bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 957: Regulation of PCGEM1 in castration resistant prostate cancer
Authors: Ho Tsui-Ting , Mo Yin-Yuan 
Published: July 2016

Abstract
PCGEM1 has been shown to be prostate cancer specific long non-coding RNA (lncRNA). Our previous study indicates that PCGEM1 plays a role in castration resistance through regulation of androgen receptor (AR) splice variants. Although it is known that PCGEM1 is often upregulated in prostate cancer, little is known how PCGEM1 is regulated. In the present study, we show that p54/nrb is a positive regulator for PCGEM1. PCGEM1 is higher in castration resistant CWR22Rv1 than in androgen sensitive LNCaP cells. Moreover, androgen deprivation induces PCGEM1 in LNCaP cells. Histone ChIP assays suggest that the active binding site is within 500 bp upstream of putative transcriptional start site. By using biotin-labelled PCR product and pulldown assays combined with mass spectrometry analysis, we show that p54/nrb interacts with the promoter of PCGEM1. While ectopic expression increases, suppression of p54/nrb by RNAi or knockout (KO) suppresses PCGEM1, supporting a role for p54/nrb in PCGEM1 regulation. Moreover, rescue experiments indicate that re-expression of p54/nrb in KO cells restores the ability to induce PCGEM1. Finally, 3, 3’-Diindolylmethane (DIM), a known chemoprevention agent derived from plants such as broccoli, is capable of suppressing PCGEM1 expression by preventing the interaction of p54/nrb with the PCGEM1 promoter. In particular, DIM reduces tumor growth by suppression of PCGEM1 and promoting apoptosis in the castrated xenograft mouse model. Together, these results demonstrate a novel mechanism of how PCGEM1 and AR splicing are regulated. As a result, PCGEM1 may ultimately contribute to castration resistance.
Citation Format: Tsui-Ting Ho, Yin-Yuan Mo. Regulation of PCGEM1 in castration resistant prostate cancer. [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 957.
Abstract 966: Circulating exosomal miRNAs as potential biomarker in liposarcoma
Authors: Casadei Lucia , Creighton Chad , Batte Kara , Chelouche-Lev Dina , Croce Carlo M. , Pollock Raphael E. 
Published: July 2016

Abstract
Liposarcoma (LPS) is the most common soft tissue sarcoma histological subtype. Despite the development of combined modality treatments in recent years, a significant proportion of patients respond poorly to chemotherapy, leading to local recurrence or distant metastasis. Thus, early detection of recurrent or metastatic disease or early decision making could improve patient prognosis. However, there are no useful biomarkers for these purposes. Thus, the discovery of novel biomarkers to detect tumors, predict their drug sensitivity, and monitor their progression is one of the most important challenges that must be overcome.
miRNAs are short (approximately 22 nucleotides in length) non-coding RNAs (ncRNAs) that regulate gene expression by binding to specific mRNA targets and promoting their degradation and/or translational inhibition; since their discovery in body fluids (secreted in cell-borne membrane vesicles or associated with macromolecular complexes), circulating blood-borne microRNAs are being investigated as potent minimally invasive biomarkers of several diseases including tumors.
In this study, our goal is to identify potential biomarkers in the peripheral blood of LPS patients that could be useful for LPS diagnostic, prognostic and therapeutic purposes.
To determine the miRNA expression profiles of LPS in peripheral blood (PB) and in peripheral blood exosomes (PBX), a series of 16 human LPS patient specimens and 8 healthy controls was analyzed on a miRNA microarray platform capable of detecting 800 human miRNAs (nCounter Human microRNA expression Assay Nanostring v3). Validation of the array was performed by qRT-PCR on a new set of samples (10 human LPS and 9 healthy controls).
To identify differentially expressed miRNAs, we compared miRNAs expression profiles from PBX of 15 patients to 8 healthy samples. A total of 26 miRNAs were significantly upregulated and 3 miRNAs were significantly down regulated (p&lt;0.004). When we compared miRNA expression profiles from PB to healthy controls, fewer miRNAs were consistently deregulated (18 miRNAs were upregulated and 3 miRNAs were downregulated, p&lt;0.02). Moreover the miRNAs found to be consistently deregulated in PB were all also significantly deregulated in the PBX. Validation of the miRNA panel in an independent cohort of LPS patients confirmed this signature.
Our study has identified a specific miRNA signature in circulating exosomes that may have a novel role in the diagnosis, prognosis and or treatment of LPS patients in a clinical setting.
Citation Format: Lucia Casadei, Chad Creighton, Kara Batte, Dina Chelouche-Lev, Carlo M. Croce, Raphael E. Pollock. Circulating exosomal miRNAs as potential biomarker in liposarcoma. [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 966.
Abstract 967: Vemurafenib regulates miRNA-211 expression in melanoma - effects on extracellular vesicle RNA cargo and function
Authors: Lunavat Taral R. , Cheng Lesley , Einarsdottir Berglind , Lässer Cecilia , Nilsson Jonas A. , Hill Andrew F. , Lötvall Jan 
Published: July 2016

Abstract
In melanoma, more than 50% of the patients harbor BRAF somatic missense mutations, most affecting the V600 region. Vemurafenib, a potent BRAF inhibitor used for the treatment of late stage melanoma, has shown promising results by causing programmed cell death in melanoma cells. Recently, extracellular vesicles including apoptotic bodies, microvesicles and exosomes has been shown to contain genetic information especially RNA with distinct repertoire of RNA, which could be transferred from one cell to another. Here we investigate the effects of Vemurafenib on melanoma cells and the RNA content in their subsets of extracellular vesicles. Upon vemurafenib treatment, we found that the melanoma cells harboring the BRAF mutation significantly increases the RNA and protein cargo in the different subsets of extracellular vesicles. The RNA profile also changes substantially in apoptotic bodies and microvesicles with significant changes in the ribosomal RNA ratio. Further, using small RNA sequencing, we found that extracellular vesicles from treated cells harbor unique miRNAs. The significantly different miRNA detected with sequencing analysis was validated in vitro with PCR and confirmed that miR-211 is upregulated in cells as well as subsets of extracellular vesicles after treatment. Furthermore, miR-211 was validated to be significantly upregulated in tumors tissues harvested from patient derived xenograft (PDX) as well as cell line derived xenograft and its vesicular subsets. This shows that vemurafenib induces miR-211 upregulation in BRAF mutant cells and PDX especially in the subsets of extracellular vesicles. miR-211 induction upon oncogene treatment could be potentially used as a biomarker in melanoma patients with BRAF mutation.
Citation Format: Taral R. Lunavat, Lesley Cheng, Berglind Einarsdottir, Cecilia Lässer, Jonas A. Nilsson, Andrew F. Hill, Jan Lötvall. Vemurafenib regulates miRNA-211 expression in melanoma - effects on extracellular vesicle RNA cargo and function. [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 967.
Abstract 973: A long noncoding RNA-regulating enhancer links Ewing sarcoma susceptibility to stress response
Authors: Aryee Dave NT , Tomazou Eleni , Kauer Maximilian , Grünewald Thomas , Tirode Franck , Delattre Olivier , Kovar Heinrich 
Published: July 2016

Abstract
Ewing sarcoma is the second most frequent bone cancer in Caucasian children and young adults, but hardly occurs in Africans. It is characterized by a relatively quiet genome with only one highly recurrent chromosomal aberration, a EWS-ETS (predominantly EWS-FLI1) gene rearrangement. The resulting fusion gene encodes for an aberrant ETS transcription factor which drives sarcomagenesis. In a large GWAS study, three Ewing sarcoma susceptibility loci were discovered on chromosomes 1, 10 and 15, but the molecular mechanisms, how these loci affect tumorigenesis, remained largely unknown.
By epigenomic mapping, EWS-FLI1 ChIP-seq, and reporter gene assays we found one of the susceptibility loci to localize to an EWS-FLI1 bound enhancer in the intron of a long non-coding antisense RNA, which we termed lncESST1 (Ewing Sarcoma Susceptibility Transcript 1). Deletion of the ETS binding region in the enhancer by CRISPR/Cas9 mediated gene editing lead to a drastic decrease in lncESST1 expression. Modulation of lncESST expression by siRNA or enhancer deletion significantly reduced soft agar colony formation of Ewing sarcoma cells without affecting growth under adherent culture conditions. Detachment of Ewing sarcoma cells from the plastic surface and growth under spheroid culture conditions induced stress granule formation as an immediate response, and a steady increase in lncESST1 expression over a period of at least 72 hours. We report that lncESST1 binds to a stress granule component with which it shares the promoter, and that loss of lncESST1 expression due to enhancer deletion perturbs stress granule formation. Our study therefore unveils a novel mechanism of lncRNA mediated cancer susceptibility.
Supported by FWF grant I1225-B19
Citation Format: Dave NT Aryee, Eleni Tomazou, Maximilian Kauer, Thomas Grünewald, Franck Tirode, Olivier Delattre, Heinrich Kovar. A long noncoding RNA-regulating enhancer links Ewing sarcoma susceptibility to stress response. [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 973.
Abstract 977: RNA-sequencing analysis implicates novel non-coding RNAs in human papillomavirus-associated head and neck squamous cell carcinoma
Authors: Zou Angela E. , Krishnan Aswini R. , Xuan Yinan , Saad Maarouf A. , Korrapati Avinaash , Advani Sunil J. , Wang-Rodriguez Jessica , Ongkeko Weg 
Published: July 2016

Abstract
Head and neck squamous cell carcinoma (HNSCC) is an aggressive disease marked by frequent recurrence and metastasis and stagnant survival rates. Given the recent emergence of human papillomavirus (HPV) as a major etiological factor in head and neck cancers, there exists a pressing need to better resolve the molecular heterogeneity of HNSCCs, define more precise diagnostic and prognostic tools, and develop a wider repertoire of targeted therapies. Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been increasingly viewed as promising sources of insight into cancer onset and progression, with their diverse regulatory roles, tissue specificity, and aberrant expression in various human diseases now established by a multitude of studies. Using RNA-sequencing data from 466 HNSCC patients in The Cancer Genome Atlas (TCGA), we sought to investigate the transcriptome-wide dysregulation of both classes of ncRNAs in HPV-associated HNSCCs. Differential expression analyses controlled for patient smoking status revealed 5 lncRNAs and 9 miRNAs exhibiting significantly altered regulation between HPV-negative and HPV-positive HNSCC tumors (FDR &lt; 1 × 10-10). Among these, 8 ncRNAs were additionally correlated with HNSCC tumor stage, invasion, and anatomic site, among other clinical characteristics (Kruskal-Wallis, p &lt; 0.05). We subsequently validated the dysregulation of several candidate HPV-associated ncRNAs in vitro after ectopically expressing HPV16 E6/E7 in a panel of normal oral epithelial and HPV-negative HNSCC cell lines. To explore the functional consequences of our identified HPV-associated ncRNAs, we further investigated lnc-SP9-1:1, an lncRNA upregulated by 73.89 fold in HPV-positive compared to HPV-negative HNSCCs (FDR &lt; 1 × 10-10). Cell proliferation, migration, and matrigel invasion assays were performed to evaluate the effects of siRNA-mediated lnc-SP9-1:1 knockdown in E6/E7 overexpressing cell lines. While the specific roles of the vast majority of non-coding transcripts remain unknown, their consistent dysregulation in HPV-positive HNSCCs, coupled with their ongoing functional characterization, promises to unravel new layers of understanding of the molecular underpinnings of HPV-associated HNSCCs and nominate new biomarkers and therapeutic candidates for this specific disease.
Citation Format: Angela E. Zou, Aswini R. Krishnan, Yinan Xuan, Maarouf A. Saad, Avinaash Korrapati, Sunil J. Advani, Jessica Wang-Rodriguez, Weg Ongkeko. RNA-sequencing analysis implicates novel non-coding RNAs in human papillomavirus-associated head and neck 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 977.
Abstract 983: Integrative analysis of androgen receptor regulated long non-coding RNA in prostate cancer
Authors: Malik Rohit , Zhang Yajia , Cieslik Marcin , Niknafs Yashar S. , Pitchiaya Sethuramasundaram , Hosono Yasuyuki , Subramaniam Shruthi , Yazdani Sahr , Cao Xuhong , Robinson Dan , Chinnaiyan Arul 
Published: July 2016

Abstract
Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer. AR regulates a large repertoire of genes; however, the effect of androgen signaling on the regulation of long non-coding RNAs (lncRNA) remains incompletely understood. Using transcriptome sequencing (RNA-seq) of AR-positive cell lines VCaP and LNCaP treated with dihydroxytestosterone (DHT), we identified genes, including lncRNAs, which were strongly regulated by AR. To confirm direct regulation by AR, we interrogated AR-ChIP-seq data from VCaP and LNCaP cells, identifying the lncRNAs with direct AR binding. Existence of these lncRNAs in prostate cancer tissue samples was confirmed by analysis of RNA-seq data from prostate tumors, and the degree of differential expression in prostate tumors (localized and castration resistant metastases) versus benign was determined. The most highly overexpressed lncRNA in this analysis was a 2.7kb multi-exonic transcript present on chromosome 16 called ARlnc1. RACE was utilized to determine the exact exon structure of this gene, and its expression levels in various prostate cancer cell lines as well as independent prostate cancer tissue cohorts was assessed. Further, knockdown of ARlnc1 in AR dependent cell lines inhibited cell proliferation and induced apoptosis. Knockdown of ARlnc1 affected molecular signatures related to cell cycle, mitosis and DNA damage. Interestingly, ARlnc1 knockdown also suppressed global androgen signaling as determined by Gene set enrichment analysis using AR gene signature. Upon investigation of the mechanism through which PRCAT47 regulate AR signaling, we discovered that ARlnc1 regulates AR at the level of translation. Taken together, our data suggests that many lncRNAs are regulated by androgen signaling, and we identify one such lncRNA that is involved in a protein-lncRNA positive feedback loop.
Citation Format: Rohit Malik, Yajia Zhang, Marcin Cieslik, Yashar S. Niknafs, Sethuramasundaram Pitchiaya, Yasuyuki Hosono, Shruthi Subramaniam, Sahr Yazdani, Xuhong Cao, Dan Robinson, Arul Chinnaiyan. Integrative analysis of androgen receptor regulated long non-coding RNA in prostate cancer. [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 983.
Abstract 989: A novel function of LncRNA AK023948—regulation of PI3K signaling
Authors: Koirala Pratirodh , Mo Yin Yuan 
Published: July 2016

Abstract
The human genome expresses a large number of long non-coding RNAs (lncRNAs) and increasing evidences suggest their physiological functions.However, the roles vast majority of lncRNAs are elusive in breast cancer. In the present study, we identified a set of lncRNAs that were differentially expressed in breast cancer tissues as compared to normal tissue. AK023948 is one of such lncRNAs which is up-regulated in breast cancer tissue and in breast cancer cell lines. Ectopic expression of AK023948 in breast cancer MCF-7 cells promotes proliferation and anchorage independent cell growth along with activation of AKT phosphorylation. On the other hand, knockdown or knockout of AK023948 in MCF-7 cells reduces the proliferation of cells and phosphorylation of AKT. Furthermore, there is a positive correlation between AK023948 and pAKT expression in breast cancer tissue microarray. To determine the underlying mechanism of AK023948-mediated activation of AKT, we performed RNA precipitation assays using biotin-labeled AK023948 RNA probe combined with mass spectrometry analysis and identified that ATP dependent RNA helicase A (RHA/DHX9) is AK023948. The interaction of AK023948 with DHX9 was confirmed by Western blot and RNA immunoprecipitation (IP), respectively. Co-IP indicated that DHX9 interacts with PI3K regulatory subunit p85. Further characterization revealed that AK023948 works as scaffold for p85-DHX9 interaction, which is essential for stability of p85 and AKT activity. Finally, we showed that AK023948 is essential to AKT activation induced by growth factors and acidosis, but it has no effect on activation of ERK phosphorylation, suggesting that AK023948 specifically regulate AKT signaling via PI3K. Together, these results suggest that AK023948 contributes to breast cancer pathogenesis by activating AKT and AK023948 may serve as a novel target for breast cancer therapy.
Citation Format: Pratirodh Koirala, Yin Yuan Mo. A novel function of LncRNA AK023948—regulation of PI3K signaling. [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 989.
Abstract 99: Ovarian cancer specific therapeutic vulnerability
Authors: Yoshihara Kosuke , Tamura Ryo , Suda Kazuaki , Ishiguro Tatsuya , Enomoto Takayuki 
Published: July 2016

Abstract
High-grade serous ovarian cancer comprises approximately 40% of epithelial ovarian cancer cases and is the most aggressive histologic type. Because this type of cancer usually presents as advanced stage disease at the time of diagnosis, the clinical outcome in patients with advanced stage ovarian cancer remains poor.
A recent study has identified that homozygous deleted essential-redundant genes generate therapeutic vulnerabilities in glioblastoma multiforme. On the other hand, a pan-cancer analysis of somatic copy number alterations demonstrates that ovarian cancer has high frequent somatic copy number alterations compared to other tumor types including glioblastoma. Therefore, we hypothesized that ovarian cancer has also therapeutic vulnerabilities leading to development of new therapeutic strategies. To discover ovarian cancer specific vulnerability, we used DNA copy number and mRNA expression data submitted to the Cancer Genome Atlas. First, we performed GISTIC 2.0 to detect copy number alterations and found 4107 genes with homozygous deletion in at least 1% of 562 ovarian cancer samples. Of them, 3060 genes had at least one paralogue gene defined by Ensembl. We focused on metabolism pathway to extract 182 metabolism-related genes. By comparing gene expression between homozygous deletion samples and others using unpaired t-test, we identified 73 genes that were significantly down-regulated in homozygous deletion samples (p &lt; 0.05). Next, we used copy number data submitted to Cancer Cell Line Encyclopedia to discover 41 candidate genes that were homozygously deleted in at least one ovarian cancer cell line. These findings suggest that cancer specific vulnerability exists not only glioblastoma multiforme but also other tumor types including ovaryan cancer and that further functional validation of 41 candidate genes might lead to development of new therapeutic strategies in ovarian cancer in the near future.
Citation Format: Kosuke Yoshihara, Ryo Tamura, Kazuaki Suda, Tatsuya Ishiguro, Takayuki Enomoto. Ovarian cancer specific therapeutic vulnerability. [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 99.
Abstract 992: Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1
Authors: Taniue Kenzui , Takeda Yasuko , Akiyama Tetsu 
Published: July 2016

Abstract
Increasing evidence suggests that lncRNAs play critical roles in a diverse set of biological processes, including proliferation, differentiation, embryogenesis, neurogenesis and stem cell pluripotency. It has been reported that many lncRNAs regulate gene expression and various post-transcriptional processes, including splicing, transport, translation and degradation of mRNA. Furthermore, recent studies have shown that Many lncRNAs play critical roles in tumor development and progression.
We attempted to identify lncRNAs critical for the tumorigenicity of colon tumor cells. We have found that a lncRNA termed UPAT is required for the survival and tumorigenicity of colorectal cancer cells. We also show that UPAT interacts with and stabilizes the epigenetic factor UHRF1 by interfering with its β-TrCP-mediated ubiquitination. UHRF1 plays key roles in multiple biological processes, including proliferation and development. Moreover, UHRF1 is overexpressed in various tumors, including colon cancer, and plays a critical role in the proliferation and survival of tumor cells. Furthermore, we demonstrate that UHRF1-UPAT complex upregulate SCD1 and SPRY4, which play critical roles in the survival and proliferation of colon cancer cells.
Our findings suggest that UPAT-mediated stabilization of UHRF1 is critical for the proliferation and tumorigenicity of colon tumor cells. Our results suggest that UHRF1-UPAT axis may be a promising molecular target for colon cancer therapies.
Citation Format: Kenzui Taniue, Yasuko Takeda, Tetsu Akiyama. Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1. [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 992.