multi-phase, multi-year, international data-sharing consortium whose goal is to generate an evidence base for precision cancer medicine by integrating and linking clinical-grade cancer genomic data with clinical outcome data for tens of thousands of cancer patients treated at multiple institutions worldwide. The project fulfills an unmet need in oncology by providing the statistical power necessary to identify novel therapeutic targets, to understand genomic determinants of response to therapy, to design new biomarker-driven clinical trials and ultimately, to improve clinical decision-making and the care delivered to patients. Here we describe the goals, structure and data standards of the GENIE consortium and conclusions from a high-level analysis of the first public release of genomic and limited clinical data from approximately 19,000 patients treated at eight cancer centers obtained during this initial phase of the project. We also explore the clinical utility of these genomic data by examining rates of clinical actionability across multiple cancer types and by estimating patient enrollment rates to the NCI MATCH Trial. Based on yearly rates of sequencing at each of the eight founding institutions, together with the planned addition of new members, we estimate the GENIE database could grow to &gt;100,000 samples within five years. Consistent with the goals of the proposed Cancer Moonshot National Cancer Data Ecosystem, GENIE is committed to the principles of generating interoperable, open access data that can be widely shared across the entire scientific community.
Citation Format: Ethan Cerami, Alexander S. Baras, Justin Guinney, Eva Lepisto, Trevor J. Pugh, Nikolaus Schultz, Thomas Stricker, Shawn M. Sweeney, Laura J. van't Veer, Gerrit A. Meijer, Fabrice Andre, Victor E. Velculescu, Kenna R. Shaw, Mia A. Levy, Philippe L. Bedard, Barrett J. Rollins, Charles L. Sawyers, on behalf of the AACR Project GENIE Consortium. Landscape analysis of the initial data release from AACR Project GENIE [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-102. doi:10.1158/1538-7445.AM2017-LB-102
Abstract LB-126: PPARgamma agonists sensitize PTEN-deficient lung cancer cells resistant to EGFR tyrosine kinase inhibitors
Authors: To Kenneth KW , Tong Wing Sum , Wu William KK , Loong Herbert HF 
Published: July 2017

Abstract
We aimed to develop novel drug combination strategy to overcome drug resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in the treatment of lung cancer. EGFR TKIs are approved for treating advanced lung cancer that harbors the sensitizing EGFR mutations. However, resistance to EGFR TKIs is almost inevitable for all patients due to multifactorial mechanisms. The PI3K/Akt/mTOR pathway is a major signaling pathway regulated by EGFR to drive cancer survival. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor, which upon activation upregulates PTEN to inhibit cell signaling downstream of PI3K to mediate apoptosis. To this end, PTEN loss is a known mechanism contributing to intrinsic resistance to EGFR TKIs. Therefore, PPARγ agonists are hypothesized to overcome EGFR TKI resistance. Using well defined human non-small cell lung cancer (NSCLC) cell model with PTEN deficiency, the potentiation of EGFR TKI anticancer activity by PPARγ agonists was demonstrated. PPARγ agonists were found to upregulate PTEN, subsequently inhibit the PI3K-Akt signaling pathway, and thus enhancing the anticancer activity of gefitinib (a first generation EGFR TKI). Specific PPARγ inhibitor (GW9662) and genetic silencing of PPARγ were shown to prevent this potentiation of anticancer activity by PPARγ agonists, thus confirming the crucial role played by PPARγ activation. Interestingly, the tested PPARγ agonists were also found to induce autophagy, as evidenced by the increased expression of an autophagy marker LC3-II and the autophagic degradation of p62/SQSTM1. PPARγ agonists-induced autophagic cell death was believed to contribute to the circumvention of resistance in PTEN-deficient cells because the genetic silencing of ATG5 (an autophagy mediator) was found to eliminate the drug potentiation effect by the PPARγ agonists.
Our findings thus provide the basis for the rational and personalized use of PPARγ agonists in combination with EGFR TKIs in lung cancer patients with specific resistance mechanism.
Citation Format: Kenneth KW To, Wing Sum Tong, William KK Wu, Herbert HF Loong. PPARgamma agonists sensitize PTEN-deficient lung cancer cells resistant to EGFR tyrosine kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-126. doi:10.1158/1538-7445.AM2017-LB-126
Abstract LB-130: Tumor regression in novel triple therapy BRAF mutant metastatic melanoma patient-derived preclinical models
Authors: Harris Antoneicka L. , Thompson Michael , Markovic Svetomir , Durham William , Dawson Louis , Small Daniel , Copland John A. 
Published: July 2017

Abstract
Metastatic melanoma (MM) is the most aggressive type of skin cancer contributing to approximately 80% of all skin cancer related deaths. In 2016, it was estimated that more 76,000 cases would be diagnosed in the United States. The high metastatic potential and aggressive clinical behavior of this disease makes it a major health problem. As a consequence there has been notable development in for novel targeted (i.e. BRAF inhibitors) and immune therapies (i.e. anti-PD1 and CTLA4 inhibitors). However, despite improvements in patient outcomes, most patients develop resistance within 6-11 months on dual BRAF/MEK inhibition, and 5 months on immune therapy, highlighting the need to identify new therapies that improve disease management and patient survival. Increased expression of CyclinD1 has been reported to occur as a mechanism of resistance to BRAF inhibition, resulting in reactivation of the canonical activating pathway in melanoma, MAPK. Thus, we hypothesize that combined inhibition of CDK4/6 and MAPK signaling will provide a novel anti-tumor synergy drug combination superior to current standard of care in BRAF mutant patient-derived preclinical models. Using MM human tissue from patients we developed 3 BRAF mutant preclinical models investigating a novel triple therapy drug combination BRAFi/MEKi/CDK4/6i. Protein analysis and drug proliferation assays were used to design the novel combination. In vivo, we found statistically significant differences in tumor inhibition between the novel combination and the current standard of care. The triple therapy also showed promising results, in vivo, when assessed as a salvage therapy following tumor escape from BRAFi/MEKi combination treatment.
Citation Format: Antoneicka L. Harris, Michael Thompson, Svetomir Markovic, William Durham, Louis Dawson, Daniel Small, John A. Copland. Tumor regression in novel triple therapy BRAF mutant metastatic melanoma patient-derived preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-130. doi:10.1158/1538-7445.AM2017-LB-130
Abstract LB-142: Identification of STK33 as a cancer stemness kinase and regulator of Nanog function
Authors: Tran Susan L. , Furuta Yudai , Zhu Chen , Yang Ao , Sun Xiangao , Rogoff Harry A. , Li Chiang J. 
Published: July 2017

Abstract
In recent years evidence has accumulated in support of the cancer stem cell (CSC) model in cancer chemotherapy resistance, highlighting the urgency and necessity of identifying CSC targets for developing novel cancer therapeutics. A number of studies have suggested that Nanog is a crucial factor that can confer stemness properties to a portion of the heterogeneous cancer cell population. Although latent in normal somatic cells, aberrant expression of Nanog has been reported in many types of human cancers. Importantly, the expression levels of Nanog are often positively correlated with treatment resistance and poor survival of cancer patients. Various studies have shown that upregulation of Nanog expression enhances the tumorigenicity both in vivo and in vitro whereas repression or ablation of Nanog inhibits tumor initiation. Thus, expression of the stemness factor Nanog is linked to tumor progression, therapeutic resistance, relapse and metastasis.
However, Nanog is considered a non-druggable target. Here we provide data to support a role for STK33 (Serine Threonine Kinase 33) as a novel regulator of Nanog and as a potential therapeutic target. Ectopic STK33 expression promotes stemness phenotypes of cancer cells and increases expression levels of CSC drivers including Nanog, KLF4, and SOX2. On the other hand, knockdown of STK33 inhibits expression of Nanog and results in a reduction of the stemness phenotype. STK33 directly interacts with Nanog and appears to promote its stabilization through phosphorylation, resulting in increased Nanog transcriptional activity. Moreover, BBI-503 (Amcasertib), a first-in-class cancer stemness inhibitor, potently inhibits STK33, which led to inhibition of phosphorylation of Nanog. Collectively, our data demonstrate STK33 is a critical element in the signaling network that governs the stemness of cancer cells, and as a promising therapeutic target for cancer.
Citation Format: Susan L. Tran, Yudai Furuta, Chen Zhu, Ao Yang, Xiangao Sun, Harry A. Rogoff, Chiang J. Li. Identification of STK33 as a cancer stemness kinase and regulator of Nanog function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-142. doi:10.1158/1538-7445.AM2017-LB-142
Abstract LB-143: Identification of STAT3-NRF2-hypoxia as a novel reinforcing mechanism for promoting cancer stemness
Authors: Tavera Luz Elisa , Simon Karen , Li Juying , Geromini Katherine , Zhang Zhuo , Keates Sarah , Rogoff Harry A. , Li Chiang J. 
Published: July 2017

Abstract
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor constitutively activated in many cancer types, and has been identified as a major mediator of cancer stemness (Li et.al., PNAS 2015). The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2) is the reactive oxygen species (ROS) sensor and a master regulator of antioxidant gene expression. NRF2 has recently been implicated in contributing to cancer stem cell phenotypes, chemoresistance, and is associated with poor clinical prognosis. Hypoxia is considered a major feature of the tumor microenvironment as it can promote tumor progression, increased stemness characteristic, and resistance to conventional therapeutic intervention. Hypoxia can regulate a series of stress-sensor transcription factors, notably, the reactive oxygen species (ROS) sensor and response modulator NRF2.
We studied NRF2 transcript and protein levels in breast cancer cell lines MCF7 and AU565 cells under both hypoxic and normoxic conditions. Our data shows that in response to STAT3 pathway activators, NRF2 is upregulated at both mRNA and protein levels under hypoxia and this upregulation is STAT3 dependent. NRF2 ChIP-Seq experiments demonstrate that both hypoxia and STAT3 stimulation can modulate NRF2 binding in MCF-7 breast cancer cells. Surprisingly, under hypoxic conditions, STAT3 activation dramatically enhances (10 fold) NRF2 binding sites across the genome. Downstream analysis of NRF2 target genes revealed a significant change from stress response to activation of gene signaling pathways involved in stemness-high cancer cells and metastatic cells under both hypoxic and STAT3 stimulation. Finally, we investigated whether the stemness inhibitor BBI-608 (Napabucasin) could reduce chemotherapy-induced NRF2 upregulation. Our results indicate that STAT3 modulates NRF2 levels and transcriptional activity, and that stemness inhibitor BBI-608 can prevent this upregulation. Our data revealed STAT3-NRF2-Hypoxia as a novel reinforcing regulatory mechanism for promoting cancer stemness and chemoresistance.
Citation Format: Luz Elisa Tavera, Karen Simon, Juying Li, Katherine Geromini, Zhuo Zhang, Sarah Keates, Harry A. Rogoff, Chiang J. Li. Identification of STAT3-NRF2-hypoxia as a novel reinforcing mechanism for promoting cancer stemness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-143. doi:10.1158/1538-7445.AM2017-LB-143