bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3072: Characterization of TCL1-Tg:p53-/- mice that resemble human chronic lymphocytic leukemia with 17p-deletion: alterations in p53→Mir30→EZH2 axis.
Authors: Liu Jinyun , Ogasawara Marcia A. , Chen Gang , Pelicano Helene , Huang Peng 
Published: August 2014

Abstract
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States and Europe. CLL patients with deletion of chromosome 17p, where the tumor suppressor p53 gene is located, often develop a more aggressive disease with poor clinical outcomes. However, the underlying mechanism remains unclear. We have recently generated mice with Eμ-Tcl1-Tg:p53-/- genotype and showed that these mice develop aggressive leukemia that resembles human CLL with 17p deletion. In the present study, we further demonstrated that the p53 deficiency in the Tcl1 transgenic mice resulted in significant down-regulation of microRNAs miR-15a and miR16-1, associated with a substantial up-regulation of Mcl-1, suggesting that the p53-miR15a/16-Mcl-1 axis may play an important role in CLL pathogenesis. Interestingly, we also found that loss of p53 resulted in a significant decrease in expression of the miR-30 family in leukemia lymphocytes from the Eμ-Tcl1-Tg:p53-/- mice. Consistently, primary leukemia cells from CLL patients with 17p deletion also showed a decrease in the miR-30d expression. To further exam the biological significance of decrease in the miR-30 family in CLL, we investigated the potential involvement of EZH2 (enhancer of zeste homolog 2), a component of the Polycomb repressive complex known to be a downstream target of miR-30d and plays a role in disease progression in several solid cancers. RT-PCR and western blot analyses showed that both EZH2 mRNA transcript and protein levels were significantly increased in the lymphocytes of Eμ-Tcl1-Tg:p53-/- mice relative to Eμ-Tcl1-Tg:p53+/+ mice. Exposure of leukemia cells isolated from Eμ-Tcl1-Tg:p53-/- mice to the EZH2 inhibitor 3-deazaneplanocin (DZNep) led to induction of apoptosis, suggesting EZH2 may play a role in promoting CLL cell survival and this may contribute to the aggressive phenotype of CLL with loss of p53. Our study reveals that the p53-miR30-EZH2 axis may play an important role in CLL pathogenesis, and EZH2 may potentially be a target for CLL treatment.
Citation Format: Jinyun Liu, Marcia A. Ogasawara, Gang Chen, Helene Pelicano, Peng Huang. Characterization of TCL1-Tg:p53-/- mice that resemble human chronic lymphocytic leukemia with 17p-deletion: alterations in p53→Mir30→EZH2 axis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3072. doi:10.1158/1538-7445.AM2013-3072
Abstract 308: δ-Catenin/NPRAP/Neurojungin mutation promotes prostate tumorigenesis in mice overexpressing Myc oncogene .
Authors: Nopparat Jongdee , Zhang Jiao , Chen Yan-Hua , Lu Qun 
Published: August 2014

Abstract
Prostate cancer is the most common non-cutaneous malignant neoplasm in men in Western countries. In humans, prostate cancer progresses from precursor lesions, termed prostatic intraepithelial neoplasia (PIN), to overt carcinoma confined to the prostate, and finally to metastatic disease that often results in lethality. Previous studies in our laboratory have shown that δ-catenin/NPRAP/Neurojungin (gene designation: CTNND2), a primarily neural-enriched protein in the brain of healthy individuals, is overexpressed corresponding to human prostate cancer progression. This finding has led us to investigate the roles of δ-catenin in prostate cancer progression. We utilized a novel transgenic model of mouse prostate cancer with overexpression of human Myc oncogene driven by rat-probasin promoter as the initiating event, which has been proven to mimic human disease conditions. These Myc overexpressing mice were further crossbred with δ-catenin mutant (δ-cat−/−) mice whose exon 9 of δ-catenin gene was disrupted. In this study, we examined the histological differences of mouse prostate in wild type and Myc overexpression with δ-catenin mutant mice (Myc/δ-cat−/−). We observed that morphological alterations characteristic of high grade PIN developed in luminal epithelial cells of transgenic mice by 6 weeks. These changes include an increase of nuclear size, multi-layering, and cribriform formation. Surprisingly, Myc/δ-cat−/- mice at 6 months of age displayed the dramatically increased tumor size and progression from PIN to adenocarcinomas. We also discovered that Myc/δ-cat−/- mice increased in both number of proliferating cells and cells undergoing apoptosis compared with that of wild type animals. However, in Myc/δ-cat−/- mice, proliferative index was greater than apoptotic index by 3.7 fold. Collectively, our findings suggest that mutation of δ-catenin may contribute to tumorigenesis of mouse prostate by enhancing the effects of Myc oncogene resulting in an increase of cell proliferation and thereby promoting prostate tumor growth. Supported by NIHCA111891 and NIHCA165202.
Citation Format: Jongdee Nopparat, Jiao Zhang, Yan-Hua Chen, Qun Lu. δ-Catenin/NPRAP/Neurojungin mutation promotes prostate tumorigenesis in mice overexpressing Myc oncogene . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 308. doi:10.1158/1538-7445.AM2013-308
Abstract 3080: DBP-RB, a novel RNA-binding protein promotes microRNA processing in the DNA damage response.
Authors: Han Cecil , Lu Xiongbin 
Published: August 2014

Abstract
Defects in the DNA damage response (DDR) and global dysregulation of microRNA (miRNAs) are considered hallmarks of many types of human cancer. Recent studies show that DNA damage such as irradiation, UV and genotoxic agents induce global changes in miRNA expression profile in a variety of cell types. DDR-regulated miRNAs are known to be involved in the initiation and progression of tumorigenesis and also modulate the sensitivity of cells to DNA damaging agents. However, mechanism about how miRNA expression is regulated in response to DNA damage stress is largely unknown. DBP-RB, one of RNA binding protein is known to be overexpressed or amplified in several types of human cancer including neuroblastoma, breast and colon cancer and the biological function of DBP-RB in the cancer is not determined yet. Here, we found that that DBP-RB is interacted with not only Drosha/DGCR8 but also Dicer microprocessors. We also found that DBP-RB is colocalized with DNA damage foci after DNA damage and associated with ATM (Ataxia Telangiectasia Mutated), RAD50 and NBS1 in the DNA damage signaling. DBP-RB knockdown results in increased resistant to genotoxic drugs and inhibition of cell proliferation. We investigated the level of 742 human miRNAs in the DBP-RB knockdown cells and compared with DNA damage induced miRNAs using miRNA quantitative PCR. DBP-RB knockdown cell showed significant changes in the expression levels of a subset of miRNA and in particular, 75% of DBP-RB dependent miRNAs were also regulated in DNA damage-dependent manner. RNA-Immunoprecipitation (IP) reveals that DBP-RB is associated with that specific subset of microRNAs and depletion of DBP-RB inhibits the function of Drosha microprocessor. Taken together, our findings suggest that DBP-RB function as a mediator by transmitting DNA damage signal to the miRNA processors to modulate miRNAs processing through binding Drosha/DGCR8 and Dicer.
Citation Format: Cecil Han, Xiongbin Lu. DBP-RB, a novel RNA-binding protein promotes microRNA processing in the DNA damage response. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3080. doi:10.1158/1538-7445.AM2013-3080
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 3081: miR-885-5p, a p53-activated microRNA, inhibits the Wnt/β-catenin signaling pathway and hepatocellular carcinoma metastasis.
Authors: Zhang Zhuhong , Yin Jing , Lv Dan , Liu Chenghu , Yang Jian , Chang Antao , Sun Peiqing , Chen Si , Stupack Dwayne , Tian Yaping , Xiang Rong 
Published: August 2014

Abstract
The regulation of hepatocelluar carcinoma (HCC) progression by microRNAs (miRNAs) has attracted attention in recent years. Our previous study reported that the levels of circulating miR-885-5p were significantly up-regulated in patients with HCC and chronic hepatitis B (CHB). However, the role of miR-885-5p in HCC metastasis and the underlying mechanisms remain unknown. In this study, we used in situ hybridization to analyze the expression of miR-885-5p in HCC tissues and found that its expression was negatively associated with TNM stage of HCC. Consistent with this, the expression of miR-885-5p was negatively correlated with the invasive and metastatic abilities of human HCC cell lines. Kaplan-Meier analysis revealed that miR-885-5p levels correlated with the survival of HCC patients. Furthermore, enforced expression of miR-885-5p in high-metastatic HCC cells inhibited migration and invasion in vitro and in vivo. In addition, we identified that miR-885-5p directly targeted genes encoding the β-catenin CTNNB1 and the transcription factor TCF4, leading to decreased activity of the Wnt/β-catenin signaling pathway, which in turn contributes to metastasis in various cancers, including HCC. Notably, our results also showed that p53 up-regulated the expression of miR-885-5p and significantly inactivated the Wnt/β-catenin signaling pathway in HCC cells. We found that miR-885-5p levels correlated with wild-type TP53 status in HCC tissues. Taken together, these findings suggest that miR-885-5p is a negative regulator of HCC metastasis and indicate a potent rationale for developing miR-885-5p as a potential therapeutic agent against HCC metastasis.
Citation Format: Zhuhong Zhang, Jing Yin, Dan Lv, Chenghu Liu, Jian Yang, Antao Chang, Peiqing Sun, Si Chen, Dwayne Stupack, Yaping Tian, Rong Xiang. miR-885-5p, a p53-activated microRNA, inhibits the Wnt/β-catenin signaling pathway and hepatocellular carcinoma metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3081. doi:10.1158/1538-7445.AM2013-3081
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 3082: miRNA-10b promotes medulloblastoma proliferation and survival via Bcl-2.
Authors: Pal Rekha , Greene Stephanie 
Published: August 2014

Abstract
Introduction: The role of microRNAs (miRNAs) in the pathology of medulloblastoma (MB), the most common malignant brain tumor in children, is being elucidated at present. miRNA expression profiling studies have revealed a number of miRNAs implicated in medulloblastoma initiation and progression by controlling the expression of various genes responsible for cell proliferation or cell death. The effect of miRNA-10b on MB growth and proliferation through transcriptional induction of Bcl-2, an anti-apoptotic cellular proto-oncogene and tumor promoter, was explored in this study.
Methods: Assays were carried out using six established MB cell lines and 13 primary MB samples. A screening cancer-specific miRNA array identified miRNA-10b as highly expressed in MB compared to normal cerebellum. Real-time PCR showed that miRNA-10b is significantly up-regulated (42-100 fold) compared to the normal cerebellum in all MB cell lines. Two MB cell lines (DAOY and UW228) were transiently transfected with control miRNA, miRNA-10b inhibitor, and miRNA-10b mimic for 48 to 72 hrs. The transfected cells were subjected to RT-PCR, MTT, apoptosis, clonogenic assay, and western blot analysis.
Results: Transfection of miRNA-10b inhibitor induced a significant down-regulation of miRNA-10b expression in the MB cell lines, while miRNA-10b mimic induced miRNA-10b expression as measured by RT-PCR. Down-regulation of miRNA-10b expression resulted in a significant down-regulation of mRNA and protein levels of Bcl-2 and Mcl-1, decreased proliferation (p ≤ 0.001) and induced apoptosis (p ≤ 0.001) as compared to control. Inhibition of miRNA-10B further blocked the colony-forming capability of MB cells (p ≤ 0.001). miRNA-10b mimic transfection exerted an opposite effect. Down-regulation of miRNA-10b resulted in abrogation of phosphorylation of Bcl-2 at Ser70, a site previously reported to be critical in inhibiting apoptosis. Analyses of miRNA-10b levels in 13 primary MB samples revealed that the 2 patients with high levels of miRNA-10b (more than 200-fold increase versus control) had multiple recurrences (4.5) and died within 5 years of diagnosis, compared with the 11 patients with low levels of miRNA-10b who had a mean of 1.2 recurrences and 40% long-term survival.
Conclusions: In conclusion, our data indicate that miRNA-10b may act as an oncomir in MB tumorigenesis, and reveal a previously unreported mechanism with Bcl-2 as an important mediator of miRNA-10b activity in MB cell survival. Targeting of miRNA-10b may provide a novel therapeutic approach in the treatment of MB.
Citation Format: Rekha Pal, Stephanie Greene. miRNA-10b promotes medulloblastoma proliferation and survival via Bcl-2. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3082. doi:10.1158/1538-7445.AM2013-3082
Abstract 309: Loss of IL-6 or Stat3 drives advanced prostate cancer by promoting p53 inactivation.
Authors: Pencik Jan 
Published: August 2014

Abstract
Prostate cancer is the second most common cause of death in men. Approximately 258000 men in worldwide die each year from prostate cancer. The Jak/Stat pathway (Jak - Janus kinase, Stat - signal transducer and activators of transcription) is an important signaling cascade in prostate cancer. Stat3 seems to play a fundamental role in the regulation of proliferation, apoptosis, angiogenesis and hormone-resistance in prostate cancer. Although there has been evidence for an oncogenic function of Stat3, observations from several laboratories suggest the opposite. Under certain conditions activation of Stat3 leads to decreased growth of prostate cancer cells in vitro (LNCaP) and can exert an inhibitory effect on prostate cancer xenografts. To elucidate the role of IL-6/Stat3 signaling in prostate cancer (PCa), we have established Pten-deficient (Ptenpc-/−) PCa mouse models with additional deletion of IL-6 or Stat3. Ablation of IL-6 in Ptenpc-/− mice led to increased tumor formation and signs of massive chronic inflammation. In addition, Ptenpc-/- IL-6−/- mice showed decreased expression of p53-dependent cellular senescence markers when compared to PCa in Ptenpc-/- mice. The concomitant Pten and Stat3 inactivation (Pten/Stat3pc-/−) enhanced cell proliferation and accelerated the prostate cancer progression as well as production of inflammatory cytokines. Pten/Stat3pc-/− mice showed also significant downregulation of crucial components of the p53-dependent cellular senescence pathway. Furthermore, Pten/Stat3pc-/- PCa mice revealed high expression of AR and P-Akt correlated with advanced prostate cancer. These data suggest that disruption of IL-6/Stat3 signaling promotes tumorigenesis in Ptenpc-/- induced prostate cancer via p53 inactivation.
Citation Format: Jan Pencik. Loss of IL-6 or Stat3 drives advanced prostate cancer by promoting p53 inactivation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 309. doi:10.1158/1538-7445.AM2013-309
Abstract 3093: AR responsive miR-148a targets p27 and regulates the cell cycle in LNCaP cells.
Authors: Lombard Alan , Libertini Steve , Mudryj Maria 
Published: August 2014

Abstract
Prostate cancer is a commonly diagnosed malignancy and represents the second leading cause of cancer-related death in US men. Prostate cancer is initially dependent on androgens for survival and androgen signaling is mediated by the androgen receptor (AR). Due to the androgen dependency of prostate cancer, castration-therapy is a common course of action to combat the progression of this disease. However, almost inevitably, androgen independent prostate cancer later arises for which few strongly effective treatment options exist. In many of these cases, despite the androgen refractive nature of the disease, AR signaling is still necessary for the survival of the cancer but the downstream mechanisms that allow the AR to influence cellular proliferation remain to be fully understood. Further research elucidating these pathways is needed to discover novel therapeutic options for this disease. It has been shown that the AR represses the function of the cyclin dependent kinase inhibitor p27 but the way in which this happens is not completely known and seems to be multi-pronged. Research from Murata et al. (2010) demonstrated that miR-148a is an androgen responsive microRNA. Furthermore, it was shown by Guo et al. (2011) that miR-148a targets p27 in gastric cancer. Here we attempt to link these lines of research and uncover a novel pathway in which the relationship between the AR and p27 is mediated by miR-148a. We validated previous results showing that inhibition of AR signaling leads to an increase in p27 expression at both the protein and mRNA levels in the androgen responsive prostate cancer cell line LNCaP. It was shown that AR inhibition leads to an ∼2 fold decrease in miR-148a expression. Using a microRNA mimic, we demonstrated the ability of miR-148a to target p27 expression at both the protein and mRNA levels. We next showed that the miR-148a mimic can rescue the attenuated androgen signaling phenotype by reducing p27 levels and further demonstrate that this treatment leads to positive regulation of the cell cycle. Interestingly, inhibition of function using an antagomir against miR-148a leads to attenuated growth in LNCaPs suggesting a putative therapeutic angle by targeting this pathway. These results demonstrate a novel pathway mediated by the AR in which a miRNA is expressed which potentiates the cell cycle by targeting p27.
Citation Format: Alan Lombard, Steve Libertini, Maria Mudryj. AR responsive miR-148a targets p27 and regulates the cell cycle in LNCaP cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3093. doi:10.1158/1538-7445.AM2013-3093
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 3094: MiRNAs 484 and 210 control Pax-5 expression and function in breast cancer.
Authors: Harquail Jason M. , Robichaud Gilles A. 
Published: August 2014

Abstract
Every hour, approximately 21 people are diagnosed with cancer where 9 will succumb to their disease. Recent studies have enabled the identification of important factors regulating cancer progression, one of these being the Pax-5 gene. Pax-5, an essential developmental factor, is aberrantly expressed in various B cell cancer lesions and solid tumors such as carcinoma. Although Pax-5 downstream activity is well characterized, the regulation of aberrant Pax-5 expression in a cancer specific context is poorly understood. To investigate the regulation of Pax-5 expression, we turned our attention to micro-RNAs (miRNAs). MiRNAs are highly conserved, small non-coding RNA molecules that regulate key biological processes. Extensive studies also show their deregulation in multiple cancer lesions. This study aims to elucidate a correlation between differentially expressed miRNAs in cancer cells and deregulated Pax-5 expression levels. Using bioinformatics platforms we observe that miRNAs 484, and 210 are aberrantly expressed in breast cancer cells and cross-reference with their capacity to target the Pax-5 mRNA 3’ untranslated region (UTR 3’). Using anti-miRNAs transfected into Pax-5 expressing breast cancer cell lines (MCF-7 and MB231), we demonstrate that miRNAs 484 and 210 are capable of regulating Pax-5 expression. In addition, miRNA-regulated Pax-5 expression resulted in a concomitant alteration in Pax-5-dependant phenotype and cancer processes. This is the first study demonstrating the regulation of Pax-5 expression and function by non-coding RNAs in cancer cells. We believe that the aberrant expression of Pax-5 in cancer cells is in part due to deregulated miRNA expression profiles. This study will bring insight in regards to cancer regulating processes associated with miRNA and Pax-5 deregulations, thus helping us to better understand the aberrant Pax-5 expression levels within cancerous states. This study can therefore provide the eventual possibility of earlier, more efficient diagnostics as well as more targeted treatments for cancer patients.
Citation Format: Jason M. Harquail, Gilles A. Robichaud. MiRNAs 484 and 210 control Pax-5 expression and function in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3094. doi:10.1158/1538-7445.AM2013-3094
Abstract 3105: Orphan nuclear receptor NR4A2 exhibits oncogenic activity in lung cancer cells.
Authors: Cao Chunxia , Zhang Min , Gao Ruli , Cress Douglas , Chen Zirong , Wu Lizi , Kaye Maria Zajac , Kaye Frederic 
Published: August 2014

Abstract
LKB1 (also known as STK11) is a frequent target for mutations in lung cancer, however, the role of LKB1 loss in tumorigenesis is undefined. NR4A2, together with NR4A1, and NR4A3, constitute the nuclear receptor (NR) subfamily 4A (NR4A), which are orphan NRs lacking identified ligands. NR4A family has been implicated in cell cycle regulation, apoptosis, inflammation, metabolism and more recently in carcinogenesis. However, there are conflicting data for tumorigenesis as NR4A1 and NR4A3 act as tumor suppressors in leukemia mouse models, while NR4A2 appears to stimulate tumor cell growth in vitro. Our laboratory discovered that the CRTC1 gene was aberrantly activated in LKB1-null cancer cells, stimulating the transcription of cAMP/CREB targets including NR4A gene members.
The aim of this study is to examine NR4A2 as a potential oncogene and therapeutic target under the regulation of CRTC1 in LKB1 wildtype and null lung cancer cells. We demonstrated here that somatic loss of LKB1 in tumor cells was associated with underphosphorylation and nuclear localization of CRTC1, this resulted in upregulated expression and stronger transcriptional activity of NR4A2 in LKB1 mutant lung cancer cells and clinical primary lung cancer samples. We confirmed that forskolin, which can activate adenylate cyclase then catalyze the transformation of ATP to cAMP, could induce CRTC1 dephosphorylation resulting in enhanced NR4A2 expression. We identified that activation of the CRTC gene family induced NR4A2 expression, whereas knockdown of CRTCs decreased the expression of NR4A2. Furthermore, short hairpin RNA-mediated down-regulation of NR4A2, results in attenuated lung cancer cell proliferation and colony formation in vitro and decreased the tumor sizes in vivo in nude mice.
In summary, our data suggested a CRTC-mediated transcriptional regulatory mechanism for NR4A2 activity, and proposed an oncogenic role of NR4A2 in LKB1 null lung cancer cell lines.
Citation Format: Chunxia Cao, Min Zhang, Ruli Gao, Douglas Cress, Zirong Chen, Lizi Wu, Maria Zajac Kaye, Frederic Kaye. Orphan nuclear receptor NR4A2 exhibits oncogenic activity in lung cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3105. doi:10.1158/1538-7445.AM2013-3105