bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 331: SIRPB1 promotes prostate cancer cell proliferation & migration
Authors: Song Qiong , Qin Siyuan , Zou Chunlin , Wang Wenchu , Wang Lihui , Tong Haibo , Catalona William J. , Zhang Jian , Lu Yi , Wang Zhou 
Published: July 2017

Abstract
Signal-regulatory-protein beta 1(SIRPB1) is a member of the signal-regulatory-protein (SIRP) family that belongs to the immunoglobulin superfamily and is capable of modulating receptor tyrosine kinase-coupled signaling. The copy-number variations (CNV) at the SIRPB1 locus were associated with aggressiveness of prostate cancer in patients. To test if SIRPB1 could affect prostate cancer development and progression, we investigated the potential role and mechanisms of SIRPB1 action in prostate cancer cell lines in vitro and in xenograft tumors. Knockdown of SIRPRB1 by RNA interference resulted in significant suppression of cell colony formation, cell mobility, cell migration, and invasion. The knockdown also induced cell cycle arrest during the G0/G1 phase and a remarkable enhancement of apoptosis in PC3 prostate cancer cells. In contrast, overexpression of SIPRB1 significantly induced cell migration, invasion, colony formation and cell cycle in C4-2 prostate cancer cells. Furthermore, overexpression of SIRPB1 in C4-2 cell model enhanced its tumor take rate in nude mice. Also, SIRPB1 mRNA expression was increased in up to 39% of the prostate cancer specimens based on in silico analysis of several public databases. These results suggest that SIRPB1 is a potential oncogene in the prostate and could be used as a biomarker to identify patients at risk of developing aggressive prostate cancer.
Citation Format: Qiong Song, Siyuan Qin, Chunlin Zou, Wenchu Wang, Lihui Wang, Haibo Tong, William J. Catalona, Jian Zhang, Yi Lu, Zhou Wang. SIRPB1 promotes prostate cancer cell proliferation & migration [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 331. doi:10.1158/1538-7445.AM2017-331
Abstract 3314: Synergistic effects of chemotherapy-induced autophagy and epigenetic remodeling
Authors: Tyutyunyk Liliya , Landry Joseph , Saleh Tareq , Gewirtz David 
Published: July 2017

Abstract
Cytotoxic chemotherapy has been shown to enhance tumor cell immunogenicity by promoting the secretion of damage-associated molecular pattern (DAMP) molecules which, in turn, stimulates the immune response. These effects can be further stimulated by combining chemotherapy with an immunotherapy designed to enhance effector cell (CD8 T cell or NK cell) anti-tumor activity. Our studies demonstrate that knockdown of the epigenetic regulator NURF increases DNA damage (gamma H2AX staining) and autophagy (acridine orange staining) in breast tumor cells exposed to doxorubicin and enhances growth inhibition as well as suppressing the capacity of the cells to recover and proliferate. Similar increases in autophagy were observed using a small molecule inhibitor of NURF, suggesting that NURF can be targeted therapeutically. Sensitization was not observed with ionizing radiation or cisplatin. Studies are in progress to assess the nature of autophagy in the NURF KD and NURF WT cells, distinguishing between the cytoprotective, cytotoxic, cytostatic and nonprotective forms. How NURF regulates doxorubicin induced DNA damage is being investigated by mapping sites of damage genome wide. It is anticipated that enhanced cell autonomous tumor cell sensitivity in concert with improvements in tumor cell antigenicity (cell non-autonomous sensitization) achieved by NURF depletion could improve anti-tumor immunogenicity, achieve tumor regression, reduce metastasis, and possibly achieve long term remission in breast cancer.
Citation Format: Liliya Tyutyunyk, Joseph Landry, Tareq Saleh, David Gewirtz. Synergistic effects of chemotherapy-induced autophagy and epigenetic remodeling [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 3314. doi:10.1158/1538-7445.AM2017-3314
Abstract 3339: Muscarinic acetylcholine receptor subtype 3 regulates gastric stem cell expansion and gastric cancer progression by controlling YAP activation
Authors: Hayakawa Yoku , Konishi Mitsuru , Sakitani Kosuke , Koike Kazuhiko , Wang Timothy 
Published: July 2017

Abstract
Within the gastrointestine, nerves help to regulate both normal and neoplastic stem cell dynamics. Several previous studies suggested that cholinergic nerve signaling plays an important role in gastrointestinal cancer development, but the exact underlying mechanism has not been clarified. In this study, we examined the role of muscarinic acetylcholine receptor subtype 3 (M3R) in gastric homeostasis and cancer development by using mouse models and human cancer cell lines. In situ hybridization revealed M3R expression in gastric stem cell zone, and its expression was markedly upregulated in gastric cancer cells. We knocked out M3R in Lgr5+ gastric stem cells in Lgr5-CreERT; M3Rflox/flox mice, and found that deletion of M3R inhibited clonal expansion of Lgr5+ cells in regenerative states. In a gastric tumor model of Mist1-CreERT; Apcflox/flox mice, knockout of M3R dramatically suppressed tumor growth. RNA sequencing analysis of these tumors revealed that several important pathways were significantly inhibited in M3R knockout samples, including YAP/TAZ pathway. We established M3R-expressing gastric cancer cell lines, and western blotting, luciferase assay, and RT-PCR analysis confirmed that acetylcholine (ACh) agonist activates YAP pathway through M3R. YAP is upregulated in approximately half of gastric cancer patients, and its expression is significantly associated with disease stage and histological form. This M3R-YAP axis activates the gastric stem cell niche and offers a compelling target for tumor treatment and prevention.
Note: This abstract was not presented at the meeting.
Citation Format: Yoku Hayakawa, Mitsuru Konishi, Kosuke Sakitani, Kazuhiko Koike, Timothy Wang. Muscarinic acetylcholine receptor subtype 3 regulates gastric stem cell expansion and gastric cancer progression by controlling YAP activation [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 3339. doi:10.1158/1538-7445.AM2017-3339
Abstract 3350: Cell-free DNA fragmentation patterns analyzed in over 15000 cancer patients reveal changes associated with tumor somatic mutations and result in improved sensitivity and specificity of somatic variant detection
Authors: Abdueva Diana , Eltoukhy Helmy , Chudova Darya , Talasaz AmirAli 
Published: July 2017

Abstract
Background: Cell-free DNA (cfDNA) isolated from plasma consists of DNA fragments surviving clearance of dying cells and bloodstream trafficking. In cancer, these fragments carry the footprint of tumor somatic variation as well as its microenvironment. Since genomic distribution of cell free DNA fragments was shown to reflect nucleosomal occupancy in hematopoietic cells, we hypothesized that (a) heterogeneous patterns of cfDNA positioning would be associated with distinct mutations in patient tumors and (b) integration of fragmentation patterns into analysis would allow increased sensitivity and specificity of somatic mutation detection.
Methods: cfDNA fragment length and position distributions as well as associated somatic genomic profiles of over 15,000 patients with advanced-stage clinical cancer were determined by a highly accurate, deep-coverage (15,000x) ctDNA NGS test targeting 70 genes (Guardant360). An integrative data analysis of variant-free fragmentomics domain across different driver mutations was performed to identify patterns associated with detected somatic alterations.
Results: We discovered distinct classes of fragmentomics subtypes significantly enriched in samples with different genomic subtypes. An independent cohort of samples with known HER2 immunohistochemistry status was interrogated to confirm discovered association between fragmentation patterns and HER2 status. Integrating fragmentomics amplification signature with ERBB2 copy number analysis has resulted in 42% increase in the sensitivity and 7% increase in specificity of detection. Observed lung adenocarcinoma fragmentomics subtypes co-occured with mutually exclusive genomic alterations and previously described intrinsic molecular subtypes of lung cancer.
Conclusions: Fragmentomics classification of cancer cfDNA provides independent evidence for observed somatic variation and underlying tumor microenviroment, leading to higher sensitivity and accuracy of variant detection.
Citation Format: Diana Abdueva, Helmy Eltoukhy, Darya Chudova, AmirAli Talasaz. Cell-free DNA fragmentation patterns analyzed in over 15000 cancer patients reveal changes associated with tumor somatic mutations and result in improved sensitivity and specificity of somatic variant detection [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 3350. doi:10.1158/1538-7445.AM2017-3350
Abstract 3386: Brazilian melanoma genome project: mutational landscape based on whole-genome sequencing
Authors: Vazquez Vinicius L. , Evangelista Adriane , Silveira Henrique C. , Crovador Camila , Carvalho Andre L. , Scapulatempo-Neto Cristovam , Lee Jin , Landman Gilles , Kitagima Joao P. , Reis Rui M. 
Published: July 2017

Abstract
Melanoma is the most aggressive form of skin cancer with increasing prevalence in Brazil. The comprehensive molecular profiling of these tumors and the recent genomic classification has improved the knowledge of melanoma biology and foster the identification of potential clinical biomarkers. The aim of this project, as part of the International Cancer Genome Consortium (ICGC) is to perform a genomic profile by whole genome sequencing (WGS) of Brazilian melanomas patients. We reported the WGS using Illumina paired-end sequencing strategy (&gt;30 X-fold coverage) of 66 cases (45% primary and 55% metastatic) and respective matched normal. Overall we observed an average of 46K mutations/genome. The most frequent type of substitutions identified were: C&gt;T (22.5%), T&gt;C (6.4%), T&gt;G (4.4%), T&gt;A (2.9%), C&gt;A (2.8%) and C&gt;G (1.7%). A significative difference between frequency of C&gt;T substitutions was observed among histological subtypes, i.e., acral lentiginous (11.3%), nodular (31.2%) and superficial spreading (25.9%). Among the classic genes involved in melanoma biology, we found that 31.8% of patients had BRAF mutations, being the V600E the most frequent (82.6%). A total of 6.1% of patients had NRAS, 3.0% showed KRAS, one case (1.5%) showed HRAS, and 12.1% showed NF1 mutations. TERT promoter mutation (C250T) was found in 28.8% of patients. TP53 mutations found 4.5% and RB1 in 1.5% of cases. Oncogenic KIT and PDGFRA mutations were observed in 6.1%and 1.5%, respectively. BRAF, NRAS, HRAS, KRAS and NF1 mutation were mutually exclusive. BRAF and TERT mutations were significantly more frequent in superficial than acral lentiginous melanomas. We showed that Brazilian melanoma patients exhibit a high number of single mutations and a similar mutation profile to the one reported in other populations. Acral/lentiginous melanoma subtype, which is a common subtype in our setting, showed a distinct mutation frequency. Further analysis will extend to other relevant genes and will also include the study of additional genomes to reach the goal of genomic landscape of 100 Brazilian melanomas cases.
Citation Format: Vinicius L. Vazquez, Adriane Evangelista, Henrique C. Silveira, Camila Crovador, Andre L. Carvalho, Cristovam Scapulatempo-Neto, Jin Lee, Gilles Landman, Joao P. Kitagima, Rui M. Reis. Brazilian melanoma genome project: mutational landscape based on whole-genome sequencing [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 3386. doi:10.1158/1538-7445.AM2017-3386
Abstract 3397: Post-mortem examination of an aggressive case of medullary thyroid cancer characterised by catastrophic genomic abnormalities
Authors: O'Connor Darran P. , Das Sudipto , Kelly Deirdre , Moran Bruce , Han Kathleen , Mulligan Niall , Barrett Ciara , Buckley Patrick , McMahon Peter , McCaffrey J , Essen Henrik van , Connor Kate , Ylstra Bauke , Lambrechts Diether , Gallagher William M. , Kelly Catherine M. 
Published: July 2017

Abstract
Catastrophic genomic alterations may drive aggressive cancer phenotypes. We describe a diagnostically challenging and rapidly fatal case of medullary thyroid carcinoma (MTC) occurring in a young, morbidly obese man presenting with diffuse bone marrow involvement and disseminated intravascular coagulation. Whole-exome (WES) and shallow whole-genome sequencing (sWGS) were carried out for the primary tumour, adjacent normal, bone marrow tissues, multiple metastases and blood samples derived from the patient. We identified three germline single nucleotide polymorphisms (SNPs) within the RET proto-oncogene that remained undetected using routine hospital genetic testing procedures. One variant (L769L) has been previously reported to be associated with aggressive MTC presentation yet remains untested for in the routine diagnosis of MTC. Supported by findings from both WES and sWGS, we report for the first time in thyroid cancer on the occurrence of a “chromothripsis-like pattern”, which involved shattering of chromosome 4 leading to complete abrogation of normal chromosomal function, along with dramatic widespread copy number aberrations across both primary tumour and bone marrow samples. Based on the somatic variants identified, we describe the evolutionary pathway of the case, showing that bone marrow metastasis occurred separately to other metastatic sites. The presence of disease-associated SNPs within the RET proto-oncogene supports their inclusion as part of routine genetic testing for MTC cases. The copy number aberrations and chromothripsis-like pattern affected a much broader range of genes than single mutations and may have led to the widespread chromosomal instability evident, possibly contributing to the rapid fatal course of the case. These results provide a rationale for the application of comprehensive genomic analysis of cancers presenting with unusual and aggressive phenotypes to facilitate more appropriate therapeutic options and diagnoses.
Citation Format: Darran P. O'Connor, Sudipto Das, Deirdre Kelly, Bruce Moran, Kathleen Han, Niall Mulligan, Ciara Barrett, Patrick Buckley, Peter McMahon, J McCaffrey, Henrik van Essen, Kate Connor, Bauke Ylstra, Diether Lambrechts, William M. Gallagher, Catherine M. Kelly. Post-mortem examination of an aggressive case of medullary thyroid cancer characterised by catastrophic genomic abnormalities [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 3397. doi:10.1158/1538-7445.AM2017-3397
Abstract 3434: Loss of regulation of β-Catenin expression by miR-214 and oncogenic role of miR-214 in metastatic melanoma cells
Authors: Prabhakar Kirthana , Jayanthy Ashika , Setaluri Vijay 
Published: July 2017

Abstract
Dysregulation of β-catenin facilitates melanoma metastasis by activating the transcription of oncogenes like Myc, CyclinD1 and TCF-1. It is important to understand the regulation of β-catenin to develop strategies to target Wnt signaling for melanoma treatment. MicroRNAs are small non-coding RNAs that are primarily involved in post-transcriptional regulation of target genes. Hence, miRNAs can be used to manipulate protein levels by causing instability of the transcript or by inhibiting translation. MiR-214 has been documented as regulator of β-catenin in cancer cells other than melanoma cells. The role of miR-214 in regulation of β-catenin has not been investigated. In this study, we investigated regulation of β-catenin by miR-214 in melanoma cell lines and studied the effect of overexpression miR-214 on the malignant phenotype of metastatic melanoma cells and their sensitivity to MAP kinase inhibitors. Our data show that β-catenin is upregulated in a panel of metastatic melanoma cells and the expression levels of β-catenin is negatively correlated with endogenous expression of miR-214. However, overexpression of miR-214 by transfection with a miRNA mimic did not show significant decrease in β-catenin mRNA or protein expression. RNA-Seq showed that multiple isoforms of β-catenin transcript are present in melanoma where the binding site is absent or mutated. The alternatively spliced transcript with no binding site for miR-214 is seen to be more abundant than the other isoforms. Paradoxically, overexpression of miR-214 increased survival, proliferation and migration of metastatic melanoma. In addition, miR-214 overexpression decreased their sensitivity to vemurafenib and selumetinib. In melanoma cells with acquired resistance (in vitro), miR-214 overexpression further enhanced their resistance to MEK inhibitor, but not vemurafenib. In light of the published studies that proposed that miR-214 acts as tumor suppressor by negatively regulating β-catenin, our study is interesting since we find that in metastatic melanoma miR-214 has oncogenic role. Ongoing studies are aimed at understanding the mechanisms by which miR-214 promotes malignant behavior of melanoma cells.
Citation Format: Kirthana Prabhakar, Ashika Jayanthy, Vijay Setaluri. Loss of regulation of β-Catenin expression by miR-214 and oncogenic role of miR-214 in metastatic melanoma cells [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 3434. doi:10.1158/1538-7445.AM2017-3434
Abstract 3437: Targeting microRNA-143 in glioblastoma in vivo increases tumor growth
Authors: Lozada-Delgado Eunice , Valiyeva Fatma , Marcos Maria , Vivas Pablo 
Published: July 2017

Abstract
The purpose of this study is to assess the biological role of the microRNA-143 (miR-143) in Glioblastoma multiforme (GBM). GBM is the most common and lethal of all brain tumors. In the United States, the incidence of GBM is about 17% of all primary brain tumors and about 60-75% of all Astrocytomas (American Brain Tumor Association, 2014). The standard therapy is surgical tumor removal followed by chemotherapy and radiotherapy. However, many patients recur after treatment and the median survival rate for GBM has remained 15 months for the past 20 years. Thus, novel therapies for GBM treatment are urgently necessary. MicroRNAs (miRNAs) are a class of small non-coding RNAs (18-22 nucleotides in length) that regulate gene expression at the post-transcriptional level. MiRNAs bind to the 3’-untranslate region (UTR) of messenger RNAs (mRNAs) and regulate protein synthesis. Several deregulated miRNAs have been identified in all cancer types including GBM. In this study we aim to thoroughly uncover the role of miR-143 by using GBM cell lines, mouse models and patient samples. Total RNA was isolated from FFPE samples from brain tumor patients. TaqMan-based Real-time PCR showed that the relative expression of miR-143 was higher in GBM patients compared to control individuals, and with paired surrounding non-cancerous tissue. Furthermore, GBM cells transiently transfected with a miR-143 oligonucleotide inhibitor showed reduced cell proliferation (68.5%) (clonogenicity assay), increased apoptosis and cell cycle arrest of GBM cells in the S phase (Flow cytometry and Western blots). In vivo studies using primary GBM cells injected in the flank of nude mice showed that repeated doses of miR-143-inhibitor liposomal formulation increased the tumor size compared with control mice. These contradictory results could be due to effects of the microenvironment where the tumor is growing. Further studies will be made using intracranial injections in an orthotopic xenograft mouse model to confirm this hypothesis. Western blot analysis and luciferase reporter assays are also underway to identify novel miR-143 target genes in GBM cells. This research project is being supported by: PRCTRC: NCRR (U54 RR 026139-01A1), NIMHD (8U54 MD 007587-03), and RCMI: MBRS-RISE, NCRR (2G12-RR003051) and NIMHD (8G12-MD007600) from the NIH.
Citation Format: Eunice Lozada-Delgado, Fatma Valiyeva, Maria Marcos, Pablo Vivas. Targeting microRNA-143 in glioblastoma in vivo increases tumor growth [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 3437. doi:10.1158/1538-7445.AM2017-3437
Abstract 3439: MicroRNA-34a epigenetically silences epithelial-mesenchymal transitions (EMT)-TFs in metastatic breast cancer cells
Authors: Imani Saber , Wei Chunli , Cheng Jingliang , Fu Junjiang 
Published: July 2017

Abstract
MicroRNA-34a (miR-34a) as key regulator of tumor suppression gene potentially plays a profound role in the tumorigenesis and progression of several cancers including breast cancer. In the present study, we invstigated the expression, targets and functional effects of miR-34a and its correlation with tumour characteristics and clinical outcome in the epithelial to mesenchymal transitions (EMT) stage of metastatic breast cancer (MBC). We focused to analyze EMT-inducing transcription factors (EMT-TFs)/miR-34a feedback loop, like TWIST1, SLUG, ZEB1/2, NOTCH1, on promotes MBC migration, invasion and metastasis. We found that miR-34a potently inhibits NOTCH1, ZEB1 protein expression activity in breast cancer cells. Importantly, the miR-34a do not have any inhibitory effects upon the SLUG and ZEB2. Using quantitative reverse transcription-PCR and western blot analysis, we showed that average pre-miR-34a expression is down regulated in human metastatic breast tissues as compared to normal human breast and negatively correlates with clinicopathological features of MBC patients. Ectopic expression of miR-34a in metastatic breast cancer cell-line BT-549 significantly inhibited cell proliferation, migrations, survival and cell invasion, but no clear effect on cancer cell growth. We provide indication that these regulatory pathways may stabilize epithelial and mesenchymal states, individually. We have consequently revealed that miR-34a is downregulated in MBC tissues and that it suppresses tumor growth by affecting several malignancy endpoints via downregulation of multiple EMT-TFs. Mutational or epigenetic inactivation of the EMT-TFs/miR-34a pathway probably alterations the equilibrium of these regulations toward EMT and the mesenchymal state and thereby contributes to metastasis. The results also suggest that miR-34a could serve as a potential therapeutic agent for MBC. Funding support: This work was supported by the NSFC (81172049, 81672887), Corresponding author email:fujunjiang@hotmail.com;fujunjiang@swmu.edu.cn
Citation Format: Saber Imani, Chunli Wei, Jingliang Cheng, Junjiang Fu. MicroRNA-34a epigenetically silences epithelial-mesenchymal transitions (EMT)-TFs in metastatic breast cancer cells [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 3439. doi:10.1158/1538-7445.AM2017-3439