bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1080: Protein phosphatase 2A regulates Chk2 phosphorylation at constitutive level in human ovarian cancer cells
Authors: Liang Xiaobing , Guo Yi , Yu Jing Jie 
Published: June 2012

Abstract
Protein phosphatase 2A (PP2A) comprises a diverse family of phosphoserine- and phosphothreonine-specific enzymes ubiquitously expressed in eukaryotic cells. This principal Ser/Thr phosphatase plays an integral role in the regulation of a number of major signaling pathways, the deregulation of which can contribute to multiple human cancers, Alzheimer's disease and increased susceptibility to pathogen infections. The checkpoint kinase Chk2 is an important multifunctional regulator of the cellular DNA damage repair response. Chk2 activation is triggered by the phosphorylation of Thr-68 following DNA damage and protects genome integrity by promoting cell cycle arrest or apoptosis. We have previously reported that ovarian cancer A2780 cells show an interaction between PP2A and Chk2 after cisplatin treatment, and PP2A negatively regulates Chk2 phosphorylation at Thr-68. In this study we report that Chk2 and PP2A are associated to maintain the cell normal function. This conclusion is based on the following observations: 1) Co-immunoprecipatation of the holoenzyme PP2A (subunits A, B and C) with p-Chk2 shown immune complexes; 2) Inhibition of PP2A activity by okadaic acid, an inhibitor of PP2A, and by siRNA to PP2A, resulted in enhanced Chk2 phosphorylation at Thr-68 in studied cell model. These findings demonstrate that PP2A has a role in controlling the constitutive Chk2 phosphorylation at Thr-68 and that Chk2 and PP2A are responsible for maintenance of cell metabolic equilibrium.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1080. doi:10.1158/1538-7445.AM2011-1080
Abstract 1082: The amplification and overexpression of the calcium activated chloride channel TMEM16A (aka DOG1) has a prognostic role in patients with head and neck squamous cell carcinoma
Authors: Ruiz Christian , Zlobec Inti , Rudin Florian , Schneider Sandra , Rufle Alex , Fischer Claude , Tornillo Luigi , Terracciano Luigi M. , Kunzelmann Karl , Bubendorf Lukas 
Published: June 2012

Abstract
Introduction: The calcium activated chloride channel TMEM16A, which is also known as DOG1, is used as a sensitive marker for the diagnosis of gastrointestinal tumors (GIST). Its expression has also been described in head and neck squamous cell carcinomas (HNSCC) and in esophageal SCC. Surprisingly, until recently (2008) its role as chloride channel was not known. The TMEM16A gene is localized very close to the Cyclin D1 gene (CCND1), which is a putative target gene of the 11q13 amplicon. Aim of this study was the analysis of the genomic and expression status of TMEM16A in HNSCC.
Methods: We applied fluorescence in-situ hybridization (FISH) and immunohistochemistry to a tissue microarray (TMA) containing tissue specimens from 216 primary tumors from the oral cavity, 40 local recurrences and 76 neck dissections. We validated our results on a second cohort consisting of additional 158 HNSCCs. In order to analyze the prognostic role of TMEM16A, a subset of 365 primary tumors with complete follow-up data was selected.
Results: We found genomic amplification of the TMEM16A gene in 13% of the primary head and neck squamous cell carcinomas and in 12% of the local recurrences. Although the prevalence of TMEM16A protein expression was lower (8%), a strong correlation between TMEM16A amplification and overexpression was found (p&lt;0.0001). FISH analysis of Cyclin D1 (CCND1) revealed co-amplification of these two genes (p&lt;0.0001). Interestingly, both, genomic amplification and expression of TMEM16A identified a subgroup of HNSCC patients with poor survival (p&lt;0.05).
Conclusions: TMEM16A positivity characterizes a small subgroup of HNSCC with poor survival. The strong correlation between genomic amplification and expression suggests that TMEM16A is one of the driving genes of the 11q13 amplicon in HNSCC. Additional studies may show how this chloride channel can be used as a therapeutic target in patients with TMEM16A positive tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1082. doi:10.1158/1538-7445.AM2011-1082
Abstract 1086: RHA plays an important role in EGFR-mediated gene transcription in cancer cells
Authors: Huo Longfei , Wang Ying-Nai , Xia Weiya , Hsu Sheng-Chieh , Lai Chein-Chen , Li Long-Yuan , Chang Wei-Chao , Wang Yan , Hsu Ming-Chuan , Yu Yung-Luen , Huang Tzu-Hsuan , Ding Qingqing , Chen Chung-Hsuan , Tsai Chang-Hai , Hung Mien-Chie 
Published: June 2012

Abstract
EGF treatment induces the translocation of its receptor (i.e. EGFR) from the cell surface into the nucleus. Nuclear expression of EGFR is negatively correlated with overall survival of cancer patients and EGFR nuclear translocation is important for cancer cell's resistance to the treatment with Cetuximab, cisplatin and radiation. Moreover, EGFR in the nucleus can associates with other proteins including STAT3, STAT5A, DNA-PK and PCNA to regulate cell transformation, proliferation, and DNA repair and replication. It has been demonstrated that nuclear EGFR regulates gene transcription through its binding to an AT-rich sequence (ATRS) of target gene promoter. However, EGFR does not have a DNA-binding domain and there is no evidence to support the direct binding of EGFR to the specific DNA sequence. Thus, identification of a DNA-binding partner of nuclear EGFR is crucial for us to understand how EGFR regulates gene transcription in the nucleus. Using a non-biased approach, we identified RNA helicase A (i.e. RHA), which is a highly conserved, multiple functional transcriptional activator, could interact with nuclear EGFR upon EGF stimulation in several cancer cells. The EGFR/RHA complex then associated with gene promoter through binding of RHA to the AT-rich sequence of the promoter to activate its transcription. Knockdown of RHA expression was found to abrogate the binding of EGFR to its target gene promoter, thereby reducing EGF/EGFR-induced gene expression. Moreover, interruption of EGFR-RHA interaction decreased EGFR-induced promoter activity. Interestingly, we found that the EGFR/RHA-regulated gene promoter activity is dependent on the EGFR tyrosine kinase activity but independent of RHA helicase activity. Finally, we observed a positive correlation among nuclear expression of EGFR, RHA and cyclin D1 in human breast cancer tissue samples. These results, taken together, indicate that RHA is an important mediator for EGFR-induced gene transactivation in cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1086. doi:10.1158/1538-7445.AM2011-1086
Abstract 1087: The role of fibroblast growth factor 9 in the recurrence after radical prostatectomy
Authors: Teishima Jun , Hayashi Tetsutaro , Shoji Koichi , Matsubara Akio 
Published: June 2012

Abstract
Introduction and Objectives: The aim of this study was to investigate the role of fibroblast growth factor 9 (FGF9) in the recurrence after radical prostatectomy. Methods: Immunohistochemical staining using anti-FGF9 antibody was performed for tissues derived from radical prostatectomy in 133 male patients. Cell viability, apoptosis and invasion of LNCaP and androgen-independent LNCaP (AI-LNCaP) cells were assessed with the MTT assay, Apopercentage apoptosis assay and Matrigel invasion assay, respectively, in the presence or absence of treatment with recombinant FGF9 or anti-FGF9 neutralizing antibody. Results: In immunohistochemical staining, FGF9-positive cells were detected in 20 samples. In cases with a Gleason score of 8 or higher, the incidence of cases with FGF9-positive cells was 34.2%, which was significantly higher than that for those with Gleason scores of 7 or lower (7.3%, p=0.0003), respectively. The 3-year biochemical relapse-free survival rate in cases with FGF9-positive cells was 17.5%, which was significantly lower than that in cases in which FGF9-positive cells were not detectable (76.6%, p&lt;0.0001). In androgen-depleted medium, the cell viability of LNCaP was significantly lower than that of AI-LNCaP, and was enhanced to the same level by treatment with recombinant FGF9. Invasion was significantly enhanced and apoptosis by androgen deprivation was significantly suppressed by treatment of LNCaP cells with recombinant FGF9. Furthermore, these effects were significantly suppressed by treatment with anti-FGF9 neutralizing antibody. Conclusions: These results indicate that FGF9 contributes to postoperative recurrence of prostate cancer through stimulation of cell proliferation and invasion, and induction of an anti-apoptotic effect.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1087. doi:10.1158/1538-7445.AM2011-1087
Abstract 1088: Characterizing the effects of alcohol on the ER-alpha status of HER2 breast cancer
Authors: Wong Amy W. , Smith Sarah M. , Nunez Nomeli P. 
Published: June 2012

Abstract
Alcohol consumption is a major risk factor for breast cancer. Approximately 400,000 cases of cancer in 2002 were attributable to alcohol consumption worldwide. In women, breast cancer accounts for 60% of these alcohol-related cancers. Over 25% of all breast cancer cases are HER2 (ErbB2) positive and have poor prognosis. Unfortunately, the mechanism by which alcohol promotes breast cancer is unclear.
Our research focuses on characterizing the effects of alcohol on HER2 positive breast cancer. More specifically, we determine if and how alcohol affects the ER-alpha status of ErbB2-expressing tumors in the presence and absence of ovarian hormones using the MMTV-neu mouse model of ErbB2-induced breast cancer. We show alcohol consumption increases tumor incidence as well as tumor proliferation as demonstrated by Ki67 immunohistochemical staining. We measure systemic estrogen levels and ER-alpha expression in the mammary tumors developed from alcohol and water consuming mice to determine if their levels are associated with the higher tumor incidence in alcohol consuming mice. We show that both systemic estrogen and ER-alpha expression levels are elevated in alcohol consuming mice. Our data suggest that alcohol increases tumor development in HER2 transgenic mice via the estrogen pathway. In fact, the effects of alcohol on tumor incidence were blocked with ovariectomy, suggesting that indeed the effects of alcohol on HER2 tumors are mediated via the estrogen pathway.
Our results suggest that the effects of alcohol on HER2 positive breast cancers can be prevented by targeting or blocking the estrogen pathway. For this purpose, we will determine in future studies if the effects of alcohol can be prevented with tamoxifen, a selective ER modulator (SERM), and letrozole, an aromatase inhibitor, both of which blocks the estrogen pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1088. doi:10.1158/1538-7445.AM2011-1088
Abstract 1092: Insulin-like growth factors modulate chemosensitivity to cisplatin and 5-fluorouracil in human esophageal cell lines
Authors: Zhao Ronghua , Casson Alan G. 
Published: June 2012

Abstract
Resistance to chemotherapy remains a major obstacle to survival of patients with esophageal adenocarcinoma (EADC). The aim of this study was to evaluate whether insulin-like growth factors (IGFs), recently implicated in the molecular pathogenesis of EADC, modulate chemosensitivity to Cisplatin (CDDP) and 5-Fluoruracil (5-Fu), two agents widely used in current clinical practice.
Expression of IGF1, its receptor (IGF1R), and IGF2 (mRNA and protein) were studied using quantitative (real-time) PCR and Western blot in human esophageal cell lines: Het1A (derived from immortalized normal esophageal epithelium), OE33 and JHEsoAd1 (each derived from a primary EADC). For each cell line, the effect of various concentrations of IGFs, CDDP and 5-Fu, alone and in combination, on cell proliferation and clonogenicity were evaluated by standard MTT and colony formation assays, respectively. Changes in expression of 84 critical genes downstream from IGF1R were studied by PCR-array.
Relative to Het1A, IGF1 and IGF2 mRNA were significantly (P&lt;0.05) underexpressed by OE33; by contrast, JHEsoAd1 underexpressed IGF1 but overexpressed IGF2. Administration of either IGF1 (250ng/ml) or IGF2 (500ng/ml) to cell cultures resulted in increased cellular proliferation of JHEsoAD1 cells (after IGF1: 1.24+/-0.05 vs. 1.00+/-0.00 untreated, P&lt;0.01; after IGF2: 1.15+/-0.06 vs. 1.00+/-0.06 untreated, P&lt;0.05). As expected, cell proliferation and clonogenicity of all cell lines were inhibited by CDDP and/or 5-FU (at all dosages ranging from 1-4ug/ml). However, these cytotoxic effects were overcome by the administration of either IGF1 or IGF2 with the exception of: 1) JHEsoAd1 cells treated with CDDP, where IGF2 administration further reduced cellular proliferation (0.35+/-0.06 vs. 0.53+/-0.03 for cells treated with CDDP alone; P&lt;0.05), and 2) JHEsoAd1 cells treated with 5-Fu, where IGF1 administration significantly reduced clonogenicity (0.07+/-0.07 vs. 0.49+/-0.06 for cells treated with 5-Fu alone; P&lt;0.05). PCR-array analysis revealed up-regulation (Het1A and JHEsoAd1) and down-regulation (OE33 and JHEsoAd1) of selected PI3K/AKT pathway genes following IGF1 and IGF2 therapy.
These pre-clinical studies confirm a central role for the IGF axis in esophageal tumor biology, with potential for IGFs to enhance the cytotoxic efficacy of standard chemotherapeutic agents in esophageal cell lines. The identification of novel molecular regulatory pathways downstream from IGF1R modulated by IGF therapy may well inform future cytotoxic and targeting strategies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1092. doi:10.1158/1538-7445.AM2011-1092
Abstract 1094: Role of the CRLF2 ligand TSLP in normal human B-cell development
Authors: Payne Kimberly J. , Milford Terry-Ann , Francis Olivia , Baez Ineavely , Dovat Sinisa , Su Rui-Jun 
Published: June 2012

Abstract
B cell acute lymphoblastic leukemia (B-ALL) is the most common childhood malignancy. Defects that result in overexpression of CRLF2, a cytokine receptor component, have recently been linked with poor outcome in both high-risk and non-high-risk B-ALL. CRLF2, together with the IL-7R alpha chain, forms the signaling receptor for the cytokine TSLP (Thymic Stromal-derived LymphoPoietin). TSLP-induced CRLF2 signaling results in proliferation of murine B cell progenitors, however, the role of TSLP in murine B cell development remains controversial and little is known of its role in human B lymphopoiesis. Human TSLP and CRLF2, in contrast to other cytokine/receptor pairs that act on B cell progenitors, show low homology to their murine counterparts (&lt;40%), lack species cross reactivity, and activate differing intracellular pathways than in mice. Thus, human model systems are essential for understanding the role of CRLF2 function in normal and malignant B lymphopoiesis. We have developed a novel human-only in vitro culture model that allows the study of human B cell development under highly selective cytokine stimulation. This model is based on co-culturing CD34+ hematopoietic stem cells (HSCs) with primary human bone marrow stroma supplemented with selective exogenous cytokines and/or specific cytokine neutralizing antibodies. We have previously used this model to show that IL-7 increases B cell progenitors by over 60 fold and that IL-7 is essential for normal human B cell production (J. Immunol. 2009 82:4255). Here we use our human-only in vitro model to examine the role of TSLP-induced signals in normal human B cell development. Our data show that TSLP induces an expansion of human B cell progenitor populations generated from HSCs in cord blood that is similar in magnitude to that observed for IL-7. A comparison of TSLP and IL-7 effects shows that TSLP targets early B cell progenitors (CD34+) inducing expansion of this population with limited differentiation. In contrast, IL-7 induces rapid differentiation to the CD34- stage followed by proliferation. RT-PCR and ELISA analysis show that normal human bone marrow stoma express both TSLP and IL-7, thus establishing an endogenous source of these cytokines at the site of normal and malignant hematopoiesis. Our data provide evidence that TSLP and IL-7 exert differential and stage specific effects on proliferation and differentiation of B cell progenitors and suggest that deregulation of the complex interplay between these signals in normal differentiation could set the stage for malignant transformation to B-ALL in the presence of cooperative defects in JAK2 and/or Ikaros.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1094. doi:10.1158/1538-7445.AM2011-1094
Abstract 1095: Short Poly A sequence in HGF promoter region is involved in overexpression of HGF in cancer cells
Authors: Sakai Kazuko , Arao Tokuzo , Matsumoto Kazuko , Kimura Hideharu , Fujita Yoshihiko , Kaneda Hiroyasu , Tamura Daisuke , Aomatsu Keiichi , Kudo Kanae , Nagai Tomoyuki , De Velasco Marco A. , Okamoto Isamu , Nakagawa Kazuhiko , Nishio Kazuto 
Published: June 2012

Abstract
Activation of the HGF-MET signaling increases invasion, metastasis and angiogenesis in cancer cells. Therefore, HGF-MET signaling is regarded as an oncogenic signaling pathway, and intensive therapeutic approaches focusing on this signaling pathway are ongoing in the field of cancer treatment. We previously reported that the concentration of serum HGF was strongly related with the treatment outcome of EGFR-tyrosine kinase inhibitors in patients with adenocarcinoma of the lung (Kasahara K. et al, Clin Cancer Res. 2010). Meanwhile, recent study has clearly demonstrated that HGF expression was regulated by short poly A sequence in its promoter region in breast cancer cells (Ma J. et al, J Clin Invest. 2009). In this study, we evaluated the poly A sequence in HGF promoter region and expression levels of HGF in 51 cancer cell lines. The five cell lines exhibited a short poly A sequence (16A-25A) in HGF promoter compared with wild-type (30A). Two of five cell lines overexpressed HGF at mRNA and protein expression levels determined by quantitative RT-PCR and ELISA. On the other hand, there were no HGF-overexpressing cell lines among 46 cell lines with wild-type poly A sequence. Of note, we have also detected the short poly A sequence in cancer cells in patients with lung cancer. Evaluation of short poly A, HGF expression and treatment outcomes of EGFR-tyrosine kinase inhibitors is under way.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1095. doi:10.1158/1538-7445.AM2011-1095
Abstract 1112: Human rhomboid family-1 gene RHBDF1 assists trafficking of TGFa for GPCR-mediated transactivation of EGFR
Authors: Zhou Zhuan , Lu Yi , Deng Weimin , Huang Paulina , Li Lu-Yuan 
Published: June 2012

Abstract
Epidermal growth factor receptor (EGFR) can be transactivated by ligands of G protein-coupled receptors (GPCR). GPCR signaling pathways often involve the formation of clathrin-coated endosomes, which interact with endoplasmic reticulum/Golgi complex to form recycling endosome and secretion vesicles containing EGFR pro-ligands such as pro-TGFα, which is proteolytically processed and released on the cell surface to activate EGFR in an autocrine manner. We showed previously that human rhomboid family-1 gene RHBDF1 is essential for GPCR-EGFR transactivation by assisting the secretion of TGFα, a ligand of EGFR. We show here silencing the RHBDF1 with shRNA leads to inhibition of EGFR ligand-dependent transactivation induced by GPCR ligands such as gastrin release peptide (GRP) and sphingosine-1-phosphate. However, RHBDF1 is not involved in EGFR ligand-independent GPCR-EGFR transactivation induced by isoproterenol. Inhibitors of endosome formation and membrane trafficking such as chlorpromazine, nocodazole, and cytochalasin-D also inhibit GRP-induced EGFR phosphorylation. Inhibitors of endosome acidification such as chloroquine and BFA lessen the inhibitory effect of RHBDF1 shRNA on GRP-induced EGFR phosphorylation. The RHBDF1 protein localizes mainly to the endoplasmic reticulum with pro-TGFα and GRASP55 in starved, quiescent cancer cells, but is phosphorylated and translocated to the cell surface upon GPCR ligands stimulation. GPCR ligands also activate the intracellular signaling molecule Src which then co-translocates with RHBDF1 and clathrin to the plasma membrane. Src-clathrin interaction and co-localization to the cell surface are RHBDF1-dependent. These findings are consistent with the view that, in response to GPCR activation, RHBDF1 assists pro-TGFα trafficking to the cell surface through clathrin coated trafficking.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1112. doi:10.1158/1538-7445.AM2011-1112