bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1068: Keratinocyte-specific deletion in mice reveals gene dose-dependent function of SIRT1 in tumorigenesis.
Authors: Ming Mei , Soltani Keyoumars , Shea Christopher R. , Li Xiaoling , He Yu-ying 
Published: August 2014

Abstract
The protein deacetylase SIRT1, a mammalian counterpart of the yeast silent information regulator 2 (Sir2) and a proto member of the sirtuin family, regulates various pathways in metabolism, DNA repair, and cell survival. However, the role of SIRT1 in cancer is still under debate. Here we show that the role of SIRT1 in skin cancer development induced by the human skin carcinogen UVB radiation is dependent on its gene dose. Keratinocyte-specific heterozygous deletion of SIRT1 increases UVB-induced skin tumorigenesis, whereas homozygous deletion of SIRT1 decreases skin tumorigenesis. In mouse skin, SIRT1 is haploinsufficient for DNA repair and the expression of xeroderma pigmentosum C (XPC), a protein critical for repairing UVB-induced DNA damage. Similar to homozygous SIRT1 deletion, heterozygous SIRT1 deletion reduces the XPC protein levels and UVB-induced DNA damage repair. As compared with normal human skin, down-regulation of SIRT1 is in parallel with down-regulation of XPC in human cutaneous squamous cell carcinoma at both the protein and mRNA levels. In contrast, homozygous SIRT1 deletion in mouse skin augments p53 acetylation, and the expression of its transcriptional target Noxa, and sensitizes epidermis to UVB-induced apoptosis in vivo, while heterozygous SIRT1 deletion has no effect. Although mice with homozygous SIRT1 deletion do not develop tumors, these mice suffer severe sunburn. The gene dose-dependent function of SIRT1 in DNA repair and cell survival is consistent with its role in UVB-induced skin tumorigenesis and injury. Taken together, our results indicate that, depending on the SIRT1 levels, SIRT1 acts as a tumor suppressor and as an oncogene.
Citation Format: Mei Ming, Keyoumars Soltani, Christopher R. Shea, Xiaoling Li, Yu-ying He. Keratinocyte-specific deletion in mice reveals gene dose-dependent function of SIRT1 in tumorigenesis. [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 1068. doi:10.1158/1538-7445.AM2013-1068
Abstract 1070: New potent inhibitors of the androgen receptor that target its BF3 surface binding site.
Authors: Munuganti Ravi , Ban Fuqiang , Li Huifang , LeBlanc Eric , Axerio Peter , Frewin Kate , Tomlinson Guns Emma , Cherkasov Artem , Rennie Paul S. 
Published: August 2014

Abstract
In the development and progression of prostate cancer, the androgen receptor (AR) plays a critical role and its hormone/ligand-binding site is the primary therapeutic target for all antiandrogens (eg Bicalutamide, MDV3100) currently used to treat advanced, metastatic forms of this disease. While treatment with these AR inhibitors initially suppresses prostate tumor growth, resistance to these drugs invariably emerges. Accordingly, there exists a clinical need for the development of new AR antagonists with different chemical structures and different mechanisms of action for targeting and inhibiting AR transactivation. To this end, we have focused on a surface pocket on the AR called Binding Function 3 (BF3). Applying iterative in silico screening to millions of chemicals in the ZINC database, coupled with biological screening for AR binding and activity, we identified several compounds that can bind directly to the BF3 pocket and inhibit AR transactivation. Cell-based screening assays for inhibition of a fluorescent ARE-reporter and PSA expression, together with Biolayer Interferometry analysis for measuring binding to the AR, revealed several chemically distinct BF-3 binders that showed significant IC50 inhibitions of the AR in the nano-molar to low micro-molar range. Validation for binding to the BF3 site was performed by x-ray crystallography. Furthermore, none of these compounds were able to displace DHT from the hormone binding site even at concentrations more than 10-fold higher than their IC50 values. In addition to wild type LNCaP prostate cancer cells, these BF3 binders effectively inhibited cell proliferation (MTS assay) and PSA expression in derived MDV3100-resistant prostate cancer cell lines, but had no effect on cell viability of AR-negative prostate cancer cell lines. In summary, we have identified an entirely new class of anti-androgens that bind to the BF3 surface site of the AR and inhibit its transactivation by a mechanism which does not involve binding to its hormone/ligand binding site and thereby bypasses the treatment resistance seen with conventional antiandrogens. (Supported by funds from the PCF, Canada Safeway, and CIHR).
Citation Format: Ravi Munuganti, Fuqiang Ban, Huifang Li, Eric LeBlanc, Peter Axerio, Kate Frewin, Emma Tomlinson Guns, Artem Cherkasov, Paul S. Rennie. New potent inhibitors of the androgen receptor that target its BF3 surface binding site. [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 1070. doi:10.1158/1538-7445.AM2013-1070
Abstract 1083: The pivotal role of IKKalpha in the development of spontaneous lung squamous cell carcinomas.
Authors: Xiao Zuoxiang , Jiang Qun , Willette-Brown Jami , Zhu Feng , Xi Sichuan , Burkett Sandra , Lin Fanching , Back Timothy , Datla Mahesh , Sun Zhonghe , Goldszmid Romina , Wu Xiaolin , Schrump David , Young Howard , Trinchieri Georgio , Wiltrout Robert , Hu Yinling 
Published: August 2014

Abstract
During the last decades lung cancer has become the leading cause of cancer deaths in the world, and the need to develop better diagnostic techniques and therapies is urgent. To advance the understanding of this disease, various genetically engineered and chemical induced mouse models have been established. However, there are no robust animal models of lung squamous cell carcinomas (SCCs), one of the major types of lung cancer. Here, we generated Ikkα-KA/KA knock-in mice (KA/KA) in which an ATP binding site of IKKα, Lys 44 was replaced by alanine. All the knock-in mice at 4 to 6 months of age developed spontaneous lethal lung SCCs associated with markedly increased leukocyte infiltration and expression of cytokines, and chemokines in the lungs. Furthermore, we identified deregulated c-myc, Nanog, Oct3/4, p53, Rb, EGFR, MAPK, Jun-B, p63, Trim29, Rhov, CDK1, and IGF1 in mouse lung SCCs, and identified reduced IKKα and IκBα and increased ROS1 in mutant lungs and SCCs, some of which were found in human lung SCCs. Lung cancers were prevented by reintroducing epithelial-cell IKKα, depleting macrophages or depleting lymphocytes. This study not only provides a novel model for studying the pathogenesis, treatment, early detection, and prevention of human lung SCCs, but also demonstrates how a single mutation in IKKα elicits malignancy through the combined epithelial-cell-autonomous and immune mechanisms.
Citation Format: Zuoxiang Xiao, Qun Jiang, Jami Willette-Brown, Feng Zhu, Sichuan Xi, Sandra Burkett, Fanching Lin, Timothy Back, Mahesh Datla, Zhonghe Sun, Romina Goldszmid, Xiaolin Wu, David Schrump, Howard Young, Georgio Trinchieri, Robert Wiltrout, Yinling Hu. The pivotal role of IKKalpha in the development of spontaneous lung squamous cell carcinomas. [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 1083. doi:10.1158/1538-7445.AM2013-1083
Abstract 1088: HOXB13 inhibition of succinate dehydrogenase leads to epithelial-to-mesenchymal transition in mouse ovarian cancer cell lines.
Authors: Aspuria Paul-Joseph , Cheon Dong-Joo , Gozo Maricel , Salumbides Brenda , Vergnes Laurent , Asara John , Reue Karen , Kensicki Elizabeth , Karlan Beth , Orsulic Sandra 
Published: August 2014

Abstract
HOXB13 is a homeobox gene whose dysregulation has been implicated in cancer. We have previously shown that HOXB13 plays an oncogenic role in ovarian cancer by driving epithelial-to-mesenchymal transition (EMT); however the mechanism by which this occurs has not been established. Global metabolomics profiling revealed that overexpression of HOXB13 in genetically defined mouse ovarian cancer cell lines inhibits succinate dehydrogenase (SDH) activity. Targeted-knockdown of the SDH subunit SdhB by shRNA results in mislocalization of E-cadherin and a spindle-shaped morphology suggestive of EMT. Metabolomics and real-time flux analysis showed that knockdown of SdhB results in elevated levels of succinate as well as defective mitochondrial respiration. Despite the mitochondrial respiration defect, SdhB knockdown cells display increased anchorage-independent growth in soft agar and enhanced xenograft tumor formation. Elevated levels of succinate have been shown to inhibit α-ketoglutarate requiring enzymes such as the Jumanji C (JmjC)-domain containing H3K27 demethylases, UTX and JMJD3. Indeed, knockdown of SdhB results in a hypermethylated epigenome as evidenced by increased levels of H3K27me2 and H3K27me3. Both the epigenetic and EMT phenotypes can be recapitulated by pharmacological inhibition of UTX and JMJD3 in control cells. These data point to a mechanism wherein modulation of oncometabolite levels can affect the epigenome, thereby influencing cancer cell morphology and tumorigenic properties.
Citation Format: Paul-Joseph Aspuria, Dong-Joo Cheon, Maricel Gozo, Brenda Salumbides, Laurent Vergnes, John Asara, Karen Reue, Elizabeth Kensicki, Beth Karlan, Sandra Orsulic. HOXB13 inhibition of succinate dehydrogenase leads to epithelial-to-mesenchymal transition in mouse ovarian cancer cell lines. [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 1088. doi:10.1158/1538-7445.AM2013-1088
Abstract 1103: An abnormally stiff microenvironment supports the overabundance of fibroblasts in non-small cell lung cancer.
Authors: Puig Marta , Giménez Alícia , Galgoczy Roland , Lugo Roberto , Ramírez Josep , Gómez-Caro Abel , Gascón Pere , Reguart Noemí , Alcaraz Jordi 
Published: August 2014

Abstract
Breathing demands our lungs to be soft and elastic. In contrast, lung tumors exhibit an abnormal tissue hardening concomitantly with an altered lung architecture and function, which brings the mechanical microenvironment of the tumor closer to that of muscle or bone. This tissue hardening has been associated with the abundant reactive stroma rich in activated fibroblasts (also referred to as tumor associated fibroblasts or TAFs) that is a hallmark of non-small cell lung cancer (NSCLC). However, it remains unknown whether tissue hardening alone is sufficient to drive the abnormal abundance of fibroblasts in the stroma of NSCLC. To address this question, we cultured the human lung fibroblast cell line CCD-19Lu or primary human lung fibroblasts on collagen-coated polyacrylamide gels exhibiting normal- or tumor-like stiffness in the absence (0%) or presence (0.1%) of serum for 5 days. Primary cells were isolated from both tumor-free regions (referred to as control fibroblasts) or tumors of NSCLC patients diagnosed with either Adenocarcinoma (ADC, n=5) or Squamous Cell Carcinoma (SCC, n=5) histological subtypes. We observed a significantly higher density of CCD-19Lu fibroblasts in tumor-like gels compared to normal-like gels regardless the presence of serum. Similar results were obtained in both primary control fibroblasts and SCC-TAFs. In contrast, tumor-like gels induced a weaker density increase in ADC-TAFs. The increased fibroblast density in the tumor-like gels was associated with increased survival rather than proliferation, as revealed by a downregulation of caspase-3 and a rise in AKT phosphorylation. Our results indicate that extracellular hardening alone is sufficient to induce an increased density in lung fibroblasts by activating pro-survival pathways and suggest an abnormal response of ADC-TAFs to extracellular mechanical cues. Collectively these findings underline a major role of tissue hardening in the abnormal abundance of TAFs in NSCLC, particularly in the SCC subtype. These data may be useful in developing novel targeted therapies against the pro-survival effects of tissue hardening in SCC-TAFs, which act as co-conspirators of tumor progression.
Citation Format: Marta Puig, Alícia Giménez, Roland Galgoczy, Roberto Lugo, Josep Ramírez, Abel Gómez-Caro, Pere Gascón, Noemí Reguart, Jordi Alcaraz. An abnormally stiff microenvironment supports the overabundance of fibroblasts in non-small cell lung 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 1103. doi:10.1158/1538-7445.AM2013-1103
Abstract 1113: The comprehensive mutational profiling of lung adenocarcinoma through large-scale RNA sequencing analysis.
Authors: Lee Won-Chul , Ju Young Seok , Shin Jong-Yeon , Lee June Koo , Bleazard Thomas , Lee Jun-Ho , Kim Jung-Oh , Yu Saet-Byeol , Kim Jihye , Rhee Hwanseok , Lee Se-Hoon , Kim Jong-Il , Kang Jin-Hyoung , Kim Young Tae , Seo Jeong-Sun 
Published: August 2014

Abstract
All cancers harbor molecular alterations in their genomes. The transcriptional consequences of these somatic mutations have not yet been comprehensively explored in lung cancer. Here we present the first large scale RNA sequencing study of lung adenocarcinoma, demonstrating its power to identify somatic point mutations as well as transcriptional variants such as gene fusions, alternative splicing events and expression outliers. Our results reveal the genetic basis of 200 lung adenocarcinomas in Koreans including deep characterization of 87 surgical specimens by transcriptome sequencing. We identified driver somatic mutations in cancer genes including EGFR, KRAS, NRAS, BRAF, PIK3CA, MET and CTNNB1. Candidates for novel driver mutations were also identified in genes newly implicated in lung adenocarcinoma such as LMTK2, ARID1A, NOTCH2 and SMARCA4. We found 45 fusion genes, 8 of which were chimeric tyrosine kinases involving ALK, RET, ROS1, FGFR2, AXL and PDGFRA. Among 17 recurrent alternative splicing events, we identified exon 14 skipping in the proto-oncogene MET as highly likely to be a cancer driver. The number of somatic mutations and expression outliers varied markedly between individual cancers and was strongly correlated with smoking history of patients. We identified genomic blocks within which gene expression levels were consistently increased or decreased that could be explained by copy number alterations in samples. We also found an association between lymph node metastasis and somatic mutations in TP53. These findings broaden our understanding of lung adenocarcinoma and may also lead to new diagnostic and therapeutic approaches.
Citation Format: Won-Chul Lee, Young Seok Ju, Jong-Yeon Shin, June Koo Lee, Thomas Bleazard, Jun-Ho Lee, Jung-Oh Kim, Saet-Byeol Yu, Jihye Kim, Hwanseok Rhee, Se-Hoon Lee, Jong-Il Kim, Jin-Hyoung Kang, Young Tae Kim, Jeong-Sun Seo. The comprehensive mutational profiling of lung adenocarcinoma through large-scale RNA sequencing analysis. [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 1113. doi:10.1158/1538-7445.AM2013-1113
Abstract 1120: Identification and characterization of a novel androgen-regulated long non-coding RNA in prostate cancer.
Authors: Malik Rohit , Iyer Matthew K. , Prensner John R. , Patel Lalit , Han Sumin , Chen Wei , Feng Felix , Chinnaiyan Arul M. 
Published: August 2014

Abstract
Long non-coding RNAs (lncRNAs) have recently been associated with the development and progression of a variety of cancers, including prostate cancer. However, to date very few prostate cancer lncRNAs have been characterized by functional studies as bona fide oncogenes and tumor suppressors. Previously, transcriptome sequencing (RNA-Seq) of prostate tumors and benign adjacency tissues revealed a set of putative lncRNAs termed Prostate Cancer Associated Transcripts (PCATs) with significantly altered expression levels in cancer. Intriguingly, a subset of these PCATs were strikingly upregulated in treatment-resistant metastatic prostate cancer samples, suggesting that they may play a role in the development of castrate resistant disease. To explore this possibility we stimulated prostate cancer cell lines with synthetic androgen and monitored the responsiveness of several PCATs. We found that PCAT29, a six-exon nuclear transcript located in a gene desert on chromosome 15, was suppressed by androgen in a time-dependent fashion. Furthermore, androgen receptor (AR) ChIP-Seq data revealed a strong binding site upstream of the PCAT29 promoter suggesting that PCAT29 may be a direct androgen receptor target. Supporting this notion, physical castration of a mouse Xenograft model led to profound upregulation of PCAT29 suggesting that AR signaling suppresses its transcription. Knockdown of PCAT29 using two independent shRNA leads to significant increase in the proliferation of LNCaP cells. Consistently, overexpression of PCAT29 in DU145 cells suppresses proliferation. Finally, we show that in prostate cancer patients, high PCAT29 expression correlates with better overall survival. Taken together our study suggests that PCAT29 may have a tumor suppressor like function in prostate cancer. Ongoing studies are focused on understanding the potential mechanism of PCAT29 function and its relationship with androgen signaling.
Citation Format: Rohit Malik, Matthew K. Iyer, John R. Prensner, Lalit Patel, Sumin Han, Wei Chen, Felix Feng, Arul M. Chinnaiyan. Identification and characterization of a novel androgen-regulated long non-coding RNA in prostate 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 1120. doi:10.1158/1538-7445.AM2013-1120
Abstract 1121: The long non-coding RNA MALAT1 is an essential gene regulator for lung cancer metastasis in a novel human knockout model .
Authors: Gutschner Tony , Hämmerle Monika , Eißmann Moritz , Hsu Jeff , Kim Youngsoo , Hung Gene , Revenko Alexey , Arun Gayatri , Stentrup Marion , Groß Matthias , Zörnig Martin , MacLeod A. Robert , Spector David L. , Diederichs Sven 
Published: August 2014

Abstract
The long non-coding RNA MALAT1 was one of the first lncRNAs associated with cancer: it is a highly conserved nuclear ncRNA and a predictive marker for metastasis development in lung cancer. However, its high abundance and nuclear localization have greatly hampered its functional analysis since it is only inefficiently knocked down by RNA interference (RNAi).
To uncover its functional importance, we developed a MALAT1 knockout model in human lung tumor cells by genomically integrating RNA destabilizing elements site-specifically into the MALAT1 locus using Zinc Finger Nucleases (ZFN).This approach yielded a more than 1000-fold silencing of MALAT1 providing a unique loss-of-function model.
Proposed mechanisms of action of MALAT1 include regulation of splicing or gene expression. In lung cancer, MALAT1 does not alter alternative splicing but actively regulates gene expression inducing a signature of metastasis-associated genes. Consequently, MALAT1-deficient cells are impaired in migration and form fewer tumor nodules in a mouse xenograft model.
Encouraged by this discovery of the essential function of MALAT1 in lung cancer metastasis, we wanted to analyze whether MALAT1 could also be therapeutically targeted: We developed Antisense oligonucleotides (ASOs) effectively blocking MALAT1 expression in the cell culture and in the animal. Notably, MALAT1-ASO treatment prevents metastasis formation after tumor implantation. Thus, targeting MALAT1 with antisense oligonucleotides provides a potential therapeutic approach to prevent lung cancer metastasis with MALAT1 serving as both, predictive marker and therapeutic target.
Lastly, regulating gene expression, but not alternative splicing is the critical function of MALAT1 in lung cancer metastasis.
In summary, ten years after the discovery of the lncRNA MALAT1 as a biomarker for lung cancer metastasis, our loss-of-function model unravels the active function of MALAT1 as a regulator of gene expression governing hallmarks of lung cancer metastasis.
Citation Format: Tony Gutschner, Monika Hämmerle, Moritz Eißmann, Jeff Hsu, Youngsoo Kim, Gene Hung, Alexey Revenko, Gayatri Arun, Marion Stentrup, Matthias Groß, Martin Zörnig, A. Robert MacLeod, David L. Spector, Sven Diederichs. The long non-coding RNA MALAT1 is an essential gene regulator for lung cancer metastasis in a novel human knockout model . [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 1121. doi:10.1158/1538-7445.AM2013-1121