bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2095: DEPTOR is a direct NOTCH1 target that regulates proliferation, metabolism and glucocorticoid resistance in T cell leukemia
Authors: Hu Yufeng , Su Hexiu , Ye Qi , Wang Zhaojing , Huang Liang , Wang Qian , Liu Shuangyou , Chen Suning , Zhou Jianfeng , Li Peng , Qing Guoliang , Liu Hudan 
Published: August 2015

Abstract
DEP-Domain Containing mTOR-Interacting Protein (DEPTOR) is frequently overexpressed in multiple myelomas and required for cell survival. However, its implications in other hematological malignancies and the precise mechanisms of regulation remain largely undefined. Here, we systematically analyzed DEPTOR expression in human acute lymphoblastic leukemia (ALL), a hematological malignancy accounting for 80% of pediatric leukemia. Whereas substantially inhibited in B-ALLs, unexpectedly, expression of DEPTOR is significantly elevated in a subset of T-ALLs where NOTCH1 is aberrantly activated. Mechanistically, we show DEPTOR expression is dependent on NOTCH signaling in T-ALL cell lines and primary specimens, and demonstrate NOTCH1 directly binds to and activates human DEPTOR promoter. DEPTOR depletion in T-ALL cells abolishes proliferation, attenuates glucose metabolism, enhances apoptosis and sensitizes resistant cells to γ-secretase inhibitor or dexamethasone treatments. Conversely, ectopically expressed DEPTOR promotes proliferation and aerobic glycolysis, and confers dexamethasone resistance. DEPTOR functions through AKT-dependent mechanisms to sustain cell proliferation and drug resistance, while the AKT-independent roles of DEPTOR appear to promote glucose metabolism. We therefore define a novel mechanism that, in addition to the previously reported HES1/PTEN-mediated regulation of AKT, NOTCH1 alternatively activates AKT through inducing the downstream target gene DEPTOR. Our findings thereby highlight DEPTOR as a critical mediator in leukemogenesis and suggest DEPTOR expression may serve as a potential biomarker predicting glucocorticoid resistance and targeting DEPTOR may achieve better therapeutic benefits.
Citation Format: Yufeng Hu, Hexiu Su, Qi Ye, Zhaojing Wang, Liang Huang, Qian Wang, Shuangyou Liu, Suning Chen, Jianfeng Zhou, Peng Li, Guoliang Qing, Hudan Liu. DEPTOR is a direct NOTCH1 target that regulates proliferation, metabolism and glucocorticoid resistance in T cell leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2095. doi:10.1158/1538-7445.AM2015-2095
Abstract 2098: Genome-wide comparison of PU.1 and Spi-B binding sites in a mouse B lymphoma cell line
Authors: Solomon Lauren A. , Li Stephen K.h. , Piskorz Jan , Xu Li S. , DeKoter Rodney P. 
Published: August 2015

Abstract
Background. The E26-transformation-specific (ETS) transcription factor Spi-B is required for the survival of Activated B Cell-type Diffuse Large B Cell Lymphoma cell lines and is recurrently amplified in B cell lymphoma. The ETS transcription factor PU.1 is highly related to Spi-B. Both PU.1 and Spi-B are expressed in B lymphoma cell lines, and have been demonstrated to redundantly activate transcription of genes required for differentiation and function. We hypothesized that Spi-B and PU.1 occupy similar regions of chromatin within the genome of a B lymphoma cell line. Results. To compare binding regions of Spi-B and PU.1, murine WEHI-279 lymphoma cells were infected with retroviral vectors encoding 3XFLAG-tagged PU.1 or Spi-B. Anti-FLAG chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) was performed. Analysis for high-stringency enriched genomic regions demonstrated that PU.1 occupied 4528 regions and Spi-B occupied 3360 regions. 1900 of these regions exhibited at least 100 base pairs of overlap for both factors. Regions bound by Spi-B and PU.1 were frequently located within genes associated with immune response and activation of B cells. Motif-finding revealed that both transcription factors were predominantly located at the ETS core domain (GGAA), however, other unique motifs were identified when examining regions associated with only one of the two factors. Motifs associated with unique PU.1 binding included POU2F2, while unique motifs in the Spi-B regions contained a combined ETS-IRF motif. Conclusions. Our results suggest that complementary biological functions of PU.1 and Spi-B may be explained by their interaction with a similar set of regions in the genome of B lymphoma cells. However, sites uniquely occupied by PU.1 or Spi-B provide insight into their unique functions.
Citation Format: Lauren A. Solomon, Stephen K.h. Li, Jan Piskorz, Li S. Xu, Rodney P. DeKoter. Genome-wide comparison of PU.1 and Spi-B binding sites in a mouse B lymphoma cell line. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2098. doi:10.1158/1538-7445.AM2015-2098
Abstract 2099: FoxM1 drives a feed-forward STAT3-activation signaling loop to promote the self-renewal and tumorigenicity of glioblastoma stem cells
Authors: Zhang Sicong , Gong Ai-hua , Wei Ping , Zhou Aidong , Yao Jun , Yuan Ying , Lang Frederick , Rao Ganesh , Huang Suyun 
Published: August 2015

Abstract
The STAT3 signaling pathway is a nodal hub of gliomagenesis, but the mechanisms underlying elevated expression and activation of STAT3 are largely unknown. Here, we showed that FoxM1 was critical for STAT3 gene expression and protein activation. First, the expression of PDGF-A, one of the growth factor upstream of STAT3 directly correlated with the expression of FoxM1 in GBMs. FoxM1 bound to PDGF-A promoter to upregulate PDGF-A expression in GBM stem cells (GSCs) and mouse neural stem cells (NSCs). FoxM1 maintains stemness of GSCs partially via PDGF-A. Second, data from TCGA showed that GBMs expressed high levels of STAT3 as compared with normal brain. STAT3 expression directly correlated with the expression of FoxM1 in GBMs. FoxM1 regulated STAT3 expression by interacting with the β-catenin/TCF4 complex at STAT3 promoter. FoxM1 deficiency decreased both PDGF-A and STAT3 expressions in GSCs and NSCs and inhibited STAT3 activation by PDGF-A, EGF and IL-6, thereby abolished the stemness and tumorigenesis of GSCs. Moreover, constitutively active STAT3 rescued the inhibitory effects of FoxM1 knockdown on the stemness and tumorignecity of GSCs, suggesting FoxM1 regulates the stemness of GSCs by affecting STAT3 Furthermore, overexpression of FoxM1 reprogrammed glioma cells to GSCs-like cells, whereas inhibition of STAT3 diminished FoxM1-induced stemness and tumorigenesis. Collectively, these findings indicated that FoxM1 regulated the expression of both PDGF-A and STAT3 hence drived a feed-forward STAT3-activation signaling loop which was required for maintenance of self-renewal and tumorigenicity of GSCs.
Citation Format: Sicong Zhang, Ai-hua Gong, Ping Wei, Aidong Zhou, Jun Yao, Ying Yuan, Frederick Lang, Ganesh Rao, Suyun Huang. FoxM1 drives a feed-forward STAT3-activation signaling loop to promote the self-renewal and tumorigenicity of glioblastoma stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2099. doi:10.1158/1538-7445.AM2015-2099
Abstract 2101: The transcription factor POU3F2 is expressed in human gliomas and promotes tumorigenesis in vivo
Authors: Rahman Mohummad Aminur , Liess Lina , Lellahi Mohammad S. , Gjerde Christiane H. , Saed Halala S. , Mutlu Ercan , Zhu Huaiyang , Wang Jian , Enger Per Øyvind 
Published: August 2015

Abstract
The neurodevelopmental transcription factor POU3F2 (also called OCT7 / BRN2) is expressed during neurogenesis. Moreover, POU3F2 expression has been reported as a promoter of proliferation and invasion in malignant melanoma of the skin. Since both melanomas and CNS-malignancies arise in organs of neuro-ectodermal origin, we investigated whether human gliomas expressed POU3F2 and the role of POU3F2 in glioma tumorigenesis. We performed immunohistochemistry of 149 grade II-IV gliomas from our tumor bank, and subsequently performed western blots and qPCR of 12 samples from each grade. In addition, we performed flow cytometric analysis of POU3F2 expression in 5 acutely dissociated tumors. Using lentiviral transfection we established glioma cell lines with POU3F2 overexpression or knock down in order the to investigate the effect of POU3F2 on proliferation, migration and differentiation, both in vitro and in vivo. The mechanism, by which POU3F2 regulates glioma progression, was also investigated. Immunohistochemistry showed that POU3F2 was almost uniformly expressed in human gliomas. Both western blot, qPCR and flow cytometry confirmed expression of POU3F2 in human gliomas. In acutely dissociated tumors, the POU3F2 positive cells displayed an increased cell percentage in the S and G2/M phase of the cell cycle. Moreover, POU3F2 overexpression in the glioma cell lines increased growth rates and colony formation. Overexpression of POU3F2 increased the levels of phosphorylated p-44/42 indicating activation of the ERK1/2 signaling pathway. Increased levels of downstream transcriptional targets c-Myc, Elk1 and Stat3 transcription factors in the POU3F2 overexpressing cell lines confirmed activation of the MAPK signaling pathway. Furthermore, the POU3F2 overexpressing cell lines displayed increased expression of the growth factor FGF2. U0126, an inhibitor of MEK1/2, decreased the cell proliferation and decrease levels of phospho-p44/42, phospho-stat3 and FGF2. Moreover, overexpression of the POU3F2 increases the level of other neurodevelopmental transcription factors associated with a pluripotent state. Ongoing studies aim at further elucidating the multiple roles of POU3F2 in brain tumor progression.
Citation Format: Mohummad Aminur Rahman, Lina Liess, Mohammad S. Lellahi, Christiane H. Gjerde, Halala S. Saed, Ercan Mutlu, Huaiyang Zhu, Jian Wang, Per Øyvind Enger. The transcription factor POU3F2 is expressed in human gliomas and promotes tumorigenesis in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2101. doi:10.1158/1538-7445.AM2015-2101
Abstract 2103: SOX2 suppresses PTEN expression via miR-19a in esophageal squamous cell carcinoma
Authors: Gen Yasuyuki , Yasui Kohichiroh , Kitaichi Tomoko , Dohi Osamu , Ito Yoshito 
Published: August 2015

Abstract
We previously showed that SOX2, a master regulator during embryogenesis, is an amplification target of 3q26.33 in esophageal squamous cell carcinoma (ESCC), and that SOX2 promotes ESCC proliferation in vitro and in vivo via activation of the AKT/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. However, the mechanisms by which SOX2 promotes AKT/mTORC1 signaling remain to be elucidated. We determined that SOX2 decreased PTEN, a negative regulator of AKT signaling, via microRNA (miRNA) in ESCC cells. SOX2 knockdown increased PTEN and decreased phosphorylated AKT (p-AKT), and PTEN knockdown restored p-AKT decreased by SOX2 knockdown in SOX2 amplified ESCC cells (KYSE70, KYSE140 and TE10 cells), indicating that SOX2 elevates p-AKT via PTEN suppression in these cells. DICER knockdown increased PTEN expression without SOX2 expression change in these cells, suggesting that PTEN expression is regulated by miRNA. Therefore we hypothesized that SOX2 may suppress PTEN expression through miRNA regulation. To examine whether SOX2 modulate the expression of miRNAs, we investigated the expression of cancer-related 84 miRNAs using miRNA PCR arrays, and found that SOX2 elevated miR-17∼92 cluster (miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, and miR-92) in KYSE70 cells. Quantitative RT-PCR confirmed that the expression of mir-17∼92 cluster is elevated by SOX2 in KYSE70, KYSE140, and TE10 cells. Of these miRNA, transfection of miR-19a mimic suppressed PTEN and conversely miR-19a inhibition elevated PTEN in these cells. Collectively, SOX2 may suppress PTEN expression via miR-19a in ESCC cells.
Citation Format: Yasuyuki Gen, Kohichiroh Yasui, Tomoko Kitaichi, Osamu Dohi, Yoshito Ito. SOX2 suppresses PTEN expression via miR-19a in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2103. doi:10.1158/1538-7445.AM2015-2103
Abstract 2107: YAP protein expression and subcellular localization in pediatric liver tumors
Authors: LaQuaglia Michael J. , Grijalva James , Mueller Kaly , Perez-Atayde Antonio , Kim Heung Bae , Sadri-Vakili Ghazaleh , Vakili Khashayar 
Published: August 2015

Abstract
Purpose: Currently, there is no effective chemotherapy for the treatment of hepatocellular carcinoma (HCC). Both HCC and hepatoblastoma (HB) remain lethal in their metastatic forms. Therefore, understanding the molecular mechanisms of tumor survival and proliferation is critical for developing novel therapies. Our lab has shown that YAP, a transcription factor, is involved in liver regeneration. Specifically, increases in nuclear YAP have been coupled with expression of genes important for cell proliferation. We therefore sought to examine whether there is increased nuclear localization of YAP in liver tumors.
Methods: Tumor tissue and normal liver tissue from 3 pediatric patients with HCC (all males, mean age 10.63 years), and 6 HB patients (4 males and 2 females, mean age 2.99 years) were stained for YAP using immunohistochemistry. Multiple high-power fields were photographed for each sample. Using ImageJ software, the number of YAP-positive nuclei were counted and expressed as a mean percentage of total nuclei.
Results: The percentage of nuclei staining positive for YAP was increased in tumor cells compared to normal liver in 3/3 of the HCC tumors. In addition, YAP nuclear staining was significantly increased in 2/6 of the HB tumors.
Conclusion: All HCC tumors and 33% of the HB showed an increase in the nuclear localization of transcription factor YAP. The increased activity of YAP in the nuclei of tumor cells may indicate a crucial role for YAP in tumor proliferation and survival. Targeting YAP or its upstream pathway (Hippo) may provide a novel target for therapy.
Citation Format: Michael J. LaQuaglia, James Grijalva, Kaly Mueller, Antonio Perez-Atayde, Heung Bae Kim, Ghazaleh Sadri-Vakili, Khashayar Vakili. YAP protein expression and subcellular localization in pediatric liver tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2107. doi:10.1158/1538-7445.AM2015-2107
Abstract 2112: A novel mechanism of NF-κB regulation in bladder cancer
Authors: Mukherjee Neelam , Ghosh Rita 
Published: August 2015

Abstract
Protein methyltransferases (PMTs) methylate protein lysine and arginine residues and play an important role in regulating chromatin remodeling and gene transcription. Deregulation of SET-domain-containing PMTs has a crucial role in carcinogenesis (1). SETD6 is a novel methyltransferase that has been shown to monomethylate p65/RelA (a principal subunit of NF-κB) at Lys310. Monomethylated p65 recruits GLP (G9A-like protein), a histone dimethyl transferase to the NF-κB target genes, which results in transcriptional repression (2). The role of SETD6, in carcinogenesis in general and bladder cancer in particular is unknown. We identified SETD6 as a significantly upregulated gene in a screen of chromatin modifying genes that are differentially regulated in bladder cancer cells compared with normal urothelial cells. Subsequently qPCR and immunoblotting showed upregulation of SETD6 at the mRNA and protein level in bladder cancer cells and tissues relative to their normal counterparts. Surprisingly, we found that overexpression of SETD6 increased nuclear level of NF-κB, phosphorylation of NF-κB at Ser536 and the transcriptional activity of NF-κB. Overexpression of wild type SETD6 increased viability and proliferation of non-tumorigenic urothelial cells while overexpression of mutant SETD6 had no effect. Furthermore, knocking down SETD6 transiently with si-SETD6 significantly decreased viability and proliferation of bladder cancer cells suggesting that SETD6 may have a growth promoting role in bladder cancer. Our data shows for the first time that non-histone protein lysine methylation of NF-κB-p65 by SETD6 may be a novel way to regulate NF-κB pathway in bladder cancer. The lack of curative strategies for bladder cancer leads to recurrence rates of 45-70% with &gt;15% of patients developing muscle invasive disease (3). These observations underscore the need to understand survival mechanism in bladder cancer. In this regard our findings are highly significant and could lead to targeting SETD6/ NF-κB axis in bladder cancer in the future.
References:
1.
Schneider, R., et al. (2002) Unsafe SETs: histone lysine methyltransferases and cancer. Trends in biochemical sciences, 27, 396-402.
2.
Levy, D., et al. (2011) Lysine methylation of the NF-κB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-κB signaling. Nature immunology, 12, 29-36.
3.
Nativ, O., et al. (2009) Combined thermo-chemotherapy for recurrent bladder cancer after bacillus Calmette-Guerin. The Journal of urology, 182, 1313-1317.
Citation Format: Neelam Mukherjee, Rita Ghosh. A novel mechanism of NF-κB regulation in bladder cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2112. doi:10.1158/1538-7445.AM2015-2112
Abstract 2124: Analysis of the functional relevance of novel alternative splicing events in non-small cell lung cancer
Authors: de Miguel Fernando J. , Sharma Ravi D. , Reclusa Pablo , Pajares María J. , Rubio Angel , Pio Ruben , Montuenga Luis M. 
Published: August 2015

Abstract
Lung cancer is the most common cause of death by cancer worldwide. Deregulation of alternative splicing (AS) is becoming increasingly relevant for the understanding of the molecular mechanisms of lung tumor progression. Genome-wide microarrays containing probes in exons and junctions can be used to identify differential AS events. We developed an algorithm, called ExonPointer, which was optimized to detect AS events using this kind of platforms. Using this technique, we successfully detected splicing events regulated by the oncogene serine/arginine-rich splicing factor 1 (SRSF1) in lung cancer cell lines. Moreover, four of these genes, ATP11C, IQCB1, TUBD1 and PRRC2C, showed a significantly different pattern of AS in primary non-small cell lung cancer (NSCLC) compared with normal lung tissue. In the case of PRRC2C, we also demonstrated that the deregulation of the splicing event was important for tumor progression. We next applied the same technique to target differential AS events in NSCLC primary tissues (13 lung squamous cell carcinomas and 9 lung adenocarcinomas). Their paired normal lung tissues were used as reference. The validation rate for the top 20 events identified by ExonPointer was 70%. Gene cluster analyses showed an enrichment of clusters implicated in cancer development such as Cellular Growth and Proliferation, or Cell Death and Survival. Among others, we observed accumulation of a tumor-specific splice variant in Mitogen-Activated Protein Kinase 9 (MAPK9 or JNK2). The tumor-specific variant for this gene contains an alternative exon 2 which causes a frame shift introducing a premature stop codon. Functional analyses using isoform-specific siRNAs showed that this variant did not affect tumor growth or progression. However, its expression significantly correlated with the expression of Regulator of Nonsense Transcripts 3A and B (UPF3A and UPF3B) in 42 lung cancer cell lines. These proteins belong to the Nonsense Mediated Decay (NMD) pathway, which eliminates aberrant mRNA transcripts, suggesting that the presence of some aberrant AS variants in lung cancer are caused by a malfunction of NMD. In conclusion, we have developed a reliable tool for the high throughput analysis of AS, and have identified new splicing events in lung cancer that can be studied as potential diagnostic markers and therapeutic targets.
Citation Format: Fernando J. de Miguel, Ravi D. Sharma, Pablo Reclusa, María J. Pajares, Angel Rubio, Ruben Pio, Luis M. Montuenga. Analysis of the functional relevance of novel alternative splicing events in non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2124. doi:10.1158/1538-7445.AM2015-2124
Abstract 2126: Comprehensive transcriptome analysis reveals that nonsense-mediated mRNA decay is not globally suppressed in lung adenocarcinomas
Authors: Kong Xiangyin 
Published: August 2015

Abstract
As a well-known mRNA surveillance mechanism, the nonsense-mediated mRNA decay (NMD) pathway ensures the rapid degradation of mRNAs containing premature termination codons (PTC). Prior research has shown that features of the tumor microenvironment, such as hypoxia and amino acid deprivation, might inhibit NMD activity. However, a systemic analysis of NMD in cancer is seldom performed. Rather than focusing on only a few NMD targets and using artificial interventions as in previous experiments, we aimed to analyze NMD in cancer from a global perspective. By analyzing lung Adenocarcinomas in detail, we observed comparable decay efficiencies in tumors for both annotated and predicted NMD targets. Interestingly, the expression patterns of key NMD factors are altered, indicating that cancer cells might prefer to use different NMD degradation pathways. We also identified a subset of NMD targets with unique manners in either tumor or adjacent tissues. Besides, our analyses further demonstrate that the NMD efficiencies vary across tumors, supporting the heterozygosity of lung Adenocarcinomas.
Citation Format: Xiangyin Kong. Comprehensive transcriptome analysis reveals that nonsense-mediated mRNA decay is not globally suppressed in lung adenocarcinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2126. doi:10.1158/1538-7445.AM2015-2126