bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4453: Identification and characterization of oncogenic kinase LASK2 as a diagnostic and therapeutic target for lung cancer
Authors: Daigo Yataro , Takano Atsushi , Nakamura Yusuke 
Published: July 2017

Abstract
Lung cancer is the leading cause of cancer deaths worldwide. Since the number of patients responding well to standard therapies is still limited, further development of new anti-cancer agents with minimum risk of adverse event is urgently awaited. To screen oncoantigens which could be used for the development of new diagnostic biomarkers and molecular targeted drugs, we have established a screening system as follows; i) To identify overexpressed genes in 120 lung cancers by genome-wide screening using the microarray representing 27,648 genes and pure populations of tumor cells taken from cancer tissues by laser microdissection, ii) To verify the genes for their very low or absent expression in normal tissues by northern-blotting, iii) To validate the clinicopathological significance of their expression with tissue microarray covering hundreds of archived lung cancers, iv) To verify whether the target genes are essential for the growth or survival of lung cancer cells by RNAi and cell growth assays. During this process, we selected dozens of druggable oncogenes with various enzymatic activities, and identified overexpression of protein kinase LASK2 (lung cancer-associated kinase 2) in the majority of lung cancers, but not in normal tissues except testis. Immunocytochemical analysis found LASK2 to be mainly localized in the cytoplasm and nucleus of lung cancer cells. Immunohistochemical analysis revealed that strong LASK2 expression was an independent prognostic factor for non-small cell lung cancer (NSCLC) (P&lt;0.0001). Suppression of LASK2 expression with its specific siRNAs caused growth inhibition of lung cancer cells. The enhanced cellular proliferation by introduction of LASK2 in mammalian cells also supported its oncogenic function. Since LASK2 plays a significant role in the cell proliferation and malignant nature of lung cancers, LASK2 is likely to be a prognostic biomarker and a potential therapeutic target for developing new anti-cancer drugs.
Citation Format: Yataro Daigo, Atsushi Takano, Yusuke Nakamura. Identification and characterization of oncogenic kinase LASK2 as a diagnostic and therapeutic target for lung cancer [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 4453. doi:10.1158/1538-7445.AM2017-4453
Abstract 4460: TET1 over expression contributes to lung cancer malignancy
Authors: Filipczak Piotr Teodor , Leng Shuguang , Tellez Carmen S. , Belinsky Steven A. 
Published: July 2017

Abstract
Epigenetic alterations are a leading cause of lung carcinogenesis and malignancy. While the role of enzymes catalyzing cytosine-guanine (CpG) island methylation and chromatin modifications has been extensively studied, the role of the recently discovered demethylating enzymes represented by ten-eleven translocation methylcytosine dioxygenases (TETs) remains unknown. The goal of this study was to investigate the expression and functional significance of the TET1 gene in non-small cell lung cancer (NSCLC). QRT-PCR revealed 2- to 30-fold over expression of TET1 in 52% of squamous cell carcinoma (SCC) and 40% of adenocarcinoma (AdC) tumors compared to paired normal lung tissue. This result was validated using The Cancer Genome Atlas (TCGA) database with TET1 over expressed in 72% of SCCs and 53% of AdCs. Elevated levels of TET1 transcript were associated with increased protein levels in NSCLC cell lines compared to normal human bronchial epithelial cells (HBECs). A reporter assay analysis defined the promoter region critical for elevated transcription of the TET1 gene using lung cancer cell lines, and studies to identify the transcription factors underlying the increase in expression are underway. Transient knock down of TET1 expression in NSCLC cell lines caused global changes in the transcriptome, reduced cell proliferation, colony formation, and inhibited growth of tumor xenografts in nude mice. Cellular senescence mediated by p21 signaling and associated with β-galactosidase activation was identified as one mechanism underlying growth inhibition. This study suggests that TET1 may function as an oncogene contributing to the lung cancer malignant phenotype and thus, could serve as a potential new target for treatment. (Supported by R01 CA183296)
Citation Format: Piotr Teodor Filipczak, Shuguang Leng, Carmen S. Tellez, Steven A. Belinsky. TET1 over expression contributes to lung cancer malignancy [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 4460. doi:10.1158/1538-7445.AM2017-4460
Abstract 4462: ACTN4 stabilises RIPK1 to function as an oncogenic driver in melanoma
Authors: Jin Lei , Tabatabaeehatambakhsh Hessam , Jiang Chen Chen , Yan Xu Guang , Wang Jia Yu , Zhang Yuan Yuan , Yari Hamed , Wang Chun Yan , La Ting , Lei Fu Xi , Feng Yu Chen , Guo Su Tang , Zhang Xu Dong 
Published: July 2017

Abstract
We have recently reported that receptor-interacting protein kinase 1 (RIPK1) is commonly up-regulated through cellular inhibitor apoptosis protein (cIAP)-mediated stabilization and functions as an oncogenic driver via activation of NF-κB in melanoma cells. Here we show that α-actinin-4 (ACTN4), an isoform of α-actinins of spectrin superfamily proteins that is emerging as an oncogenic regulator, is required for cIAP-mediated stabilization of RIPK1 and plays a pro-oncogenic role in melanoma. Similar to RIPK1, ACTN4 was found to be commonly increased in melanoma cells. While knockdown of ACTN4 inhibited melanoma cell proliferation that was associated with down-regulation of RIPK1 and reduction in the basal levels of NF-κB activation, overexpression of ACTN4 resulted in enhanced proliferation of melanocytes that was associated with elevation in RIPK1 expression and increased NF-κB activation. The inhibitory effect of ACTN4 knockdown on melanoma cell proliferation and activation of NF-κB was due to decreased expression of RIPK1, as it was abolished by overexpression of RIPK1. On the other hand, knockdown of RIPK1 diminished ACTN4 overexpression-triggered enhancement in proliferation in melanocytes. Strikingly, knockdown of ACTN4 attenuated the association between cIAPs and RIPK1 and reduced K63-linked ubiquitination of the protein, leading to RIPK1 protein degradation. Mechanistic studies showed that ACTN4 bound to RIPK1 through its N-terminus, whereas it was associated with cIAPs via its C-terminus, and that dimerization of ACTN4 in an anti-parallel manner is required for the interaction between cIAPs and RIPK1. Collectively, ACTN4 is necessary for stabilization of RIPK1 by cIAPs and functions as an oncogenic driver in melanoma.
Citation Format: Lei Jin, Hessam Tabatabaeehatambakhsh, Chen Chen Jiang, Xu Guang Yan, Jia Yu Wang, Yuan Yuan Zhang, Hamed Yari, Chun Yan Wang, Ting La, Fu Xi Lei, Yu Chen Feng, Su Tang Guo, Xu Dong Zhang. ACTN4 stabilises RIPK1 to function as an oncogenic driver in melanoma [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 4462. doi:10.1158/1538-7445.AM2017-4462
Abstract 4467: ETV6 is a tumor suppressor regulated by EGFR-miR-96 pathway in prostate cancer
Authors: Liu Yen-Nien , Tsai Yuan-Chin , Chen Wei-Yu , Siu Man Kit , Yeh Hsiu-Lien 
Published: July 2017

Abstract
ETV6 is an ETS transcription factor and a putative tumor suppressor in prostate cancer according to several genomic analyses. However, its cellular functions and upstream regulating signaling remain unclear. We demonstrated that ETV6 suppresses the prostate cancer progression and that ETV6 levels are negatively associated with advanced prostate cancer, supporting the idea that ETV6 acts as a tumor suppressor. Furthermore, ETV6 can be regulated by epidermal growth factor receptor (EGFR) signaling through microRNA (miR)-mediated downregulation. One of the miRs, miR-96, can be transcriptionally-regulated by nuclear EGFR. The association patterns connecting miR-96, EGFR activation, and ETV6 were further validated in the clinical tissue samples. We proposed an EGFR-miR-96-ETV6 signaling pathway in promoting prostate cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Yen-Nien Liu, Yuan-Chin Tsai, Wei-Yu Chen, Man Kit Siu, Hsiu-Lien Yeh. ETV6 is a tumor suppressor regulated by EGFR-miR-96 pathway in prostate cancer [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 4467. doi:10.1158/1538-7445.AM2017-4467
Abstract 4490: Post-transcriptional regulation on PIAS3 expression in malignant mesothelioma
Authors: He Tian , McColl Karen , Sakre Nneha , Wildey Gary , Dowlati Afshin 
Published: July 2017

Abstract
Protein Inhibitor of Activated STAT3 (PIAS3) was originally identified as an endogenous suppressor of STAT3 activity which can specifically interact with activated STAT3 and block its downstream oncogenic effects. Previous studies from our lab have shown that low PIAS3 protein expression in mesothelioma tumors was associated with poor patient survival. Furthermore, low PIAS3 expression in mesothelioma cell lines correlated with higher STAT3 activity. Over-expression of PIAS3 decreased STAT3 activity and cell growth. These findings suggest that low PIAS3 expression may play an important role in mesothelioma tumorigenesis, thus understanding the regulatory mechanism(s) of PIAS3 expression may provide new therapeutic strategies in mesothelioma treatment. Initially, we examined PIAS3 expression by western blotting and RT-qPCR among six mesothelioma cell lines (H28, 211H, H2052, H2452, HAY, YOU) and found that while PIAS3 mRNA levels were relatively constant, PIAS3 protein expression was highly variable. This finding indicated a potential post-transcriptional regulation of PIAS3 expression in mesothelioma. To investigate this further, we first examined PIAS3 protein stability in the presence of proteasome inhibitors and cycloheximide (CHX). We observed no increase in PIAS3 protein levels during proteasome inhibition using either MG132 (10 μM) or bortezemib (1 μM) for up to 8 h in 211H, H2052 and H2452 cells, whereas TP53 protein expression was increased. Blocking translational protein synthesis with 50 or 100 μg/ml CHX for up to 24 h also produced little change in PIAS3 protein expression in mesothelioma cells, indicating that PIAS3 is a very stable protein. We next explored the PIAS3 3’UTR as a potential site for translational regulation. We initially utilized a miR microarray and computational analysis, followed by a PIAS3 3’UTR luciferase reporter assay, to screen miRNAs that are both increased in cells with low PIAS3 and have seed sequences targeting the PIAS3 3’UTR and identified miR-18a as our first candidate. Taken together, our study suggests that variable expression of PIAS3 protein in mesothelioma is regulated by translational control and not by protein stability.
Citation Format: Tian He, Karen McColl, Nneha Sakre, Gary Wildey, Afshin Dowlati. Post-transcriptional regulation on PIAS3 expression in malignant mesothelioma [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 4490. doi:10.1158/1538-7445.AM2017-4490
Abstract 4498: Targeting IRE1a-XBP1 signaling in lung cancer
Authors: Crowley Michael J. , Yomtoubian Shira , Markowitz Geoffrey , Altorki Nasser K. , Gao Dingcheng , Cubillos-Ruiz Juan , Mittal Vivek 
Published: July 2017

Abstract
Every year 1.5 million people die from lung cancer worldwide. Approximately ~15-30% of non small cell lung cancers (NSCLC) are driven by KRAS mutations and currently possess no viable therapeutic options. As such the discovery of effective therapeutic alternatives for the treatment of KRAS driven NSCLC are sorely needed. One prospect being explored in other solid tumors, but currently unexplored in NSCLC, is targeting the endoplasmic reticulum (ER) stress response. Adverse conditions in tumors such as hypoxia, nutrient starvation and reactive oxygen species disrupt protein folding, and induce ER stress. The most evolutionarily conserved pathway by which this insult is alleviated is the IRE1α-XBP1 axis, which responds by increasing the expression of a broad range of protein folding and quality control genes. Previous work has demonstrated that several cancers utilize this pathway to promote tumorigenesis, progression, epithelial to mesenchymal transition and metastasis. A preliminary analysis of a tissue microarray containing 304 human NSCLC samples, 254 demonstrated at least some positivity and &gt;50% were strongly positive for the active isoform of XBP1. Given these preliminary findings we investigated the status of IRE1a-XB1 in our murine orthotopic model and confirmed the activation of IRE1a-XBP1 signaling in tumor cells in the context of the tumor microenvironment. Furthermore, in both cell types we can see the activation of canonical downstream targets of XBP1. Utilizing the CRISPR-CAS9 system, we knocked out IRE1a in the orthotopic tumor cell line. IRE1a abrogation was confirmed by western blot, evaluating the fraction of active XBP1 after induced ER stress in vitro, and qPCR of canonical downstream targets. Additionally, this knockout did not alter proliferation or morphology in vitro. However, when tumors were grown orthotopically, Cas9-IRE1a knockouts failed to grow past 10 days, whereas Cas9-Scramble controls and the parental tumor line grew comparably until end stage. Given these preliminary findings and data from prior studies, we hypothesize that the abnormal activation of the IRE1α-XBP1 axis may influence KRAS NSCLC progression and aggressiveness and serve as a potential novel avenue for the treatment of NSCLC. After probing the impact of the underlying mechanism on tumor growth we will finally evaluate the translational utility of targeting the ER stress pathway with a small molecule inhibitor against IRE1a.
Citation Format: Michael J. Crowley, Shira Yomtoubian, Geoffrey Markowitz, Nasser K. Altorki, Dingcheng Gao, Juan Cubillos-Ruiz, Vivek Mittal. Targeting IRE1a-XBP1 signaling in lung cancer [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 4498. doi:10.1158/1538-7445.AM2017-4498
Abstract 4519: ATM/ATR-SerRS pathway dominates hypoxic angiogenesis in tumor
Authors: Shi Yi , Liu Ze , Yang Xiang-Lei 
Published: July 2017

Abstract
Hypoxia-induced angiogenesis is a critical response in multicellular organisms to maintain oxygen homeostasis. It is also an important mechanism to support tumor progression. Hypoxia activates hypoxia-inducible factor (HIF) and HIF-independent pathways to transcriptionally induce the expression of pro-angiogenic genes. However, our knowledge on transcriptional repressors of angiogenesis and how they are regulated during hypoxia are limited. Here we report that seryl-tRNA synthetase (SerRS), a newly identified transcriptional repressor of vascular endothelial growth factor (VEGFA), is a major inhibitor of angiogenesis that is inactivated during hypoxia1-4. Inactivation of SerRS is achieved through its phosphorylation at serine 101 and serine 241 by ataxia telangiectasia mutated (ATM) and the related kinase ATR. Knockdown of HIF is not sufficient to completely block hypoxia-induced VEGFA expression in human cells unless a phosphorylation-deficient form of SerRS (SerRSS101A/S241A) is simultaneously expressed to escape ATM/ATR inactivation. Consistently, in mice, SerRSS101A/S241A can bypass hypoxia response despite HIF activation to strongly inhibit angiogenesis in a matrigel assay and a xenograft model of human breast cancer. These findings reveal ATM/ATR-SerRS pathway as a key negative regulator of angiogenesis related to hypoxia and a new target for cancer therapy.
References 1. Fukui, H., Hanaoka, R., and Kawahara, A. (2009). Noncanonical activity of seryl-tRNA synthetase is involved in vascular development. Circ Res 104, 1253-1259. 2. Herzog, W., Muller, K., Huisken, J., and Stainier, D. Y. (2009). Genetic evidence for a noncanonical function of seryl-tRNA synthetase in vascular development. Circ Res 104, 1260-1266. 3. Shi, Y., Xu, X., Zhang, Q., Fu, G., Mo, Z., Wang, G. S., Kishi, S., and Yang, X. L. (2014). tRNA synthetase counteracts c-Myc to develop functional vasculature. Elife 3, e02349. 4. Xu, X., Shi, Y., Zhang, H. M., Swindell, E. C., Marshall, A. G., Guo, M., Kishi, S., and Yang, X. L. (2012). Unique domain appended to vertebrate tRNA synthetase is essential for vascular development. Nat Commun 3, 681.
Citation Format: Yi Shi, Ze Liu, Xiang-Lei Yang. ATM/ATR-SerRS pathway dominates hypoxic angiogenesis in tumor [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 4519. doi:10.1158/1538-7445.AM2017-4519
Abstract 4525: Hypoxia signaling pathway plays a role in ovarian cancer chemoresistance
Authors: Cutter Noelle L. , Walther Tyler , Doyle Kimberly H. , Frank Ryan 
Published: July 2017

Abstract
Hypoxia-inducible factor 1 (HIF-1) is a basic helix-loop-helix transcription factor that when induced regulates the expression of many genes involved in cytoprotective stimuli, which attenuates apoptosis and improves survival.. Increased expression of HIF-1α gene (HIF1A) has been found in several carcinomas, including ovarian cancer. Ovarian cancers are generally refractory to platinum-based chemotherapy. Despite the large number of studies, molecular events that govern the emergence of aggressive therapy-resistant cells after chemotherapy are poorly defined. Genomic instabilities, such as copy number variation(CNV), may play an important role in chemoresistance and have been implicated in many complex diseases, like cancer.. We analyzed CNV data that is publically available through the Cancer Genome Atlas and others. Of particular interest was the transcription factor HIF1A which plays an integral role in oxidative stress response such as those induced by chemotherapy reagents. The present study provides evidence for the rare escape of tumor cells from drug-induced cell death by entering a non-cycling senescent state. We report the adaptive response of human ovarian surface epithelium cells to CoCl2, a chemical hypoxia-mimicking agent resulting in a senescent-like state of chemoresistant cells. The effect of the treatment was evaluated on CNV of HIF-1α gene expression, cell proliferation, survival, and tumor invasiveness. We show here that CNV duplication events of HIF1α results in an oxidative stress response in cells leading to chemoresistance through the induction of cellular senescence. Understanding the molecular events associated with chemoresistance will ultimately lead to better patient treatment and outcomes.
Note: This abstract was not presented at the meeting.
Citation Format: Noelle L. Cutter, Tyler Walther, Kimberly H. Doyle, Ryan Frank. Hypoxia signaling pathway plays a role in ovarian cancer chemoresistance [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 4525. doi:10.1158/1538-7445.AM2017-4525
Abstract 4533: In silico analysis of enhanced radiosensitivity in radiation treatment combined with androgen deprivation therapy for prostate cancer
Authors: Qian Mengdi , Almasan Alexandru , Gürkan-Çavusoglu Evren 
Published: July 2017

Abstract
The purpose of this study is to quantitatively analyze the improved radiosensitivity of prostate cancer cells to ionizing radiation (IR) when radiation treatment is combined with androgen deprivation therapy (ADT). The double strand breaks (DSBs) induced by ionizing radiation are repaired primarily by non-homologous end joining (NHEJ). It is reported in the literature that NHEJ is impaired after ADT, which then results in increased radiosensitivity and better IR treatment outcomes in prostate cancer. In this study, we have used our models for NHEJ repair of DSBs under IR treatment and IR + ADT combination treatment conditions to determine how the combination treatment results in better outcomes. We have modeled the effect of multiple doses of IR that are delivered 24 hours apart to mimic the conventional, fractionated radiation treatment. The analysis results showed that the DSBs accumulate more in the case of combined treatment with ADT compared to faster and more efficient repair when only IR is applied. We have used the experimental data on relative cell numbers and relative sub-G1 cell numbers from the literature to determine the difference in the levels of DSBs that lead to cell death differences between the two treatment strategies. The literature data also shows that there is patient response variability to ADT in terms of the reduction in the levels of Ku70/80, which is the first NHEJ protein complex that is recruited to DSBs. We have modeled this patient variability in our models by introducing variability to Ku70/80 protein concentrations used in the simulations. Our simulation results agree with the observation from clinical data that lower concentration levels of Ku70/80 lead to better radiosensitization. The amount of IR can be adjusted with respect to the level of radiosensitization after ADT on a patient specific level to achieve a desired level of DSBs that will lead to maximum cell death; this dose optimization effort will be the next step in our quantitative analysis.
Citation Format: Mengdi Qian, Alexandru Almasan, Evren Gürkan-Çavusoglu. In silico analysis of enhanced radiosensitivity in radiation treatment combined with androgen deprivation therapy for prostate cancer [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 4533. doi:10.1158/1538-7445.AM2017-4533