bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3028: Peroxisome proliferator-activated receptor ≤ (PPARδ) reveals a critical role in promoting the TGFβ-induced EMT and metastasis of non-small cell lung cancer cell (H460)
Authors: Lin Li-Chiung , Hsu Shih-Lan , Wu Chieh-Liang , Hsueh Chi-Mei 
Published: August 2012

Abstract
Although transforming growth factor ≤ (TGFβ) is anti-cancer identified, it was also known to promote tumor malignancy by enhancing the growth, epithelial to mesenchymal transition (EMT), tissue invasion and metastasis in a variety of cancer cells, including non-small cell lung cancers (NSCLCs). The aim of this study was to know the contribution of peroxisome proliferator-activated receptor ≤ (PPARδ) to TGFβ-promoted EMT and metastasis in NSCLCs. The degree of EMT, cell scattering, migration and invasion, and protein expression of PPARδ were first analyzed and compared between H460 and CH27 cells with or without TGFβ treatment (both are NSCLC cell lines). Chemical or shRNA blocking assay was also utilized to further confirm the importance of PPARδ in promoting TGFβ-induced tumor metastasis. Finally, signaling pathway(s) responsible for TGFβ/PPARδ-mediated metastasis was evaluated. The results demonstrated that TGFβ can effectively triggered the EMT, cell scattering, migration and invasion in H460 cell, but only a slight EMT was seen in TGFβ-treated CH27 cell. Meanwhile, PPARδ expression was induced by TGFβ in H460 cells but remained unchanged in CH27 cell. This indicated that PPARδ may involve in TGFβ-mediated metastasis. Co-treatment of TGFβ with GW9662 (a specific PPARδ inhibitor) significantly blocked TGFβ-promoted metastasis of H460 cell indicating the presence of PPARδ was indeed critical for TGFβ-attributed tumor metastasis. TGFβ appeared to act through P38 signaling pathway to trigger the expression of PPARδ and the subsequent activation of epidermal growth factor receptor (EGFR)/c-mesenchymal-epithelial transition factor (c-MET) signaling pathway and the reduction of E-cadherin that eventually led to the EMT and metastasis of H460 cell. Additionally, TGFβ also act through P38 to trigger the expression of β-catenin which could bind to and up-regulate the expression of PPARδ. Blocking of β-catenin activity, however, did not interfere with the metastasis indicating β-catenin may not play a direct role in promoting the metastasis of H460 cell. Nevertheless, we can not preclude the possibility that β-catenin may still act through PPARδ to regulate the metastasis of H460 cell, indirectly. In summary, TGFβ-induced EMT and metastasis in H460 cell was PPARδ-dependent and GW9662 revealed a therapeutical value in the control of NSCLCs (H460).
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 3028. doi:1538-7445.AM2012-3028
Abstract 303: Host-derived CCL2 plays a critical role in prostate cancer growth and skeletal metastasis
Authors: Fu Jiejun , Zhang Jian , Wang Jianhua , Lu Yi 
Published: August 2012

Abstract
We have previously reported that the presence of CC chemokine ligand 2 (CCL2) produced by prostate cancer (PCa) epithelial cells, stroma/osteoblasts, and bone marrow endothelial cells, is pro-tumorigenic for prostate cancer cells. CCL2 increases prostate cancer cell proliferation, migration, and survival and induces osteoclast formation. Moreover, the key role of CCL2 in the tumor growth and metastasis has been linked to its regulatory role in mediating monocyte/macrophage infiltration into the tumor microenvironment. Using a model of human PCa cells implanted in mice, Loberg R. et al. reported that anti-murine CCL2 neutralizing antibodies resulted in greater reduction of overall tumor burden compared to the use of anti-human antibody (anti-tumor cell-derived). This suggests that host-derived CCL2 may play a key role in prostate tumor growth and metastasis. Therefore, in this study, we have employed CCL2 knockouts which were interbred to SCID mice to generate colonies of homozygous SCID/CCL2−/− mice. PCa cells (PC3Luc) were injected into the left ventricle (Intracardiac-injection) of SCID/CCL2−/- and wild-type controls (n=20/group). The effects of deletion of CCL2 in the host on prostate cancer cell homing, growth in bone and bone destruction were evaluated for 4 weeks. In a parallel experiment, PC3Luc cells were subcutaneously implanted and tumor size was monitored weekly for 4 weeks. This parallel study addressed bone-specific vs. generalized influences of host-derived CCL2 on prostate cancer growth. We found that skeletal metastases occurred in 4/20 SCID/CCL2−/− mice vs 14/20 WT mice. In addition, X-ray photographs showed significantly fewer bone resorptive lesions in SCID/CCL2−/− mice vs. WT mice. Histology examinations confirmed x-ray findings. In the parallel experiment, PC3Luc tumor grew slower in SCID/CCL2−/- mice vs. WT mice. These results indicate that host-derived CCL2 production defines a permissive microenvironment for prostate cancer growth and skeletal metastasis. These findings may significantly impact the therapeutic field through targeting “the host” instead of “the tumor cells” in prostate cancer. Supported by U.S. Department of Defense PC061231 (J. Zhang), National Natural Sciences Foundation Key Project (81130046, J. Zhang) and National Natural Science Foundation Project (81171993, Y. Lu).
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 303. doi:1538-7445.AM2012-303
Abstract 3038: Delineating the role of Arid3B in normal and malignant differentiation of esophageal and cervical stratified squamous epithelia
Authors: Roy Lynn , Samyesudhas Serene , Dahl Karen Cowden 
Published: August 2012

Abstract
ARID3B is DNA binding protein overexpressed in neuroblastoma and ovarian cancer. We have determined that ARID3B expression is also upregulated during squamous epithelial differentiation (cervix, skin, and esophagus). Therefore, we wanted to assess the role of ARID3B in development of squamous cell carcinomas of the esophagus and cervix. In addition to examining the expression of ARID3B, we also wanted to determine the mechanism for ARID3B regulation in cancer and normal squamous cell epithelia. Recent evidence suggests that p63, specifically the ΔNp63α isoform, transcriptionally regulates Arid3B. p63 is a member of the p53 transcription factor family and is essential for the proliferative potential of stem cells in stratified squamous epithelia. p63 is also involved in various cancers including skin cancer and esophageal cancer. In esophageal squamous cell carcinoma, p63 is ubiquitously expressed and low levels are associated with a poor prognosis. We hypothesize that p63 regulates Arid3B in normal and malignant differentiation of stratified squamous epithelium. To evaluate ARID3B expression in cancer we performed immunohistochemistry on tissue microarrays using two independent Arid3B antibodies. Loss of nuclear Arid3B appears to be common in squamous cell carcinoma of cervix and esophagus. We also examined expression of ARID3B in a normal and a squamous cell carcinoma esophageal cell line. We are also examining the coordinate expression of p63 and Arid3B in serial sections of normal and malignant tissue sections of esophagus, cervix, and skin. We are also investigating the regulation of ARID3B in 3D cell culture models of esophagus differentiation. Our data suggests that misregulation of ARID3B may contribute to the development of cancer in stratified epithelia specifically of the cervix and esophagus.
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 3038. doi:1538-7445.AM2012-3038
Abstract 3044: A new paradigm for ABCB6: Role in growth and proliferation
Authors: Polireddy Kishore K. , Chavan Hemant , Krishnamurthy Partha C. 
Published: August 2012

Abstract
ABCB6 is a mitochondrial ATP binding cassette (ABC) transporter whose expression is upregulated in a broad spectrum of primary human cancers, including hepatocellular carcinoma (HCC). We recently demonstrated that in hepatoma cells ABCB6 expression promotes growth and proliferation. In contrast, loss of ABCB6 expression in these hepatomas precipitates a delay in progression through G2/M phase of the cell cycle. As histone H3 is specifically phopshorylated during mitosis, we took advantage of the H3 phosphorylated antibody to separate G2 phase of the cell cycle from the M-phase. Using this approach, we demonstrate that loss of ABCB6 expression leads to a delay in M phase and not the G2 phase of the cell cycle. However, it is not clear how a mitochondrial transporter, originally characterized as a transporter of porphyrins, regulates cell growth. We have proposed two broad hypotheses to evaluate the mechanism by which ABCB6 regulates growth and proliferation; 1) ABCB6 functionally interacts with one or more of the cell cycle regulatory components, thus precipitating M phase delay; 2) ABCB6s’ location and function as a mitochondrial membrane transporter alters mitochondrial dynamics leading to some level of control over cellular proliferation. To test our proposed first hypothesis we have begun a systematic evaluation of the expression and function of cell cycle regulatory components in response to ABCB6 expression. Results from these studies demonstrate that ABCB6 expression alters the expression of cyclin-dependent kinase inhibitors p16, p21 and p27. In addition, yeast two-hybrid screening and protein interaction studies reveal that ABCB6 interacts with p21 and a novel tumor susceptibility protein-101 (TSG-101). TSG 101 co-localizes with microtubule organizing centers and mitotic spindles during mitosis and its deficiency is associated with abnormalities in microtubules, genetic instability and carcinogenesis. In this report, we provide evidence of the physical and functional interactions between ABCB6 and cell cycle regulatory components and explore the significance of these interactions to growth and proliferation.
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 3044. doi:1538-7445.AM2012-3044
Abstract 3046: Cathepsin B and uPAR downregulation sensitizes glioma initiating cells to radiation induced cell cycle arrest
Authors: Gopinath Sreelatha , Malla Rama Rao , Alapati Kiranmai , Tsung Andrew J. , Rao Jasti S. 
Published: August 2012

Abstract
Ionizing radiation is the standard treatment for glioblastoma multiforme (GBM). Radiation and chemoresistance have been attributed to a small population of cells known as glioma stem cells (GSCs) or glioma initiating cells (GICs). In the present study, we studied the effect of ionizing radiation on the progression of cell cycle of glioma initiating cells, non glioma initiating cells (non-GICs), and the respective parental cell lines (U251 and U87). Initial experiments showed that GICs were resistant to lower doses of radiation (3 and 5 Gy) as compared to parental and non-GICs. Radiation dosage of 10 Gy induced significant G2/M arrest as early as 12 and 24 hours in non-GICs (U251 and U87) and parental cell lines (U251 and U87), respectively and a low percentage of GICs were observed in the G2/M phase 48 hours after radiation. Apart from cathepsin B and uPAR, expression levels of cyclin B1, pcdc2, pchk2 and pERK were also elevated when cells were exposed to radiation. shRNA-mediated simultaneous knockdown of cathepsin B and uPAR (pCU) decreased radiation-induced expression of cyclin B1, pcdc2, pchk2 and pERK and induced apoptosis. Further, immunoblot analysis indicated that cathepsin B and uPAR downregulation reduced the expression of neural stem cell markers, such as CD133, Sox-2 and Bmi-1. Activation of pERK played an important role in inducing the G2/M arrest of GICs of both cell lines as its inhibition induced cell differentiation and sensitized the cells to radiation. Irradiation induced aggressive tumors in vivo and the knockdown of uPAR and cathepsin B significantly decreased radiation-induced tumor growth. Thus, these results indicate that uPAR and cathepsin B downregulation sensitized GICs to ionizing radiation and targeting these proteins could be an efficient approach to eradicate tumors, particularly GICs in the tumor bulk.
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 3046. doi:1538-7445.AM2012-3046
Abstract 3048: High frequencies of centrosome amplification in MMTV-Her2/Neu pre-malignant mammary lesions and in Her2+ breast cancer cells suggest that centrosome amplification is involved in Her2-dependent breast cancer biogenesis
Authors: Harrison Mary Kathryn , Saavedra Harold I. 
Published: August 2012

Abstract
Centrosome amplification (CA) is a major force in cancer initiation and progression, as it generates aneuploidy and chromosome instability. Observations in breast tumors show that adenocarcinomas have a higher frequency of centrosome defects when compared to normal breast tissue. Similar phenotypes are also found in pre-malignant lesions and in pre-invasive in situ ductal carcinoma, suggesting that these aberrations occur early in breast carcinogenesis. Identification of the pathways and regulatory molecules involved in the generation of CA is essential to understanding the role of CA in breast tumorigenesis. Our published results showed that CA is specific to the Her2 effector Ras at mammary pre-malignancy and in tumorigenesis. Due to the strong association between Her2 over-expression and CA in human breast cancers, our goal is to identify cell and centrosome cycle regulators that are de-regulated by aberrant Her2 signaling in human and mouse mammary epithelial cells. Our results show breast cancer cells over-expressing Her2 and pre-malignant mouse mammary hyperplasias expressing Her2/Neu harbor CA. In Her2+ cells that display a plethora of genetic alterations, this process is dependent on Her2, as revealed by shRNA and shRNA downregulation of Her2. Human breast cancer cells expressing Her2 show up-regulation of cyclin D1 and other important centrosome regulatory molecules. In fact, abrogation of Cdk4 or Cdk6, catalytic partners of cyclin D1 reduced the frequencies of CA in Her2+ cells. In contrast, downregulation of Cdk2 did not affect CA. We want to elucidate the mechanism responsible for CA in Her2+ breast cancers. Cells overexpressing Her2 also display increased frequencies of binucleation, suggesting a defect in cytokinesis. We propose that in Her2+ cells, Cdk4 signals CA through either by hyperphosphorylation of NPM at Thr199, a site that negatively regulates centrosome duplication, and/or through the Rb/E2F pathway.
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 3048. doi:1538-7445.AM2012-3048
Abstract 3055: PD-0332991, a selective cyclin-dependent-kinase 4/6 Inhibitor, upregulates multiple genes promoting invasion and metastasis in pancreatic ductal adenocarcinoma
Authors: Liu Fang , Korc Murray 
Published: August 2012

Abstract
Deregulation of the Cyclin D-CDK4/6-Rb-E2F signaling pathway is among the most commonly found aberrations in human pancreatic ductal adenocarcinoma (PDAC). PD-0332991 is an orally available, highly specific and reversible inhibitor for Cdk4 and Cdk6, and demonstrates in vitro and in vivo growth inhibitory effects in multiple tumor types. However, the potential usefulness of PD-0332991 in PDAC is currently unknown. In this study, we examined the effects of PD-0332991 on multiple human pancreatic cancer cell lines, and we found that this agent inhibited Rb phosphorylation and E2F target gene expression, and induced G0/G1 cell cycle arrest. However, the growth inhibitory effect was only transient, due to the rapidly emerging compensatory changes of the G1/S machinery components, including upregulation of CyclinD1, Cdk4, and Cdk6, and downregulation of Rb, p107, and p130. Microarray analysis revealed that incubation with PD-0332991 upregulated multiple genes which promote pancreatic cancer invasion, metastasis, angiogenesis, and chemoresistance, including LAMC2, CYR61, SERPINE1, F3, ABCA1, ASNS, and DUSP1. In addition, using matrigel-coated transwell invasion chambers, we demonstrated that incubation with PD-0332991 enhanced the invasiveness of human pancreatic cancer cells. These observations suggest that PD-0332991 may have the potential to cause deleterious effects in PDAC by modulating gene expression in a manner that could promote cancer spread, metastasis, and chemoresistance.
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 3055. doi:1538-7445.AM2012-3055
Abstract 3122: The DNA-PK inhibitor NU7441 inhibits non-homologous end joining, enhances radio- and chemosensitivity and increases dependence on homologous recombination in hepatocellular carcinoma cell lines
Authors: Cornell Liam , Munck Joanne M. , Reeves Helen L. , Curtin Nicola J. 
Published: August 2012

Abstract
Background DNA double-strand breaks (DSBs), the most cytotoxic lesions induced by ionizing radiation (IR) and anticancer drugs such as topoisomerase II poisons (e.g., doxorubicin), are repaired by non-homologous end joining (NHEJ) and homologous recombination (HR). DNA-dependent protein kinase (DNA-PK), which initiates NHEJ, is up-regulated in hepatocellular carcinoma (HCC) (GEO profiles), possibly contributing to anticancer therapy resistance. To assess DNA-PK as a potential therapeutic target for chemo- and radio-sensitisation in HCC we determined the effect of the DNA-PK inhibitor, NU7441, on DSB repair and cytotoxicity in HCC cells. Methods DNA-PK protein levels and activation by IR (Western blot), DSB levels (y-H2AX foci), HR (RAD51 foci), cell growth (DAPI fluorescence) and cytotoxicity (colony formation) following exposure to IR or doxorubicin was determined in a panel of 6 hepatoma cell lines (HepG2, Hep3B, Huh7, SNU-182, SNU475 and PLC/PRF/5). Results DNA-PK protein concentration and activity did not vary significantly across the panel (±24% and ±37%, respectively) but there were cell-specific sensitivities to IR and doxorubicin (e.g. HepG2 2-fold more resistant than Hep3B). NU7441 significantly sensitised all cells to both doxorubicin (average PF50 4.3±3.0) and IR (average PF50 3.9±1.1) in growth inhibition assays and significantly reduced survival (4.8 to 3.3-fold) in colony forming assays. Following exposure to IR, NU7441 significantly delayed yH2AX focus clearance in all cell lines (e.g. only 13% cleared at 4 hr compared to 50% in control), but increased RAD51 focus formation (3-fold). Conclusion While chemo- and radio-sensitivity in HCC cells was not dependent on DNA-PK expression or activity, NU7441 causes greater than 2-fold chemo- and radiosensitisation in all cells. This was accompanied by a substantial reduction in the rapid phase of DNA repair (NHEJ-dependent) and a shift to a greater reliance on the slower HR repair. DNA-PK inhibitors may have potential as chemo- and radio-sensitisors in hepatoma patients.
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 3122. doi:1538-7445.AM2012-3122
Abstract 3148: Frequent epigenetic inactivation of keap1 gene in non small cell lung cancer
Authors: Muscarella Lucia Anna , Parrella Paola , la Torre Annamaria , D'Alessandro Vito , Barbano Raffaela , Pellegrini Fabio , Tancredi Antonio , Guarnieri Vito , Coco Michelina , Balsamo Teresa , Vendemiale Gianluigi , Maiello Evaristo , Fazio Vito Michele 
Published: August 2012

Abstract
The KEAP1/NRF2 pathway is a master regulator of several redox-sensitive genes implicated in resistance of tumour cells against chemotherapeutic drugs. Recent data suggest that epigenetic mechanisms may play a pivotal role in the regulation of KEAP1 expression. We performed a comprehensive genetic and epigenetic analysis of the KEAP1 gene in 47 Non Small Cell Lung Cancer tissues and 12 normal lung specimens. Promoter methylation analysis was performed using a quantitative methylation specific PCR assay in real time. Methylation at the KEAP1 promoter region was detected in 22 out of the 47 NSCLCs (47%) and in none of the normal tissues analyzed. Somatic mutations were detected in 7 out of the 47 tumours (15%), and loss of heterozygosity (LOH) in 10 out of the 47 (21%) of the cases. Overall, we found at least one molecular alteration in 57% of the cases. Approximately one third of the tumours had two alterations and this feature was associated with higher risk of disease progression in univariate COX regression analysis (HR=3.62; 95% CI 1.24-10.65, p=0.02). This result was confirmed by Kaplan-Meier analysis which demonstrated an association between worst outcome and KEAP1 double alterations (p=0.01, Log rank test). Our results further suggest that deregulation of the NRF2/KEAP1 system could play a pivotal role in the cancerogenesis of NSCLC. In addition identifying patients with KEAP1 genetic and epigenetic abnormalities may contribute to disease progression prediction and response to therapy in lung cancer patients.
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 3148. doi:1538-7445.AM2012-3148