bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 113: Effect of targeting Aurora kinase A in human oral squamous cell carcinoma cells
Authors: Tanaka Hiroshi , Nakashiro Koh-ichi , Oka Ryota , Hamakawa Hiroyuki 
Published: August 2012

Abstract
Oncogene addiction has provided therapeutic opportunities in many human malignancies, but molecular targeted therapy for oral squamous cell carcinoma (OSCC) is not available. In this study, we identified an appropriate molecule for treatment of patients with OSCC. We determined the gene expression profiles in 10 human OSCC cell lines and a non-neoplastic keratinocyte cell line by microarray analysis, and then identified Aurora kinase A (AURKA) as a cancer-related gene which was commonly overexpressed in OSCC cells. We also confirmed the overexpression of AURKA mRNA in OSCC tissues and compared to normal oral mucosa tissues by quantitative RT-PCR. AURKA plays an essential role in centrosome duplication, mitoic entry, and spindle assembly. Overexpression of AURKA in human malignancies is associated with gene amplification, genetic instability, poor histological differentiation, and poor prognosis. To determine if the AURKA is a plausible therapeutic target, we investigated the effect of small interfering RNAs specific for AURKA(siAURKA) and an AURKA selective inhibitor MLN8237 on the growth of human OSCC cells in vitro and in vivo. Knockdown of AURKA by RNA interference (RNAi) markedly inhibited the growth of OSCC cells and observed the change of colony formation and cell size looked like cell cycle arrest. We examined the RNAi effect of siAURKA in OSCC cells by Western blotting. Compared with non-target siRNA, the protein expression level of AURKA was almost completely suppressed. MLN8237 also reduced the cell growth, but showed relatively resistant to cells expressing AURKA at high levels. Transfection of siAURKA inhibited the growth of OSCC cells more potent than treatment with MLN8237 in vitro. Furthermore, we confirmed the effect of siAURKA and MLN8237 on the growth of human OSCC tumors which had been subcutaneously xenografted in athymic nude mice. Atelocollagen-siAURKA (8 nmol) complexes were injected into the tail vein every 3 days and MLN8237 (30 mg/kg) were received orally for 14 consecutive days. We found that siAURKA and MLN8237 significantly reduced the size of subcutaneously xenografted OSSC tumors. Interestingly, the combination of siAURKA and MLN8237 induced remarkable anti-tumor activity compared with single agent groups. These results suggest that AURKA functions as a critical gene for supporting the growth of human OSCC cells and targeting AURKA may be a useful therapeutic strategy for OSCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 113. doi:1538-7445.AM2012-113
Abstract 1147: Molecular characterization of PI3K pathway alterations in non-small cell lung carcinoma
Authors: Huw Ling-Yuh , Spoerke Jill , O'Brien Carol , Koeppen Hartmut , Fridlyand Jane , Amler Lukas , Hampton Garret , Shames David , Lackner Mark , Pandita Ajay 
Published: August 2012

Abstract
Lung cancer is the leading cause of cancer deaths worldwide. Several oncogenes and tumor suppressor genes have been implicated in lung carcinogenesis. Among them, PIK3CA pathway activation is one of the key pathways that link cell surface receptor kinases to effectors for tumor growth, metabolism and survival. To support predictive diagnostic biomarker efforts for the selective PI3K inhibitor GDC-0941, we conducted detailed molecular characterization of NSCLC tumor samples. We evaluated the key oncogenic mutations (KRAS, EGFR, PIK3CA, BRAF and NRAS), gene expression, protein expression (PTEN) and gene copy number alterations in genes in the PI3K pathway in NSCLC tumors. We found that oncogenic mutations and copy number alternations were associated with histological subtype. Of note, mutations in KRAS and EGFR were found with high frequency (30%) in adenocarcinoma, as was loss of the tumor suppressor LKB1. On the other hand, amplification of PI3K was found in the squamous subtype, as were rare mutations in PI3K. The tumor suppressor PTEN showed a high frequency of reduced expression in both squamous and adenocarcinomas, though total loss of PTEN was more common in squamous carcinomas. Our studies suggest that the PI3K pathway is an attractive therapeutic target in NSCLC, and that distinct biomarker strategies may be required for development in squamous and non-squamous patient populations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1147. doi:1538-7445.AM2012-1147
Abstract 1167: The expression of urokinase plasminogen activator (uPA) system genes in prostate carcinoma is related to clinicopathological parameters
Authors: Al-Janabi Omar , Wach Sven , Nolte Elke Nolte , Wullich Bernd , Taubert Helge , Füssel Susanne , Lohse Andrea , Kotzsch Matthias , Wieland Wolf , Stoehr Robert , Hartmann Arndt 
Published: August 2012

Abstract
Background: Prostate cancer (PCa) is a leading cause of tumor mortality. Members of the urokinase plasminogen activator (uPA) system play an important role in tumorigenesis in many human malignancies. We sought to characterize the mRNA expression of uPA members in primary PCa samples and to correlate this expression to clinicopathological parameters. Material and methods: We investigated the mRNA expression level of three members of the uPA system (uPA, PAI-1 and uPAR) using 26 paired samples of PCa and adjacent non-malignant tissue. Absolute quantification of gene expression was performed by quantitative PCR and subsequent standardization on the reference gene TBP. Gene expression measures were further correlated to clinicopathological characteristics as TNM classification, Gleason sum, and tumor grade. Results: Although we did not detect significant differences in expression of uPA system genes between tumor and matched nonmalingnant tissue in our patient cohort, we identified a positive correlation of all three uPA family members (p&lt;0.01; bivariate correlation). When stratifying PAI-1 expression according to the median mRNA level we discovered correlations to defined tumor characteristics. Tumors with PAI-1 expression above median displayed a higher Gleason sum (8 or 9) than tumors expressing less-than-median PAI-1 (p=0.03, Fisher's exact test). Likewise, an elevated PAI-1 expression was correlated with higher tumor grade (p=0.01; Fisher exact test) and tumor stage (p=0.046; Fisher exact test). Conclusion: Our results demonstrate that mRNA expression of PAI-1 as a member of the uPA family correlates with characteristic pathological parameters of PCa.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1167. doi:1538-7445.AM2012-1167
Abstract 1176: Bypassing the dominant-negative effect of mutant p53 in cancer cells
Authors: Okal Abood , Mossalam Mohanad , Matissek Karina J. , Lim Carol S. 
Published: August 2012

Abstract
The tumor suppressor p53 is mutated in more than 50% of all cancers. The transcriptional activity of p53 depends on localization to the nucleus and formation of p53 tetramers. Use of wild-type (wt) p53 for gene therapy is limited due to the dominant-negative effect of mutant (mut) p53 over wt p53. Mut p53 will hetero-oligomerize with wt p53 via the tetramerization domain (TD) found in p53, deactivating the tumor suppressor function of wt p53. In order to use p53 for gene therapy, an alternative oligomerization domain for p53 was investigated. The coiled-coil (CC) domain from Bcr (breakpoint cluster region), similar to the native TD of p53, can form an antiparallel dimer of dimers. The TD from p53 was then substituted with this CC, and the activity of this new p53 (p53-CC) was tested. We evaluated the transcriptional activity of p53-CC compared to wt p53 in a dual luciferase reporter gene assay. To demonstrate the ability of our p53-CC to bypass the dominant-negative effect prompted by hetero-oligomers, the reporter gene assay was carried in human breast adenocarcinoma (MCF-7) and human breast ductal carcinoma (T47D) cell lines. MCF-7 cells contain wt p53 population that is mislocalized to the cytoplasm, whereas, T47D cells contain mutant p53. Indeed, data from the reporter gene experiment shows a reduction in wt p53 activity introduced to T47D cells compared to MCF-7 cells, while the activity of p53-CC remains consistent regardless of the presence of an endogenous mut p53 population. We also tested the biological activity of p53-CC and its ability to induce apoptosis using 7-AAD and Annexin-V assays (late stage apoptosis). In addition, Caspase-3/7 assay (mid-stage apoptosis) was performed to further validate a p53-dependent apoptotic pathway. Data obtained from the aforementioned experiments suggest that p53-CC has a very similar biological activity to wt p53. Furthermore, we examined the gene expression profile of p53-CC using wt p53 as a reference. The assay was performed using real-time PCR array technology to analyze the expression of 84 genes related to p53-mediated signal transduction. Two negative controls were used; the first is a p53 construct that lacks its tetramerization domain (p53ΔTDC) and should not possess any transcriptional activity, and the second is the CC by itself. Indeed, p53-CC shows comparable gene expression profile to wt p53 and has the ability to transactivate the various p53 target genes. In summary, p53-CC retains p53 activity and excludes hetero-oligomer formation, overcoming a major barrier in using p53 for cancer gene therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1176. doi:1538-7445.AM2012-1176
Abstract 1181: P73 regulates the expression of KAI1, metastasis suppressor gene
Authors: Lee Ji Hee , Bae Woo Kyun , eul Hwang Jun , Cho Sang Hee , Chung Ik Joo 
Published: August 2012

Abstract
KAI1, a metastasis suppressor gene of various cancers, has been known to inhibit tumor metastasis without affecting primary tumor growth. Identification of transcription factor regulating KAI1 is important for understanding tumor metastasis mechanism. P73 binding site within the KAI1 promoter were characterized by luciferase assay using reporter plasmids containing serial deletion promoter regions of KAI1 gene and chromatin-IP assay. To confirm whether the over-expressed KAI1 gene regulated by p73 in the transcriptional level was active, cell motility was analysed by using an adhesion and invasion assay. Here, we first identified that KAI1 is transcriptionally regulated by p73, a p53 family member, in various cancer cell lines. In p53-deficient cell lines, p73 had highest promoter binding activity in the KAI1 promoter regions between −903 and −846 bp, known as a p53-binding site. Human colon cancer cells stably overexpressing p73 showed that in vitro extracellular matrix adhesion and invasive potential was decreased compared with parental cells. These data explain that p73 regulate the KAI1 gene expression in the transcription level by binding on the specific region of the KAI1 promoter. In addition, it could be suggested that decreased invasion suppressive effect of KAI1 in invasive tumor and tumor cell lines caused by weak expression of KAI1 could be restored by increasing the p73 level. P73 might contribute the metastasis suppressive effect through upregulating KAI1 gene expression in invasive tumor and tumor cell lines. Taken together, our present results suggest that p73 contributes to KAI1 promoter activity in cells and plays an important role in the repression of tumor metastasis function via regulation of KAI1 expression in invasive tumor and tumor cell lines.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1181. doi:1538-7445.AM2012-1181
Abstract 131: Hypomethylation of Alu repeat sequences permits activation of microRNAs in human colorectal cancer metastasis
Authors: Hur Keun , Boland Clement Richard , Goel Ajay 
Published: August 2012

Abstract
Background: Global hypomethylation of cytosines within CpG dinucleotides has been reported in various human cancers. Repetitive elements dispersed throughout the human genome, including Alu and LINE1 sequences, have been used as global surrogate markers for estimating global DNA methylation levels. Recent evidence indicates that certain human miRNAs are located downstream of Alu sequences, and these non-coding RNAs can be transcribed by the recruitment of RNA polymerase III to the promoter region of Alu repeats. Primary colorectal cancers (CRC) demonstrate frequent global Alu hypomethylation; however, it is not clear whether hypomethylation of these repeat elements may be associated with a metastatic phenotype. Aim: This study aimed to determine the role of Alu hypomethylation in the development of CRC metastasis. Materials and Methods: We analyzed a panel of CRC cells, as well as matched pairs of primary CRCs (PC) and corresponding liver metastasis (LM) tissues from 59 CRC patients. Alu methylation levels were measured by quantitative bisulfite pyrosequencing. In addition, we determined the expression status of miR-520c and miR-373, which are located immediately downstream of Alu repeats. Results: All CRC cell lines demonstrated Alu hypomethylation, which was further exacerbated by treatment with the DNA demethylating agent, 5-azacytidine. In the clinical specimens, the levels of Alu methylation were significantly lower in LM compared to the matched PC (mean methylation value; PC = 83% vs. LM = 80%; P &lt; 0.001). Moreover, methylation analysis of surrounding normal liver tissues revealed higher levels of Alu methylation (mean methylation value; 85%) compared to both PC and LM. The expression of both miR-520c and miR-373, showed significantly different expression between PC and LM, which was mediated by the hypomethylation of Alu-associated promoter region. Conclusion: Our results provide novel evidence for increased Alu hypomethylation in liver metastasis tissues from patients with CRC. We speculate that hypomethylation of Alu repeat elements permits activation of metastasis-related miRNAs, which in turn may facilitate a more aggressive malignant phenotype in these advanced stage cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 131. doi:1538-7445.AM2012-131
Abstract 1326: Magnetization transfer MRI in pancreatic cancer xenograft models
Authors: Li Weiguo , Zhang Zhuoli , Nicolai Jodi , Yang Guang-Yu , Omary Reed , Larson Andrew 
Published: August 2012

Abstract
Tumor desmoplasia is a common hallmark of pancreatic ductal adenocarcinoma (PDAC), the 4th leading cause of cancer-related mortality. Recent studies clearly indicate that desmoplasia actively facilitates disease progression, metastasis, and drug resistance. Precise quantification of tumor fibrosis levels in PDAC may be critically important for patient staging and for the prediction or monitoring of responses to therapy. The current gold-standard for characterizing desmoplasia_histologic analysis of biopsy samples_is invasive and cannot avoid misrepresentation by reason of sampling error. Therefore, new methods to permit noninvasive quantification of fibrosis levels in PDAC would be particularly useful. Magnetization transfer (MT) MRI can be used to non-invasively probe dynamic physical processes involving the exchange of magnetization between sub-populations of free water protons and those water protons bound to tissue macromolecules. MT-MRI studies have demonstrated that MT contrast (MTC) can be highly sensitive to tissue collagen concentration, the primary component of desmoplasia. Thus, we hypothesized that desmoplasia-associated fibrosis levels in PDAC may be directly reflected in MT-MRI magnetization transfer ratio (MTR) measurements. The purpose of this study was to compare non-invasive MTR measurements to invasive histologic assessments of tumor fibrosis-levels in three mouse xenograft models of PDAC. In this study, MT MRI measurements were performed in 3 PDAC mouse xenograft models. For each of 28 PDAC xenografts, MTR were calculated and compared to histologic fibrosis levels from reference standard trichrome staining. MTR was found to be significantly higher in tumors grown using BxPC-3 cell line (39.4 ± 5.1, mean ± SD) compared to the MTR for the tumors grown from Panc-1 (32.4 ± 2.8) and Capan-1 (27.3 ± 2.9) cell lines (P &lt; 0.05 for each comparison). Histologic measurements showed a similar trend with BxPC-3 tumors demonstrating significantly higher fibrosis levels (percentage of fibrotic tissue area, 6.48 ± 2.59) when compared to Panc-1 (3.54 ± 2.18) and Capan-1 (2.07 ± 1.60) tumors. MTR measurements were well correlated to quantitative fibrosis levels (r = 0.69, P = 0.01). Our results indicated that MTR measurements offer the potential to serve as a valuable in vivo biomarker of desmoplasia in PDAC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1326. doi:1538-7445.AM2012-1326
Abstract 1359: Establishment and characterization of mouse malignant rhabdoid tumor cell lines
Authors: Kuwahara Yasumichi , Mora-Blanco E Lorena , Rogers Arlin , Fletcher Christopher DM , Roberts Charles WM , Weissman Bernard E. , Weissman Bernard E. 
Published: August 2012

Abstract
Malignant rhabdoid tumors (MRTs) are rare, aggressive cancers occuring in young children primarily through inactivation of the SNF5 tumor suppressor gene. Espetially, rhabdoid tumor arised from brain is usually called AT/RT. We and others have demonstrated that mice heterozygous for a Snf5 null allele develop MRTs with partial penetrance. We have also shown that Snf5+/− mice that lacked expression of the pRb family, due to TgT121 transgene expression, developed MRTs with increased penetrance and decreased latency. In this current study, we observed that the genetic background altered MRT development in Snf5+/− and TgT121;Snf5+/− mice, resulting in increased latency and the appearance of significant frequency of brain tumors. We also report the establishment of the first mouse MRT cell lines that recapitulate many features of their human counterparts including lack of genomic instability and expression of smooth muscle and neuronal differentiation markers. The cell lines also form aggressive tumors upon inoculation into immunocompromised mice that resemble the tumors of origin. Our studies provide further insight into the genetic influences on MRT development as well as provide valuable new cell culture and genetically engineered mouse models for the study of AT/RT etiology.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1359. doi:1538-7445.AM2012-1359
Abstract 136: Suppression of the uPA/uPAR system causes the overexpression of miR124 and suppresses stemness in glioma stem cells
Authors: Asuthkar Swapna , Gorantla Bharathi , Rao Jasti S. , Gondi Christopher S. 
Published: August 2012

Abstract
The invasiveness and destructiveness of malignant neoplasms in the central nervous system are of great clinical importance. Higher-grade tumors, such as glioblastomas, are associated with poor prognosis, and patients’ average survival is only 8 to 12 months after chemotherapy and/or radiotherapy. This poor prognosis reflects the resistance of tumor cells to radiation and cytotoxic agents as well as the difficulty in achieving total tumor resection. Highly infiltrative gliomas are known to overexpress both uPA and uPAR. MicroRNAs (miRNAs) are essential post-transcriptional regulators known to determine cell identity and fate and are also known to be involved not only in development and differentiation but also in glioma progression. Acquisition of EMT has also recently been linked to stem cell phenotypes which is mediated by microRNAs. However, the molecular mechanism underlying EMT regulation still remains elusive. In the present study, we used glioma initiating cells (GICs), which show stem cell-like character, and determined whether their stemness can be suppressed by targeting the uPA/uPAR system. We raised glioma GICs from U87MG and 4910 glioma xenograft cells and observed that GICs expressed 2- to 3-fold increased levels of uPA and uPAR when compared to non-GIC. Further, the simultaneous downregulation of both uPA and uPAR suppressed GIC from establishing intracranial tumors in nude mice. Further, to understand whether this suppression of GIC involved microRNAs, we profiled miR expression in U87 cells and observed that miR124 and miR200a were significantly overexpressed. Using miRanda analysis, we determined that miR124 targets the regulation of Lhx-2 and Lhx-2 is over expressed (3- to 4-fold) in GIC when compared to non-GIC. To determine whether this suppression of Lhx-2 by downregulation of uPA and uPAR is mediated via miR124, we overexpressed miR124 in U87MG and 4910 glioma xenograft GICs and observed that miR124-overexpressed cells failed to establish intracranial tumors in nude mice. Our results demonstrate that the uPA/uPAR system may be involved in GIC maintenance via suppression of miR124.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 136. doi:1538-7445.AM2012-136