bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1067: A paradoxical observation for its upregulation and the prognostic significance about miR-7 in esophageal squamous cell carcinoma
Authors: Masayuki Kano , Matsumoto Yasunori , Hoshino Isamu , Murakami Kentaro , Akutsu Yasunori , Matsubara Hisahiro 
Published: July 2016

Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most malignant cancers of the gastrointestinal tract. However, molecular indicators of the origin of cellular deregulation in ESCC have not been identified. MicroRNAs (miRNAs), noncoding RNAs 21-25 nucleotides in length, regulate gene expression primarily at the posttranscriptional level. Growing evidence suggests that miRNAs are aberrantly expressed in many human cancers, and that they play significant roles in carcinogenesis and cancer progression. A search for miRNAs with a tumor-suppressive function in ESCC was performed using the miRNA expression signatures. miRNA signatures from ESCC identified miRNAs that are downregulated in common, and these miRNAs are candidate tumor suppressors. Gain-of-function analysis revealed that 3 transfectants (miR-145, miR-133a and miR-133b) inhibit cell proliferation and cell invasion. These miRNAs, which have conserved sequences in the 3’UTR of FSCN1, inhibited FSCN1 expression. The signal from a luciferase reporter assay was significantly decreased at 2 miR-145 target sites and 1 miR-133a/b site, suggesting both miRNAs directly regulate FSCN1. An FSCN1 loss-of-function assay found significant cell growth and invasion inhibition, implying an FSCN1 is associated with ESCC carcinogenesis. The identification of tumor-suppressive miRNAs, miR-145, miR-133a and miR-133b, directly control oncogenic FSCN1 gene. These signal pathways of ESCC could provide new insights into potential mechanisms of ESCC carcinogenesis.
On the other hands, miRNAs upregulated in cancer is the candidates of tumor marker. The miRNA expression signatures we perform for ESCC revealed seven upregulated miRNAs in ESCC. In the upregulated miRNAs of miRNA expression signatures, miR-7 downregulation is the independent poor prognostic factor for ESCC patients paradoxically.miR-7 expression is reported upregulated or downregulated variously in the same carcinoma (eg. Gastric adenocarcinoma). The correlation between patients’ prognosis and miR-7 expression has not yet reported in Pubmed research in Dec. 2015. And the target genes of miR-7 is not clarified.
Citation Format: Kano Masayuki, Yasunori Matsumoto, Isamu Hoshino, Kentaro Murakami, Yasunori Akutsu, Hisahiro Matsubara. A paradoxical observation for its upregulation and the prognostic significance about miR-7 in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1067.
Abstract 1086: Elevated level of circulating microRNA-99a correlates with serous epithelial ovarian cancer and can be used as a potential biomarker
Authors: Yoshimura Akihiko 
Published: July 2016

Abstract
[Objective] There is a critical need for improved diagnostic markers for ovarian high grade serous cancer (HGSC). Emerging evidence have shown that microRNAs (miRNAs) stably exist in circulating blood, reflecting tissue or organ conditions and these are present in circulating microvesicles such as exosomes. The purpose of this study was to identify which miRNAs are highly produced from HGSCs and to analyze whether circulating miRNA can discriminate patients with HGSC from healthy volunteers.
[Methods] Secreted exosomes from serous ovarian cancer cell lines were collected and exosomal miRNAs were extracted. miRNA microarray was performed and several elevated miRNAs specific to ovarian cancer cells were picked-up. Among these, we focused on miR-99a in this study. Sera were collected from 9 consecutive patients with HGSC and 5 healthy volunteers. Expression level of miR-99a was determined by miRNA RT-qPCR.
[Results] miRNA microarray revealed several miRNAs were highly expressed in exosomes in patients with HGSC. In patients, serum miR-99a levels were significantly increased (7.2 fold) compared with healthy controls. Receiver operating curve (ROC) analysis for miR-99a showed that at the cut-off of 2.1 times compared with control, the sensitivity and specificity of this marker were 77.8% and 100%, respectively for detecting HGSC (AUC = 0.84). Serum miR-99a levels decreased after surgery by 0.2 fold, indicating that serum miR-99a was originated from ovarian cancer.
[Conclusion] Elevated serum miR-99a were detected in sera of patients with HGSC and reflected the disease condition. This miRNA profiling in serum can be used as a diagnostic biomarker, extending its utility to screening asymptomatic populations.
Citation Format: Akihiko Yoshimura. Elevated level of circulating microRNA-99a correlates with serous epithelial ovarian cancer and can be used as a potential biomarker. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1086.
Abstract 1104: MicroRNA miR-31 regulates oral squamous cell carcinoma cell migration by targeting critical enzyme of peroxisomal lipid metabolism
Authors: Lai Yi-Shiuan , Liu Hsuan , Chen Ting-Wen , Chen Shu-Jen , Chen Hua-Chien , Tan Bertrand Chin-Ming 
Published: July 2016

Abstract
MicroRNAs (miRNAs) are small endogenous non-coding RNAs that play important roles in a variety of cellular processes, such as growth, differentiation and metabolic homeostasis. Dysregulation of microRNA has been linked to the development of various types of human diseases, including cancer. Our previous study has identified that miR-31 is significantly up-regulated in oral squamous cell carcinoma (OSCC) tissues. Further gain- and loss-of-function analyses revealed that miR-31 promotes OSCC by enhancing the migration and invasiveness of OSCC cells but not cell proliferation. However, the exact role of miR-31 in OSCC neoplastic development, especially metastasis, has not been explored. Computational microRNA target prediction and pathway analysis showed an enrichment of putative targets in lipid metabolism pathway. In this study, we aimed to investigate the role of miR-31 in the regulation of lipid metabolism and to establish the relationship between lipid metabolism and tumor pathogenesis in OSCC cells.
First, we demonstrated that ACOX1, the rate-limiting enzyme in peroxisomal β-oxidation, is the direct target of miR-31. We further analyzed publicly available mRNA and miRNA deep sequencing datasets and found that the expression levels of miR-31 inversely correlate with those of ACOX1. Furthermore, we discovered that depletion of miR-31 significantly decreased the intensity of cellular lipid droplets (LDs), and knockdown of ACOX1 conversely showed an increase of LD formation. These data suggested that miR-31 may regulate lipid metabolism by targeting ACOX1. In cultured OSCC cells, the migration capability and invasiveness were significantly increased after knockdown of ACOX1. We further confirmed that ACOX1 depletion enhances ERK1/2 expression and phosphorylation and increases the expression levels of MMP9 in OSCC cells. Collectively, our findings suggest that the elevated expression of miR-31 in OSCC cells directly contributes to the down-regulated expression of ACOX1, subsequently leading to accumulation of lipid metabolites and elevated OSCC migration and invasion through ERK pathway.
Citation Format: Yi-Shiuan Lai, Hsuan Liu, Ting-Wen Chen, Shu-Jen Chen, Hua-Chien Chen, Bertrand Chin-Ming Tan. MicroRNA miR-31 regulates oral squamous cell carcinoma cell migration by targeting critical enzyme of peroxisomal lipid metabolism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1104.
Abstract 1114: Downregulated miR-337-5p is associated with unfavorable features in acute myeloid leukemia and may play a role in modulating the extracellular signal-regulated kinase pathway
Authors: Lie Rosalind , Cheng Chi Keung , Chan Natalie Pui Ha , Ip Rosalina , Chan Nelson , Cheung Joyce , Ng Margaret 
Published: July 2016

Abstract
We previously revealed that a homozygous deletion T polymorphism in the 3’-untranslated region of the Nucleophosmin (NPM1) gene is associated with adverse outcomes and can independently predict survivals in patients with de novo acute myeloid leukemia (AML). This polymorphism creates an illegitimate binding site for miR-337-5p, which is expressed in different AML subtypes. We speculate that the delT-carrying NPM1 mRNA competes with as yet unidentified oncogenes for miR-337-5p binding, thereby activating their functions in trans and perturbing normal microRNA regulation. In this study, we aim to investigate the clinicopathological and biological significance of miR-337-5p expression in AML. Using real-time RT-PCR, we measured miR-337-5p expression in bone marrow of 156 adult patients with de novo AML excluding acute promyelocytic leukemia. Patients were dichotomized into low and high expression group at the median level for clinicopathological correlations. miR-337-5p levels were significantly reduced in the low expression patient group than the normal controls (n = 27) (P&lt;0.001). Low miR-337-5p expression correlated with higher white blood cell counts (P = 0.024), lactate dehydrogenase levels (P = 0.023), bone marrow blast counts (P = 0.001) and FLT3-ITD (P = 0.0092) mutation. Using TargetScan, DIANA, PITA and miRDB, three putative oncogenes involved in the extracellular signal-regulated kinase (ERK) pathway, namely RAP2B, MAPK1 and WNK1, were consistently indicated as the potential targets of miR-337-5p. Overexpression of miR-337-5p in OCI-AML3 cells, which have barely detectable miR-337-5p levels, downregulated the expression of all targets. Concordantly, luciferase reporter assay confirmed that miR-337-5p bound to the 3’-untranslated region of these targets and inhibited translation. The ERK signaling pathway is frequently activated in AML and confers pro-survival functions. We demonstrated that overexpression of miR-337-5p in OCI-AML3 cells significantly inhibited proliferation in both WST-1 and colony-forming assay. Together, our findings suggested that reduced miR-337-5p is associated with unfavorable clinicopathological and molecular features in AML. Restoration of miR-337-5p suppressed cell proliferation, potentially by downregulation of genes implicated in the mitogenic ERK signaling pathway.
Citation Format: Rosalind Lie, Chi Keung Cheng, Natalie Pui Ha Chan, Rosalina Ip, Nelson Chan, Joyce Cheung, Margaret Ng. Downregulated miR-337-5p is associated with unfavorable features in acute myeloid leukemia and may play a role in modulating the extracellular signal-regulated kinase pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1114.
Abstract 1118: The role of Epstein-Barr virus-encoded miRNAs in ATM regulating DNA damage response in nasopharyngeal carcinoma
Authors: LUNG RAYMOND Wai-Ming , Hau Tom Pok-Man , Chak Wing-Po , Tong Joanna Hung-Man , Yu Ken Hung-On , Tsao Sai-Wah , Yip Kevin Yuk-Lap , To Ka-Fai , Lo Kwok-Wai 
Published: July 2016

Abstract
Nasopharyngeal carcinoma (NPC) is an aggressive epithelial malignancy that has remarkably high incidence and mortality rates in Hong Kong and south China. It is well-known to be associated with Epstein-Barr virus (EBV) infection. Previous work in our team revealed that EBV-encoded miRNAs derived from the BARTs (miR-BARTs) were abundantly expressed in primary NPCs. They function in controlling apoptotic and immune responses in the infected cells during NPC development.
Most recently, we attempted to use in silico method to predict cellular targets of miR-BARTs. Results suggested that there were multiple putative miR-BART binding sites on the 3’UTRs of an important DNA double-strand breaks (DSBs) repair gene, Ataxia-Telangiectasia-Mutant (ATM). The down-regulation of ATM mRNA and protein had also been demonstrated in our local primary NPC samples. Although the interaction of miR-BARTs on each suggested putative binding site had not been completely validated, our preliminary data indicated at least three EBV-encoded miRNAs (BART5-5p, BART9-3p and BART14-3p) were involved in repressing ATM expression in NPCs. They could work either alone or cooperatively to control ATM expression in transient assays. Notably, ectopic expression of these three miR-BARTs could successfully suppress γ irradiation-induced ATM activity in two EBV-negative cell lines, NP69 and HeLa.
It had been reported that ATM null cells were defective to repair the DSB lesions and sensitive to the Poly(ADP-ribose) polymerase (PARP) inhibitor treatment in the presence of DNA-damaging agents. In contrast, the DSBs are effectively repaired in normal cells to retain genetic integrity. We believed that EBV infection, via miR-BARTs to reduce ATM activity and disrupt Homologous Recombination (HR) repair function, made the NPC cells sensitize to ionizing radiation and DNA-damaging agent treatment. Hence, the knowledge generated from this project is not only enhance our understanding of EBV biology, but also opens an avenue for the development of effective NPC therapies.
Citation Format: RAYMOND Wai-Ming LUNG, Tom Pok-Man Hau, Wing-Po Chak, Joanna Hung-Man Tong, Ken Hung-On Yu, Sai-Wah Tsao, Kevin Yuk-Lap Yip, Ka-Fai To, Kwok-Wai Lo. The role of Epstein-Barr virus-encoded miRNAs in ATM regulating DNA damage response in nasopharyngeal carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1118.
Abstract 1129: EGFR-mediated activation of RET in ASCL1+ lung adenocarcinoma
Authors: Bhinge Kaustubh N. , Lin Yang , Rahi Hamed , Aubry Marie Christine , Mansfield Aaron , Kovtun Irina , Murphy Stephen , Yang Ping , Wigle Dennis , Yi Joanne (Eunhee) , Nasir Aqsa , Terra Simone , Molina Julian , Vasmatzis George , Kosari Farhad 
Published: July 2016

Abstract
Lung cancer accounts for about 27% of the cancer related deaths in the USA annually. Pathologically, it is a very complex disease broadly classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLCs are further classified into squamous cell carcinoma, large cell carcinoma and adenocarcinoma. Achaete-scute homolog 1 (ASCL1), an important transcription factor essential in the development of neuroendocrine cells (NE) in lungs is shown to be specifically expressed in lung NE cancers and 10-20% of adenocarcinomas (AD) with NE differentiation (NED), thus suggesting a role in the pathogenesis of these tumors. Our previous study showed that ASCL1 is a regulator of the RET oncogene in AD with NED. RET is a receptor tyrosine kinase with two isoforms in humans: RET9 (short) and RET51 (long). We performed survival analysis to study implications of RET isoforms in ASCL1+ tumors and found that elevated expression of the long RET mRNA was associated with poor survival. Subsequent in vitro experiments demonstrated that treatment with EGF robustly induced phosphorylation of RET in HCC1833 and H1755 cell lines which have high endogenous levels of ASCL1 and RET but not in VMRC-LCD cell line which has high level of ASCL1 but low level of RET. EGF induced phosphorylation of RET was diminished by gefitinib and by EGFR siRNA. Immunoprecipitation results indicated direct binding between EGFR and RET in presence of EGF. Furthermore, a high throughput drug screening found 8 EGFR inhibitors that were 10 - 250 fold more cytotoxic in ASCL1+ compared with ASCL1- AD cells. These results implicate EGFR as a key regulator of RET activation in ASCL1+ AD and suggest that EGFR inhibitors may be therapeutic for this population of patients.
Citation Format: Kaustubh N. Bhinge, Yang Lin, Hamed Rahi, Marie Christine Aubry, Aaron Mansfield, Irina Kovtun, Stephen Murphy, Ping Yang, Dennis Wigle, Joanne (Eunhee) Yi, Aqsa Nasir, Simone Terra, Julian Molina, George Vasmatzis, Farhad Kosari. EGFR-mediated activation of RET in ASCL1+ lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1129.
Abstract 1135: FYN expression potentiates FLT3-ITD-induced mitogenic signaling in acute myeloid leukemia
Authors: Chougule Rohit A. , Kazi Julhash U. , Rönnstrand Lars 
Published: July 2016

Abstract
FYN is a non-receptor tyrosine kinase belonging to the SRC family of kinases. SRC family kinases are frequently over-expressed in human cancers, and play key roles in cancer cell invasion, metastasis, proliferation, survival and many other biological processes. SRC has long been recognized as an important oncogene; but little attention has been given to its other family members such as FYN. In this report, we have studied the role of FYN in FLT3 signaling with respect to acute myeloid leukemia (AML). FLT3 is a type III receptor tyrosine kinase which is found to be mutated in around 30% of AML cases. We observed that FYN displays a strong association with wild-type FLT3 as well as oncogenic FLT3-ITD. While association with wild-type FLT3 is dependent on ligand stimulation, it is constitutively associated with FLT3-ITD. In addition, a kinase-dead FLT3 mutant was unable to associate with FYN suggesting that FLT3 activation is required for association with FYN. A FYN SH2-domain mutant lacking a critical arginine residue was unable to associate with FLT3 indicating that FYN associates with FLT3 through its SH2 domain. A phopho-peptide fishing experiment identified multiple FYN binding sites in FLT3, which partially overlap with the known SRC binding sites but also differ from these sites. To understand the role of FYN in FLT3 signaling, we have generated Ba/F3-FLT3/FYN or Ba/F3-FLT3/empty vector cell lines. We observed that expression of FYN results in enhanced phosphorylation of AKT, ERK1/2 and p38 phosphorylation in response to ligand stimulation. Ba/F3-FLT3-ITD cells overexpressing FYN also showed higher STAT5 activation. Furthermore, FYN expression led to a significant increase in FLT3-ITD-dependent cell proliferation but did not alter apoptosis induced by cytokine starvation. Finally, we showed that FYN expression was deregulated in AML patient samples and that higher expression of FYN in combination with FLT3-ITD expression correlates with poor prognosis in AML. Taken together our data suggest that FYN cooperates with oncogenic FLT3-ITD which results in poor prognosis in AML and therefore inhibition of FYN in combination with FLT3 inhibition will most likely be beneficial for AML patients.
Citation Format: Rohit A. Chougule, Julhash U. Kazi, Lars Rönnstrand. FYN expression potentiates FLT3-ITD-induced mitogenic signaling in acute myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1135.
Abstract 1155: Inhibitory effect of CYP1B1 on antitumor activities induced by dysregulated CDC20 and DAPK1 in renal cell carcinoma
Authors: Mitsui Yozo , Chang Inik , Fukuhar Shinichiro , Hirata Hiroshi , Wong Ryan Kenji , Yamamura Soichiro , Shahryari Varahram , Deng Guoren , Sharanjot Saini , Majid Shahana , Shiina Hiroaki , Dahiya Rajvir , Tanaka Yuichiro 
Published: July 2016

Abstract
Introduction and Objective: Cytochrome P450 1B1 (CYP1B1) has been shown to be up-regulated in many types of cancer including renal cell carcinoma (RCC). Several reports have shown that CYP1B1 can influence the regulation of tumor development; however, its role in RCC has not been well investigated. The aim of the present study was to determine the functional effects of CYP1B1 gene on tumorigenesis in RCC. Methods: Expression of CYP1B1 was determined in RCC cell lines, and tissue microarrays of 96 RCC and 25 normal tissues. To determine the biological significance of CYP1B1 in RCC progression, we silenced the gene in Caki-1 and 769-P cells by RNA interference and performed various functional analyses.
Results: First, we confirmed that CYP1B1 protein expression was significantly higher in RCC cell lines compared to normal kidney tissue. This trend was also observed in RCC samples (p&lt;0.01). Interestingly, CYP1B1 expression was associated with tumor grade and stage. Next, we silenced the gene in Caki-1 and 769-P cells by RNA interference and performed various functional analyses to determine the biological significance of CYP1B1 in RCC progression. Inhibition of CYP1B1 expression resulted in decreased cell proliferation, migration and invasion of RCC cells. In addition, reduction of CYP1B1 induced cellular apoptosis in Caki-1. We also found that these anti-tumor effects on RCC cells caused by CYP1B1 depletion may be due to alteration of CDC20 and DAPK1 expression based on gene microarray and confirmed by real-time PCR. Interestingly, CYP1B1 expression was associated with CDC20 and DAPK1 expression in clinical samples.
Conclusions: CYP1B1 may promote RCC development by inducing CDC20 expression and inhibiting apoptosis through the down-regulation of DAPK1. Our results demonstrate that CYP1B1 can be a potential tumor biomarker and a target for anticancer therapy in RCC.
Citation Format: Yozo Mitsui, Inik Chang, Shinichiro Fukuhar, Hiroshi Hirata, Ryan Kenji Wong, Soichiro Yamamura, Varahram Shahryari, Guoren Deng, Saini Sharanjot, Shahana Majid, Hiroaki Shiina, Rajvir Dahiya, Yuichiro Tanaka. Inhibitory effect of CYP1B1 on antitumor activities induced by dysregulated CDC20 and DAPK1 in renal cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1155.