bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2073: Neutrophil serine proteases, cathepsin-G and elastase, promote metastasis through cleavage of thrombospondin-1
Authors: Rayes Tina E. , Catena Raul , Lee Sharrell , Gao Dingcheng , Stawowczyk Marcin , Altorki Nasser , Mittal Vivek 
Published: May 2015

Abstract
Inflammation is known to be inextricably associated with tumor progression. However, the role of inflammation in metastatic initiation and outgrowth remains largely unexplored. In our study, we show that CXCR2-CXCL2-dependent recruitment of neutrophils supported a pro-metastatic phenotype in acutely inflamed lungs. The increased influx of Ly6G+ neutrophils into inflamed lungs was accompanied by a loss of thrombospondin-1 (Tsp-1) protein. In vitro, the degranulation of neutrophils was marked by an increase in the activity of the neutrophil proteases elastase and cathepsin-G, leading to degradation of Tsp-1, which was protected by using the protease inhibitor Sivelestat. Whereas genetic ablation of either cathepsin-G or elastase in vivo partially impaired metastasis, pharmacological inhibition of both neutrophil proteases, using the small molecule drug Sivelestat, dramatically suppressed metastasis.
We have uncovered a novel pathway in which the serine proteases, cathepsin-G and elastase produced by degranulating neutrophils, promote a metastasis-conducive microenvironment through the cleavage of Tsp-1. Our results provide mechanistic insights into how inflammatory components of the premetastatic niche can support metastatic outgrowth, and they suggest that the neutrophil protease-Tsp-1 axis presents a therapeutic target against metastatic cancers.
Citation Format: Tina El Rayes, Raul Catena, Sharrell Lee, Dingcheng Gao, Marcin Stawowczyk, Nasser Altorki, Vivek Mittal. Neutrophil serine proteases, cathepsin-G and elastase, promote metastasis through cleavage of thrombospondin-1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2073. doi:10.1158/1538-7445.AM2014-2073
Abstract 2086: PLK1 promotes epithelial-to-mesenchymal transition, confers oncogenic potential, and targets metastasis in prostate cancer
Authors: Wu Jianguo , Ivanov Andrei , Zhang Jinglei , Fu Zheng 
Published: May 2015

Abstract
Polo-like kinase 1 (PLK1) has been well characterized as a master cell cycle regulator and implicated in the initiation and progression of different types of cancer and subsequently highlighted as a promising target for cancer therapy. It is canonically regarded that PLK1 deregulation promotes cancer development via catastrophic cell cycle events such as centrosome replication disturbance and chromosome instability. Recently, PLK1 has been shown to act as a regulator of cancer cell invasion, however, mechanisms underlying the effects of PLK1 on cell motility remain elusive. PLK1 is frequently upregulated in prostate cancer (PCa) and its expression level positively correlates with tumor grade and prognosis. Whether and how PLK1 contributes to the development and dissemination of PCa are still need to be investigated. Here, we showed PLK1 induces EMT in prostate epithelial cells and is required for prostate cancer cell lines to keep mesenchymal properties. We demonstrated that enhanced PLK1 expression transforms prostate epithelial cells to malignancy. Moreover, we found that PLK1 promotes invasion and is required for the metastasis of prostate cancer cells. Our data indicate that PLK1 is an EMT player and acts as an oncogene. These findings provide new sights into the non-mitotic function of PLK1 and suggest PLK1 as a potential target for intervention of the metastasis of prostate cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Jianguo Wu, Andrei Ivanov, Jinglei Zhang, Zheng Fu. PLK1 promotes epithelial-to-mesenchymal transition, confers oncogenic potential, and targets metastasis in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2086. doi:10.1158/1538-7445.AM2014-2086
Abstract 2089: MMP7-mediated cleavage of nucleolin at the Asp255 induces MMP9 expression to promote tumor malignancy
Authors: Hung Jan-Jong , Chang Wen-Chang 
Published: May 2015

Abstract
Nucleolin, expressed in various cellular compartments, participates in DNA transcription, ribosomal biogenesis, regulation of RNA stability. It is evidence that the posttranslational cleavage of nucleolin determine the fate of cells, apoptosis or proliferation. However, the contributions of nucleolin accumulation and cleavage to tumor development are still not clear. Herein we found that nucleolin was dramatically increased in lung cancer and correlated with poor prognosis. The overexpressed nucleolin was cleaved to the smaller fragment (55 kDa), identified in human lung cancer and mouse models of lung cancer. To study the activated mechanism found that EGF-mediated EGFR and KRAS activations could enhance nucleolin expression through increasing Sp1-mediated transcription. Furthermore, to clarify the cleavage residue and cutting enzyme found that nucleolin could be cleaved at 255th Asp by MMP7 (255-710 a.a., TNCL). By using overexpression of TNCL indicated that TNCL enhanced proliferation and metastasis in vitro and in vivo. To further clarify the mechanism of TNCL-enhanced tumor malignancy show that TNCL significantly increase several oncogenes expression including MMP9, Alk and CD74 through associating with 3′-UTR to enhance mRNA stability. Taken together, MMP7 can cleave nucleolin to increase the oncogenes expression, leading lung cancer formation
Citation Format: Jan-Jong Hung, Wen-Chang Chang. MMP7-mediated cleavage of nucleolin at the Asp255 induces MMP9 expression to promote tumor malignancy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2089. doi:10.1158/1538-7445.AM2014-2089
Abstract 2092: Elevated PKCα expression and its association with Notch signaling in localized and metastatic prostate cancers
Authors: Zhou Xinchun , Zhu He , Zhang Xu , Lewin Jack , Miele Lucio 
Published: May 2015

Abstract
Background: Conventional protein Kinase C alpha (PKCα) is linked to the regulation of cell proliferation, differentiation, motility, survival, and apoptosis. Elevated PKCα expression has been reported in human early prostate cancer (PCa) and rat prostatic tumor cell lines. In this study, the expression level of PKCα was evaluated by immunohistochemistry (IHC) and correlated with the expression levels of Notch1 and Jagged1 in localized and metastatic PCa.
Methods: : IHC for PKCα was performed on tissue microarray (TMA) slides containing 156 formalin-fixed and paraffin-embedded (FFPE) prostatic tissues specimens, including 39 benign prostatic changes, 97 localized prostate cancers and 20 metastatic prostate cancers. The expression level of PKCα was reported as a final IHC score calculated as staining extent score (0-3) multiplied by intensity score (0-3) with a maximal score of 9. ANOVA was employed to reveal the differences in IHC scores among pathologic categories, followed by Tukey-adjusted pairwise comparisons. Spearman correlation coefficient was evaluated to measure correlation between expression levels of PKCα, Notch1, and Jagged1.
Results: IHC staining for PKCα was predominantly observed in cytoplasm (in 94% specimens). The score of PKCα cytoplasmic staining in metastatic PCa (5.48 ± 1.84, Mean ±SD) was significantly higher than those in localized PCa (3.30 ± 2.10, P = 2.95E-05) and in benign prostatic tissue (1.92 ± 1.53, P = 6.45E-09). Similarly, IHC score in localized PCa was significantly higher than that observed in benign prostatic changes (P = 0.001). Correlation analysis revealed that the expression level of cytoplasmic PKCα was significantly correlated with the expression levels of cytoplasmic Notch1 (r = 0.396, P = 5.85E-05), cytoplasmic Jagged1 (r = 0.610, P = 3.42E-11), and membranous Jagged1 (r = 0.354, P = 3.76E-04, respectively) in localized and metastatic prostate cancers.
Conclusions: Our results indicate that up-regulation of PKCα plays a role not only in PCa formation and progression, but also in PCa metastasis. The evidence of significant correlation between PKCα and Jagged1-Notch1 signaling pathway supports the notion that synergy of PKCα with Jagged1-Notch1 signaling may play an important role in modulating the tumorgenesis and metastasis in human PCa.
Citation Format: Xinchun Zhou, He Zhu, Xu Zhang, Jack Lewin, Lucio Miele. Elevated PKCα expression and its association with Notch signaling in localized and metastatic prostate cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2092. doi:10.1158/1538-7445.AM2014-2092
Abstract 2097: Distinct levels of circulating tumor cell counts for the papillary thyroid cancer patients with distant metastases and in disease-free status
Authors: Lin Hung-Chih , Cheng Ju-Chien , Tseng Ching-Ping , Lin Jen-Der 
Published: May 2015

Abstract
Distant metastasis of papillary thyroid cancer (PTC) is a multistep and complex process that frequently complicates the disease with poor prognosis. The presence of circulating tumor cells (CTCs) in the peripheral blood has been reported in several cancer types to be highly related to the development of distant metastasis. Nevertheless, the CTCs status during the progression of PTC is rarely investigated. This study aimed to define and compare the CTCs counts among the healthy control individuals (Group I, n = 14), the PTC patients in disease-free status (Group II, n = 9), and the patients with distant metastasis (Group III, n = 8). The patients in group III had metastases to the lung and mediastinum (n = 4), bones (n = 3), and lung and kidney (n = 1), respectively. CTCs were enriched from the peripheral blood by the negative selection method PowerMag that has been validated in our previous study. CTCs enumeration was performed by immunofluorescence staining using the anti-epithelial cell adhesion molecule (EpCAM) and anti-thyroid stimulating hormone receptor (TSHR) antibodies. The EpCAM+ and TSHR+ CTCs counts were 2.97 ± 2.03 and 9.97 ± 9.22 cells/mL for group I, 10.43 ± 9.03 and 19.17 ± 9.77 cells/mL for group II, and 100.06 ± 73.34 and 141.60 ± 82.08 cells/mL for group III individuals, respectively (p &lt; 0.01). These data indicate that (1) some of the TSHR+-CTCs are not EpCAM+ and this type of cell population can be overlooked if CTCs were enriched by the method based on positive selection of EpCAM+ cells; (2) the PTC patients in disease-free status has higher CTCs counts than the healthy control individuals and, hence, continuous CTCs enumeration is recommended for the patient in the stage of disease-free; (3) the PTC patients with distant metastases have higher CTCs counts when compares to the healthy control subjects and the patients with disease-free status. In conclusion, CTCs enumeration is thereby warranted in the course of diagnosis and treatment of thyroid cancer.
Citation Format: Hung-Chih Lin, Ju-Chien Cheng, Ching-Ping Tseng, Jen-Der Lin. Distinct levels of circulating tumor cell counts for the papillary thyroid cancer patients with distant metastases and in disease-free status. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2097. doi:10.1158/1538-7445.AM2014-2097
Abstract 2105: Regulation of estrogen receptor turnover by lysine 302 methylation
Authors: Zoeller Elizabeth L. , Barsyte-Lovejoy Dalia , Brown Peter J. , Owen Dafydd R. , Arrowsmith Cheryl H. , Vertino Paula M. 
Published: May 2015

Abstract
The estrogen pathway promotes growth of breast cancer, the leading cancer diagnosis among US women. The antiestrogen therapy Tamoxifen has been the mainline therapy for the 70% of women whose tumors are estrogen receptor alpha (ERα) positive for over thirty years. Understanding how ERα is regulated, particularly in the context of Tamoxifen, is essential for the treatment of breast cancer. In previous work, we showed that SetD7 mediated methylation of ERα at lysine 302 (K302) is a key mediator of estrogen receptor alpha stability. Downregulation of SetD7 or mutation of K302 increased the rate of ERα turnover resulting in a compromised estrogen driven transcriptional response. However, the precise mechanism by which lysine 302 methylation regulates ERα stability and transcriptional activity is not yet known. In this study, we used a novel small molecule inhibitor of SetD7, (R)-PFI-2, as a chemical probe to further investigate the role of K302 methylation in the regulation of ERα. Treatment of ERα expressing MCF7 breast cancer cells with (R)-PFI-2 resulted in a dose-dependent shift in the 66kDa ERα species to a slower migrating form as detected by protein electrophoresis and immunoblotting. Molecular mass estimates of this slower migrating form are consistent with a sumoylation event. Interestingly, (R)-PFI-2-induced accumulation of the slower migrating form was only observed upon inhibition of the proteasome with MG132, suggesting that this alternately modified form of ERα represents an intermediate in the pathway to degradation. A similar time-dependent shift to the same slower migrating form was observed upon estrogen depletion of MCF7 cells stably knocked down for SetD7, but not in control cells. Furthermore, an inverse relationship was observed between endogenous levels of SetD7 and the levels of modified ER in two strains of MCF7 cell line that differ in their sensitivity to Tamoxifen. These data suggest that methylation of ERα at K302 by SetD7 may stabilize ERα by blocking another post-translational modification, possibly sumoylation, necessary for its turnover. The relationship between ER methylation, sumoylation and Tamoxifen sensitivity will be discussed.
Citation Format: Elizabeth L. Zoeller, Dalia Barsyte-Lovejoy, Peter J. Brown, Dafydd R. Owen, Cheryl H. Arrowsmith, Paula M. Vertino. Regulation of estrogen receptor turnover by lysine 302 methylation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2105. doi:10.1158/1538-7445.AM2014-2105
Abstract 2115: Interrogation of mechanisms that underlie augmented steroidogenesis in castration-resistant prostate cancer
Authors: Chang Kai-Hsiung , Sharifi Nima 
Published: May 2015

Abstract
The conversion of adrenal androgens, such as dehydroepiandrosterone (DHEA), to dihydrotestosterone (DHT) drives castration resistant prostate cancer (CRPC) progression. No mutations or variations in those steroidogenic enzymes have been identified as responsible for the phenotype of increased intratumoral DHT synthesis in CRPC. By analyzing CRPC cell line models and clinical samples from patients with CRPC, we found that a gain-of-stability mutation in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1, encoded by HSD3B1 gene) confers an increase in metabolic flux from DHEA to DHT in CRPC. The prolonged protein half-life of mutant 3βHSD1 results from resisting an association with the ubiquitin E3-ligase autocrine mobility factor receptor (AMFR). Genetic selection for mutant 3βHSD1 is evident from somatic mutation in human CRPC tumors, by loss of heterozygosity (LOH) of the wild type copy in patients with heterozygous inheritance, and from acquisition of same somatic mutation in a mouse xenograft tumor model treated with abiraterone. Furthermore, we found the expression of AMFR is suppressed in a CRPC xenograft model expressing wild type 3βHSD1, suggesting a compensatory mechanism that augments steroidogenesis in CRPC progression. Our discovery of this 3βHSD1 gain-of-function mutation is the first example of a mutation identified in a component of steroidogenic machinery in CRPC, which strongly validates a new target for individualized cancer therapy in CPRC.
Citation Format: Kai-Hsiung Chang, Nima Sharifi. Interrogation of mechanisms that underlie augmented steroidogenesis in castration-resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2115. doi:10.1158/1538-7445.AM2014-2115
Abstract 2120: Cdk5 involves in interleukin-6 induces AR activation through phosphorylation of serine 727 Stat3 and serine 81 AR in prostate cancer cells
Authors: Wang Jo-Hsin , Li Pei-Chi , Lin Li-Chiung , Hsu Fu-Ning , Chen Mei-Chih , Lin Ho 
Published: May 2015

Abstract
Signal transducer and activator of transcription 3 (Stat3), a common transcription factor, has been reported to regulate cancer development, including prostate cancer. Stat3 has also been suggested that its transcriptional activity is initiated by phosphorylation. The tyrosine 705 (Y705) and serine 727 (S727) phosphorylation of Stat3 were documented to Stat3 activation. Androgen receptor (AR) is a ligand-activated transcription factor that mediates the biological responses of androgens. Cyclin-dependent kinase 5 (Cdk5), which belongs to Cdk family, is a proline-directed serine/threonine kinase. Our previous results indicate that Cdk5 may phosphorylate AR at serine 81 site (S81) and increase AR stabilization and transactivation. On the other hand, previous studies have shown that Interleukin-6 (IL-6), which is a cytokine, activates androgen receptor (AR) via MAPK and Stat3-related pathway. Therefore, the aim of this study is to investigate if Cdk5 regulates S81 phosphorylation-related AR activation through S727 Stat3 phosphorylation under IL-6 treatment. First we observed IL-6 enhanced S727 phosphorylation of Stat3 and S81 phosphorylation of AR as well as AR protein level. Next, IL-6 increased AR biochemical interaction with Stat3 and AR stabilization, nuclear localization, and transactivation, which is correlated to S727 phosphorylation of Stat3. Subsequently, we found that IL-6 induced tyrosine 15 (Y15) phosphorylation of Cdk5, which is an indicator of Cdk5 activation, and this phosphorylation was inhibited by AG490 (JAK inhibitor). We also found that Y15-Cdk5 mutant (Y15F) decreased IL-6-induced phosphorylation of AR S81 and Stat3 S727 and the biochemical interaction between AR and Stat3 was also affected. In summary, these results suggest that IL-6 activated AR by S81 phosphorylation via S727 phosphorylation of Stat3 and Cdk5 might be an upstream regulator in the pathway.
Citation Format: Jo-Hsin Wang, Pei-Chi Li, Li-Chiung Lin, Fu-Ning Hsu, Mei-Chih Chen, Ho Lin. Cdk5 involves in interleukin-6 induces AR activation through phosphorylation of serine 727 Stat3 and serine 81 AR in prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2120. doi:10.1158/1538-7445.AM2014-2120
Abstract 2124: Analysis of FAM111A, a newly identified AR regulated gene, in prostate cancer
Authors: Mudryj Maria , Libertini Stephen J. , Lombard Alan P. , Saddiqui Salma , Ghosh Paramita M. 
Published: May 2015

Abstract
Prostate carcinoma (PCa) is the most commonly diagnosed cancer in men in the United States. Most PCas are dependent on the androgen receptor (AR) for growth and survival, and this dependency is exploited as androgen deprivation is the major therapeutic intervention. However, PCa inevitably progress to become castration resistant, yet remain reliant on the activity of the AR. Further understanding the mechanisms that mediate castration resistance and the pathways downstream of the AR will enhance our ability to treat this stage of the disease. RNA-seq studies of two castrate resistant cell lines following AR ablation identified a number of transcripts that were AR regulated. The studies identified FAM111A as an AR regulated gene. While little is known about FAM111A, a previous study has shown that the FAM111A gene harbors a PCa susceptibility SNP and that the FAM111A protein interacts with SV40 T-Ag. Our studies indicate that AR represses FAM111A in cell culture and xenograft models of CaP. Additionally, the expression of the only known FAM111A paralogue, FAM111B, was reciprocally regulated in cell lines and in the xenograft. FAM111A is expressed in all cultured prostate derived cell lines we looked at, and we found that there are two FAM111A isoforms. Furthermore, a siRNA mediated ablation of FAM111A modified apoptotic responses to chemotherapeutic stimuli. An immunohistochemical analysis of a prostate tumor tissue array was used to assess the expression of FAM111A. FAM111A is expressed in the cytoplasmic and nuclear compartments and expression in the cytoplasmic compartment in non-tumor prostate tissue is higher than in adjacent tumor cells. In conclusions, FAM111a is an AR regulated gene, has been associated with PCa in a GWAS study, interacts with the SV40 T-antigen and is expressed at lower levels in tumor cells. This suggests that FAM111A may be have a role in prostate tumorigenesis.
Citation Format: Maria Mudryj, Stephen J. Libertini, Alan P. Lombard, Salma Saddiqui, Paramita M. Ghosh. Analysis of FAM111A, a newly identified AR regulated gene, in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2124. doi:10.1158/1538-7445.AM2014-2124