bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3183: Dysregulated expression and function of Plexin-B1 in ovarian cancers
Authors: Oscar Wong GW , Siu Michelle KY , Ngan Hextan YS , Cheung Annie NY 
Published: February 2011

Abstract
Background: Ovarian cancer has a tendency to spread within the peritoneal cavity early in the disease course. Understanding the metastatic pathways of ovarian cancer is thus of high importance for devising ovarian cancer treatment. Plexin-B1 is a cognate receptor of Semaphorin 4D (Sema4D). This study aims at investigating the role of Plexin-B1 in ovarian cancer.
Materials and Methods: Expression of Plexin-B1 and its ligand in ovarian epithelial cell lines was examined by western blot and qPCR. Their expression in benign, borderline, and malignant tumors was revealed by immunohistochemistrty of paraffin embedded tissues. High-resolution melting (HRM) curve analysis was used to screen for mutation in Rac binding region of PLXNB1. Recombinant Sema4D was purified and used to treat OVCA420 cells which express high level of Plexin-B1. siRNA was used to knock-down Plexin-B1 in OVCA420. Cell migration and invasion ability was assayed by transwell migration and invasion assay.
Results: Plexin-B1 was most highly overexpressed in serous ovarian cancer cell lines OVCA420, OVCA429, and SW626, whereas Sema4D was ovexpressed in OVCAR3, TOV21G, and PAI. In contrast, Plexin-B1 and Sema4D were not expressed in immortalized normal ovarian epithelial cell lines. Immunohistochemical studies also revealed high Plexin B1 expression in ovarian borderline tumors and invasive cancers while no Plexin B1 expression was detectable in benign tumor. On the other hand, downregulation of Plexin-B1 was observed in the metastatic foci compared with their corresponding primary tumors. There is also a tendency of higher Plexin-B1 expression in serous histotype than in other histotypes. A preliminary HRM screening of Plexin-B1 cDNA from 28 ovarian cancers detected no mutation in the Rac binding region. Knock-down of Plexin-B1 by siRNA caused increased migration and invasion of ovarian cancer cells. In contrast to Sema4D, treatment of ovarian cancer cells OVCA420 by follicle-stimulating hormone which enhances ovarian cancer growth, led to Plexin-B1 downregulation. Conclusion: Our study suggested that Plexin-B1 may contribute to early ovarian carcinogenesis. Its dyregulation in ovarian cancers is paradoxically associated with altered cancer cell invasion and migration. The role of Plexin B1 in ovarian cancer progression is complex.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3183.
Abstract 3186: The role of fibroblast growth factor 9 for androgen-independent growth of prostate cancer cells
Authors: Teishima Jun , Hayashi Tetsutaro , Shoji Koichi , Ohara Shinya , Matsubara Akio 
Published: February 2011

Abstract
Introduction & Objectives: In prostate tissue, impairment of communication between epithelial and stromal cells through fibroblast growth factor 9 (FGF9) signaling pathway has been thought to cause failure of tissue homeostasis and development of malignant disease. Previous studies have reported that FGF9 expression increased in the prostate cancer xenografts derived from bone metastasis. The aim of our study is to investigate the role of FGF9 for progression of prostate cancer.
Material & Methods: Immunohistochemical staining using anti-FGF9 antibody were performed for tissues derived from radical prostatectomy for 98 male patients. Cell viability and apoptosis of DU145, LNCaP and androgen-independent LNCaP subline (AI-LNCaP) were assessed with MTT assay and with Apopercentage apoptosis assay in the presence or absence of treatment with recombinant FGF9 or anti-FGF9 neutralizing antibody, respectively.
Results: In immunohistochemical staining, FGF9 positive cells were detected in 12 samples. In cases with Gleason score 8 or higher, rates of cases with FGF9 positive cells were 32.1%, significantly higher than those in case with Gleason score 6 (3.3%, p=0.016) and 7 (5.0%, p=0.0079), respectively. 5-year biochemical relapse-free survival rate in cases with FGF9 positive cells were 31.3%, significantly lower than those in cases that FGF9 positive cells were not detectable (77.6%, p=0.0008). In condition with androgen-deprivated medium, cell viability of LNCaP was significantly lower than that of AI-LNCaP, and enhanced to the same level by treatment with FGF9. Furthermore, cell viability of AI-LNCaP and DU145 were significantly suppressed by treatment with anti-FGF9 neutralizing antibody. Significantly more apoptotic cells were detected in LNCaP than in AI-LNCaP by androgen deprivation, and decreased to same level as in AI-LNCaP by treatment with FGF9.
Conclusions: These results indicate that FGF9 can contribute for progression of prostate cancer through stimulation for cell proliferation and anti-apoptotic effect. FGF9 may be candidates of novel therapeutic targets for hormone-refractory prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3186.
Abstract 3187: Regulation of androgen receptor expression through angiotensin 2 receptor in prostate cancer cells
Authors: Hoshino Koji , Uemura Hiroji , Ishiguro Hitoshi , Ohta Junichi , Yoshida Shin-ichiro , Nagashima Yoji , Sasaki Takeshi , Umemura Satoshi , Kubota Yoshinobu 
Published: February 2011

Abstract
Background
We have investigated the involvement of renin-angiotensin system (RAS) in the development and progression of prostate cancer. Although the local RAS of prostate gland related to cell proliferation and angiogenesis has the potential in carcinogenesis of prostate, the detailed mechanism remains unclear. In the present study, we examined the effects of angiotensin 2 (Ang2) signal, especially through AT1 receptor (AT1R) in prostate cancer cells.
Method
Cell proliferations of prostate cancer, androgen dependent LNCaP and androgen independent DU145 cells, were examined after knocking down AT1R by AT1 small interfering RNA (siRNA) transfection. We confirmed the expression of AT1R, androgen receptor (AR) and its related proteins by Western blot analysis. Immunocytochemical staining of AR in LNCaP cells transfected with AT1R siRNA (LNCaP siRNA cells) was performed. We examined the promoter activities of AR and PSA in luciferase assay by transfection of AT1R siRNA.
Result
Cell proliferation of LNCaP siRNA and DU145 cells transfected with AT1R siRNA were decreased on 7 days by 75% and 52%, respectively. Western blot analysis showed the increase of cleaved PARP and survivin related to apoptosis. Interestingly, AR was dramatically suppressed in LNCaP siRNA cells. The flow cytometry of LNCaP siRNA cells showed G2 arrest or increase of apoptosis. In addition, PSA, COX2, NFκB, and c-myc expression were decreased in LNCaP siRNA cells. Luciferase assay showed that the activity of AR promoter or PSA promoter were inhibited by AT1R knocking down. In immunocytochemical staining, the suppression of AR translocation into nucleus by DHT was confirmed in LNCaP siRNA cells. Ang2 induced the cell proliferation associated with the enhancement of AR, PSA, and NFκB, and furthermore the activity of AR or PSA promoter.
Discussion
In this study, we focused on the involvement of RAS in the AR expression of prostate cancer cells. Knocking down AT1 receptor protein resulted in a significant inhibition of cell growth associated with a remarked decrease of AR protein. We also found that the expression level of AT1R could modulate the transcriptional level of AR by affecting c-myc and NFκB expression. Taken together, there seems to be a strong relationship between AR and Ang2-AT1R signals. These results indicate that the inhibition of AT1 receptor has a potential to influence the AR expression in prostate cells, presumably contributing to develop novel therapeutic agents for prostate cancer, especially hormone refractory cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3187.
Abstract 3189: Aggressive renal cancer cell behavior is partly mediated by CD98hc
Authors: Poettler Marina , Kalinowska Wazlawa , Susani Martin , Haitel Andrea , Zielinski Christoph , Prager Gerald W. 
Published: February 2011

Abstract
CD98, a heteromeric transmembrane protein, consists of a heavy subunit (4F2hc, SLC3A2), extracellular linked to a light subunit. The light chains provide amino acid transport activity of CD98. Recently, we could show that CD98hc directly interacts with a conserved motif in integrin beta subunits, thereby mediating outside - in signaling. A genetic knockout of CD98hc in animals is embryonic lethal, whereas overexpression of CD98hc in somatic cells leads to malignant transformation.
Recently, we reported that high CD98hc expression is a novel and reliable diagnostic marker for the more malignant subtype II papillary renal cell cancer marker (pRCC). Thereby, CD98hc expression directly correlated with grade of differentiation.
In the present study, we identified the functional role of CD98hc in clear cell renal cell cancer (ccRCC) behavior. First, we generated stable low CD98hc ccRCCs by the use of a shRNA lentiviral construct and compared tumor cell behavior with high CD98hc expressing mock infected ccRCCs. We found that downregulation of CD98hc led to an altered tumor cell behavior including tumor cell survival, migration and proliferation. Expression of a silent mutation - lacking shRNA binding motif - reconstituted CD98hc expression in lowCD98hc ccRCC, thereby restoring aggressive tumor cell behavior. By introducing CD98hc mutations either lacking integrin binding capacities or light chain interactions, we could identify the functional role of leucine amino acid transport in tumor cell proliferation, as affected C14-leucine uptake was directly correlated with tumor cell proliferative activity. In contrast, mutants lacking interaction sites for integrins showed defects adhesion-induced FAK phosphorylation and c-src activation, leading to reduced tumor cell adhesion and spreading. A biological relevance of the in vitro finding was confirmed in in vivo tumor xenotransplant assays, whereby stable low CD98hc/ccRCCs either reconstituted with wild type CD98hc or with mutated CD98hc were used. Only wild type reconstitution was capable to restore full aggressiveness of tumor growth and metastasis formation.
From our data we conclude that CD98 partially mediates functional activity of renal cancer cell behavior. Thus, CD98hc-mediated tumor cell behavior may offer a potential novel therapeutic target for the treatment of cancer.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3189.
Abstract 3194: Epidermal growth factor receptor variant type III induces angiopoietin like 4 expression through mitogen activated protein kinase pathway and promotes tumor angiogenesis in malignant glioma
Authors: Katanasaka Yasufumi , Koizumi Fumiaki 
Published: February 2011

Abstract
Epidermal growth factor receptor variant III (EGFRvIII) is the most common mutation of EGFR in glioblastomas (GBMs) and is present in approximately 50% of GBMs with EGFR gene amplification and overexpression. This variant lacks the exon 2 to 7 (the extracellular ligand-binding domain) and results in a constitutively active form of the receptor. EGFRvIII has been shown to promote tumor progression in mouse models. Since it is assumed that EGFRvIII alters the tumor microenvironment, we examined the involvement of EGFRvIII in tumor angiogenesis in GBMs. For this purpose, we transfected cDNA for wild type EGFR or EGFRvIII into human glioma LN229 cells with retroviral vector (LN229-WT or LN229-vIII, respectively). The growth of LN229-vIII-tumors was significantly accelerated compared with that of LN229-WT-tumors. The microvessel density in LN229-vIII-tumors dramatically increased compared with that in LN229-WT-tumors. To study molecular mechanism of the EGFRvIII-induced angiogenesis, real time PCR analysis of angiogenesis-related molecules was performed. The analysis revealed that the expression level of angiopoietin like 4 (Angptl4) was significantly increased in LN229-vIII compared with LN229-WT in vitro. The mRNA expression of Angptl4 was remarkably increased in LN229-vIII-tumors. These results were confirmed at the protein level in vitro and in vivo. We then investigated which the signal pathway is associated with EGFRvIII-induced Angptl4 expression. MEK inhibitor U0126 remarkably inhibited Angptl4 mRNA expression in LN229-vIII, indicating that MAPK signal pathway could be an important pathway for the transcription. In summary, EGFRvIII may induce Angptl4 expression through MAPK signal pathway and strongly promote tumor angiogenesis in malignant glioma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3194.
Abstract 3196: The role of Ga12 and Thromboxane receptor beta interaction in bladder cancer progression
Authors: Woolworth Julie A. , Watson Dennis , Halushka Perry V. , Moussa Omar 
Published: February 2011

Abstract
In the United States, it is predicted that there will be over 70,000 new cases of bladder cancer this year. Bladder cancer is the fourth most common cancer in men and eighth in women. Our lab has identified that Thromboxane receptor beta (TPβ) plays a role in bladder cancer progression. Our studies have previously shown that TPβ can induce malignant transformation in the immortalized non-transformed bladder cell line, SV-HUC. TPβ is a G-protein coupled receptor that is over-expressed in bladder cancer tumors and high levels of TPβ in bladder cancer patients correlate with decreased survival. G-proteins, such as Gα12, are involved in second messenger cascades that influence a variety of cellular functions, including transcription and motility. Constitutive activation of Gα12 has been shown to induce malignant transformation. Gα12 messenger RNA and protein are expressed in bladder cell lines and paraffin-embedded tissue obtained from bladder cancer patients. This study was designed to elucidate the TPβ and Gα12 dependent pathways that contribute to bladder cancer progression. We found that treatment with TP agonist, U46619, increases cell migration, while treatment with TP antagonist, GR32191, blocks agonist dependent increase in cell migration. We observe that knockdown of Gα12 with shRNA partially reduces U46619-induced cell migration and MAP kinase signaling. Together our results suggest that TPβ mediated malignant phenotypes are in part modulated by Gα12.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3196.
Abstract 3197: Differential senescent and apoptotic responses to HDM2 antagonism in p53 wild-type human solid cancer cells
Authors: Liu Suxing , Lin Yinghui , Mirza Asra , Seidel-Dugan Cynthia , Wang Yaolin , Hicklin Daniel J. , Bishop W. Robert 
Published: February 2011

Abstract
The p53 protein is a primary regulator of the cellular response to DNA damage and is a critical tumor suppressor. Restoration of p53 function in soft tissue sarcomas and hepatocellular carcinomas in mice was reported to cause tumor regressions associated with cellular senescence. These findings led us to investigate the ability of HDM2 antagonism to induce cellular senescence as well as apoptosis in a broad panel of wild-type p53 cell lines derived from human solid tumors. Here we report that the small molecule HDM2 antagonist Nutlin-3a activates p53 and induces cellular senescence in 10 out of 12 human tumor cell lines tested. Only two of these tumor cell lines also demonstrated an apoptotic response to Nutlin-3a. The kinetics of senescence induction by Nutlin-3a was slower than that of the apoptotic response, suggesting that apoptosis may be the first-line response, while senescence may be triggered as a back-up program when the apoptotic response fails to execute. A distinct expression profile of p53 target genes associated with apoptosis, cell cycle and senescence was observed and corresponded with the distinct phenotypic responses in this panel of cell lines. Depletion of p53 protein expression using shRNA blocked cellular senescence induced by HDM2 antagonism demonstrating the critical role for p53 in this process. The pronounced effects of Nutlin-3a on senescence in multiple wild-type p53 tumor cell lines underscores the unique anti-tumor mechanisms of HDM2 antagonism. This approach may provide a novel therapeutic strategy for future cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3197.
Abstract 3199: p53 represses TRF2 through E3 ubiquitin ligase Siah-1: Feedback regulation in telomere-initiated damage signaling
Authors: Horikawa Izumi , Fujita Kaori , Mondal Abdul M. , Vojtesek Borivoj , Bourdon Jean-Christophe , Lane David P. , Harris Curtis C. 
Published: February 2011

Abstract
p53 plays critical roles in tumor suppression, stem cell functions and aging in vivo. The telomere-capping protein complex (shelterin) prevents functional telomeres from undergoing erosion or end-to-end fusion and from initiating unwanted DNA damage response. Uncapped, dysfunctional telomeres at the end of cellular replicative lifespan lose this protective mechanism and trigger telomere-initiated DNA damage signaling to activate p53 and thereby induce cellular senescence. Here we report that p53 in turn controls a component of the shelterin complex, TRF2, through Siah-1, a p53-inducible E3 ubiquitin ligase. Endogenous TRF2 and Siah-1 were repressed and induced, respectively, in normal human fibroblasts at replicative senescence, when p53 was physiologically activated. Spontaneous allelic loss, shRNA-mediated knockdown, dominant-negative inhibition, nutlin-3a activation and overexpression of p53 all showed that p53 induced Siah-1 and repressed TRF2. TRF2 was subject to proteasomal degradation in a p53-dependent manner. Anti-TRF2 antibody-immunoprecipitated proteins were found to undergo p53- and Siah-1-mediated ubiquitination. In vitro and in vivo ubiquitination experiments showed that the E3 ligase activity of Siah-1 was responsible for TRF2 ubiquitination. Biologically, Siah-1 knockdown or TRF2 overexpression delayed the onset of replicative senescence, suggesting that the proteolytic control of TRF2 cooperates with the transcriptional regulation of p53 target genes (e.g., p21WAF1 and microRNA-34a) to regulate p53-mediated replicative senescence. This study reveals that p53, which is a downstream effector of the DNA damage signaling from uncapped telomeres, also functions upstream to regulate the telomere-capping complex, and suggests that the p53-Siah-1-TRF2 pathway takes an integral part in orchestrating the DNA damage response at telomeres. Given that TRF2 inhibits a p53-activating kinase ATM at telomeres, a positive feedback loop involving TRF2, ATM and p53 may function to amplify DNA damage-induced and p53-mediated cellular responses.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3199.
Abstract 3204: The mRNA decay factor tristetraprolin (TTP) induces senescence in human papillomavirus-transformed cervical cancer cells by targeting E6-AP ubiquitin ligase
Authors: Sanduja Sandhya , Kaza Vimala , Dixon Dan A. 
Published: February 2011

Abstract
Cervical cancer is the second most common cancer among women worldwide. A necessary factor in the development of nearly all cases of cervical cancer is the human papillomavirus (HPV) infection. High-risk HPV (HPV16 and 18) mediates cellular transformation and carcinogenesis through the concerted actions of viral oncoproteins E6 and E7 that disrupt the normal cell cycle regulation by targeting the p53 and Rb tumor suppressor pathways respectively. In the present study, we found that expression of the mRNA decay factor TTP is lost in HPV18-positive HeLa cells and introduction of TTP in cells lead to inhibition of cell proliferation and tumorigenesis by inducing cellular senescence. Consistent with this, TTP-expressing cells showed enhanced p53 protein stability and p53-dependent transcriptional activity. In cells expressing TTP, no changes were observed in the RNA levels of E6 and E7 indicating that these viral factors are not targets of TTP-mediated RNA decay. Whereas the E6-associated protein (E6-AP), the cellular ubiquitin ligase required for E6-mediated p53 degradation, was found to be down regulated both at mRNA and protein levels in presence of TTP. Furthermore, the association of E6 and E6-AP promotes transcriptional activation of hTERT, and TTP-dependent down regulation of E6-AP resulted in inhibition of hTERT expression and decreased cellular telomerase activity. Analysis of E6-AP mRNA revealed potential AU-rich element (ARE) binding sites of TTP present in the 3’ untranslated region (3′UTR) and RNA-binding studies demonstrate a physical interaction between TTP and E6-AP mRNA leading to rapid decay of E6-AP mRNA in a 3’UTR-dependent manner. Similar results were obtained with other high-risk HPV-positive cell lines that employ E6-AP pathway to control p53 and hTERT levels. Consistent with this, we found TTP expression to be lost or significantly reduced in squamous cell carcinomas as compared to normal cervical tissue. Finally, our studies indicate that loss of TTP expression in cervical cancer occurs through epigenetic mechanisms involving promoter methylation and histone deacetylation. These findings demonstrate the ability of TTP to act as a tumor suppressor through inhibition of the E6-AP pathway and indicate TTP loss to be a critical event during HPV-mediated carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3204.