bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 967: N-Myc interactor, a novel regulator of EMT
Authors: Devine Daniel J. , Andrews Joel , Rostas Jack , Shevde Lalita A. , Samant Rajeev S. 
Published: June 2012

Abstract
Dissemination of tumor cells and subsequent colonization at distant sites is the most lethal event in cancer progression. The epithelial-mesenchymal transition (EMT) has recently been recognized as a foremost phenomenon underlying such events. Because of the importance of EMT, it is vital to understand what triggers it, as well as the mechanisms by which it is regulated. We have shown that N-myc interactor (NMI) plays a role in restricting malignant activities of cancerous cell lines in vivo and in vitro. This study describes a novel function of NMI in reducing the mesenchymal phenotype of breast cancer cell lines.
Constitutive expression of NMI in the mesenchymal cell line MDA-MB-435, showed remarkable morphologic transition towards an epithelial appearance, accompanied by reduction or loss of several mesenchymal markers such as TWIST, MMP2, SNAI2 and ZEB1 and gain of epithelial markers such as E-cadherin and Keratin 18. Conversely, silencing NMI from immortalized breast epithelial line MCF10A, renders the cells more mesenchymal in appearance. Studies using a variety of additional cell lines consistently revealed that silencing of NMI expression coincided with increased expression of both ZEB1 and SNAI2, while NMI overexpression brought about decreased expression of ZEB1 and SNAI2.
Assessment of NMI in breast cancer specimens revealed a significant loss of NMI transcript with increasing grade of breast cancer. Thus, overall, our data strongly suggests that loss of NMI may be a key event allowing increased expression of EMT-inducing transcription factors that drive EMT-dependent malignant progression.
Acknowledgement: We acknowledge grant support from the NCI: 1R01CA140472
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 967. doi:10.1158/1538-7445.AM2011-967
Abstract 970: Obesity promotes melanoma metastasis by modulating Snai1 and KiSS1 expression
Authors: Kushiro Kyoko , Nunez Nomeli P. 
Published: June 2012

Abstract
Malignant melanoma accounts for 75% of deaths associated with skin cancer. Its lethality comes from its aggressive metastasis to secondary sites such as the lungs. Epidemiological and animal studies suggest that obesity may increase the ability of melanomas to metastasize. The objective of these studies was to determine the mechanism by which obesity increases the aggressiveness of melanomas to metastasize. To this end, we used ob/ob mice as a model of obesity, as well as different cell culture conditions which mimic obesity, to investigate the molecular mechanism by which obesity affects the metastatic phenotype of B16BL6 mouse metastatic melanoma cells in vitro. In cell culture, we showed that serum from obese mice increased the ability of melanoma cells to invade. We showed that both obese mouse serum and conditioned medium collected from mature 3T3L1 adipocytes promoted a mesenchymal phenotype, as seen by an increased expression of genes associated with this phenotype, such as Snai1, and a corresponding decreased expression of the metastasis suppressor gene KiSS1. Our preliminary results suggest that obesity may increase the metastatic ability of melanomas via the pro-inflammatory cytokine Interleukin 6 (IL-6). Therefore, our hypothesis is that obesity promotes melanoma metastasis by promoting the epithelial-to-mesenchymal transition (EMT) and its associated phenotypic changes by up-regulating Snai1 and down-regulating KiSS1 through IL-6. These findings will help us understand how obesity affects melanoma metastasis and allow us to identify key cellular signaling pathways that can be used to prevent or possibly inhibit melanoma metastasis.
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 970. doi:10.1158/1538-7445.AM2011-970
Abstract 989: Profiling the expression of SGLT1 in prostate cancer
Authors: Blessing Alicia , Weihua Zhang 
Published: June 2012

Abstract
Upregulation of the epidermal growth factor receptor (EGFR; HER1; erbB1), a receptor tyrosine kinase, has been linked with increased cell proliferation and decreased apoptosis and thus, with poor prognosis for cancer patients. EGFR has been found to be over-active in most tumors of epithelial origin including: non-small cell lung cancer, breast, head and neck, gastric, colorectal, esophageal, prostate, bladder, renal, pancreatic, and ovarian cancers. EGFR is elevated in prostate cancer cells along disease progression. EGFR tyrosine kinase inhibitors failed to show beneficial effects for prostate cancer patients. Previous studies have found EGFR has kinase independent prosurvival functions. Independent of its kinase activity, EGFR participates in the maintenance of the basal intracellular glucose level of cancer cells by interacting with and stabilizing SGLT1, thus preventing cancer cells from autophagic death. EGFR and SGLT1 do physically interact; however, it was previously unknown whether SGLT1 expression is upregulated along prostate cancer progression. Sodium-dependent glucose co-transporters (SGLTs) are transmemebrane glucose transporter proteins involved in the active transport of glucose. An antibody against human SGLT1 was made and used with immunohistochemistry to show in this preliminary study that SGLT1 is exclusively expressed in the hyperplastic and malignant prostate epithelial cells. SGLT1 was not expressed in the normal epithelial or BPH cells. The results from this study indicate that as the disease progresses, the increased need for glucose within the cells is at least in part being met by the continuous activity of the sodium-dependent glucose co-transporter 1. This potential role of SGLT1 in prostate cancer may provide avenues for new prostate cancer treatments. Future endeavors will focus on designing interfering peptides that ideally will interfere with the SGLT1/EGFR binding, destabilizing SGLT1 in prostate cancer cells, and promoting cell death of prostate cancer.
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 989. doi:10.1158/1538-7445.AM2011-989
Abstract 996: SFRP1 reduction results in an increased sensitivity to TGF-β signaling
Authors: Gauger Kelly , Schneider Sallie Smith , Chenausky Kerry , Murray Molly 
Published: June 2012

Abstract
Metastasis remains the most deadly aspect of breast cancer. We previously published that when the Wnt/β-catenin signaling antagonist, secreted frizzled-related protein-1 (SFRP1), is knocked down in immortalized non-malignant mammary epithelial cells, the cells (TERT-siSFRP1) exhibit a malignant phenotype which resembles the characteristics observed in metastatic breast cancer. Interestingly, the observed phenotypic and genotypic changes that occur in response to loss of SFRP1 define the EMT process. Among the genes analyzed, the drastic increase in ZEB2 expression was of particular interest to us. This protein is a zinc-finger transcription factor that represses the expression of E-cadherin, which is the mechanism by which ZEB2 is thought to contribute to EMT. Additionally, ZEB2 has been shown to interact with downstream mediators of Transforming Growth Factor (TGF)-β signaling (SMADs). TGF-β signaling is known to actively contribute to the acquisition and development of metastatic phenotypes in part through its ability to stimulate EMT and we wondered whether this cytokine plays a role in the EMT observed in response to SFRP1 loss. Therefore, we tested the hypothesis that TGF-β signaling is augmented due to SFRP1 reduction. First, we used luciferase assays and real-time PCR analysis to show that in response to TGF-β treatment, the expression of TGF-β responsive genes are elevated in TERT-siSFRP1 cells. These downstream targets were also measured after cells were treated with a TGF-βR antagonist (LY364947) to ensure these effects were specifically due to the TGF-β signaling pathway. TGF-β signaling has also been shown to increases the phosphorylation of ERK1/2 which in turn enhances cellular migration. We found that the migratory TERT-siSFRP1 cells exhibit a marked increase in ERK1/2 phosphorylation that is readily blocked by the addition of LY364947. Furthermore, transwell assays revealed that LY364947 blocks cellular migration and this phenomenon is likely due to the inhibition of ERK1/2 because the ERK1/2 inhibitor (U0126) similarly blocks cellular migration. To investigate the contribution of ZEB2, we used siZEB2 oligonucleotides to knock down the expression of this protein. Reduced levels of ZEB2 lowered the expression of exogenous and endogenous TGF-β transcriptional targets and hindered cellular migration. We can conclude from these data that the TGF-β signaling pathway is aberrantly activated in TERT-siSFRP1 cells due to the significant up-regulation of the SMAD-interacting protein, ZEB2.
This work has been supported in part by the Rays of Hope Foundation.
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 996. doi:10.1158/1538-7445.AM2011-996
Abstract 997: Stability of β-catenin decides the tumor suppressive effect of MRJ
Authors: Menezes Mitchell E. , Mitra Aparna , Shevde Lalita A. , Samant Rajeev S. 
Published: June 2012

Abstract
Mammalian relative of DnaJ (MRJ), is a member of the heat shock protein 40 family. We have found that MRJ is lost in advanced grades of breast cancer. Functional studies showed that ectopic expression of the large spliced variant of MRJ, MRJ(L), results in reduced malignant properties as indicated by reduced motility, migration, invasion and soft agar colonization. Furthermore, xenograft studies in athymic mice showed that MRJ(L) expression reduced tumor growth and metastasis. Our investigations also revealed that Wnt/β-catenin signaling is one of the pathways impacted by MRJ(L) expression. Specifically, we found that MRJ(L) expression led to enhanced degradation of β-catenin. Our studies showed that MRJ(L) mediated its tumor suppressive effects by upregulation of DKK1, a negative regulator of Wnt/β-catenin signaling, which promotes proteosome mediated degradation of β-catenin. Hence, we hypothesized that introduction of a degradation-resistant form of β-catenin will lead to restoration of malignant attributes of the MRJ(L) expressing cells. S37A mutation of β-catenin has been known to render it insensitive to ubiquitination-mediated proteosomal degradation. We established stable clones co-expressing S37A β-catenin and MRJ(L). Our analysis of these clones showed that the TCF/LEF activity, as a measure of Wnt/β-catenin signaling, was elevated 10 fold, as measured by the increased activity of the luciferase reporter, TOPFlash. We also found that downstream transcriptional target of Wnt/β-catenin signaling, cyclin D1 showed increased expression in S37A β-catenin clones as compared to the MRJ(L) expressors. Synchronized cell cycle analysis demonstrated that cells co-expressing S37A β-catenin and MRJ(L) resulted in marked increase in S phase at 2 and 24 hours after the release of cell cycle block. The MRJ(L) expressors; did not go through an increase in the S phase in the 24 hour period after the release. Analysis of tumor growth in vivo (xenograft model) revealed that S37A β-catenin was able to restore the malignant activity overriding the suppressive effect of MRJ(L). Thus controlled degradation of β-catenin, brought about by MRJ(L), is an important event in maintaining cells in a non-tumorigenic state.
Acknowledgement: We acknowledge grant support from the NCI: 1R01CA140472
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 997. doi:10.1158/1538-7445.AM2011-997
Abstract 998: Downregulation of survivin suppresses uPA through transcription factor JunB
Authors: Lee Kyung Hee , Koh Sung Ae , Lee Ha Young , Kim Min Kyoung , Kim Kyeong Ok , Lee Se Young , Jang Byung Ik , Kim Se Won , Kim Sang Woon , Song Sun Kyo , Kim Jae-Ryong 
Published: June 2012

Abstract
Background: Survivin, identified member of the inhibitor apoptosis protein family, is expressed during development and in various human cancers. However, lts role of clinical relevance in cancers are sill debated.
Purpose: We investigated the role of HGF induced activation of a transcription factor JunB, in the expression of survivin and uPA.
Methods and Results: Genes induced by HGF were screened by using cDNA microarray technology in stomach cancer cell lines, NUGC3 and MKN28. Expression level of surviving and JunB was further confirmed by read time RT-RCR and western blot analysis. Roles of JunB and survivin in the levels of HGF induced up-regulation of uPA were measured by knock down of survivin with survivin siRNA and chromatic immuno- precipitation assay. The levels of JunB, survivin and uPA were up regulated in cells treated with HGF in a dose dependent manner. HGH-induced up regulations of JunB, surviving, and uPA were inhibited by the pretreatment with an MEK inhibitor, PD 098559. HGH-induced up-regulation of uPA were repressed by survivin knockdown. HGF enhanced the binding activity of JunB to the enhanced the binding activity of JunB to the survivin promoter in control cells, but not in the JunB-sh RNA cells. Transfection with survivin-sh RNA results in decrement of cell proliferation as determined with MTT assays. In an in vitro invasion assay, significantly fewer cells transfected with survivin sh-RNA than control cells were able to invade across a matrigel membrane barrier.Conclusion: Survivin might play an important role in the up-regulation of uPA induced by HGF via JunB and contribute to HGF-mediated tumor invasion and metastasis, which might be promising target for stomach cancer therapy.
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 998. doi:10.1158/1538-7445.AM2011-998
Abstract LB-10: A gene expression signature reflects the regulatory status of Wnt/β-catenin pathway activity
Authors: Wu Zhong , DiCarlo John , Wang Yexun 
Published: June 2012

Abstract
Due to limitations of cytotoxic based chemotherapies, current oncology drug development is designed to target specific cellular signaling pathways critical for tumor growth and progression. Such targeted drug development requires specific biomarkers to monitor the activity status of pathway. Compared to the traditional method which relies on one or a few indicators within the pathway constituents, multi-gene expression based methods measure pathway alteration as a function of the downstream effect of pathway regulation on multiple gene expression changes. These downstream gene expression alterations can potentially capture all changes related to any upstream alteration of a pathway component. The Wnt/β-catenin pathway is one of the most frequently altered pathways in a number of human cancers including colorectal carcinomas, melanomas, breast cancer and hepatocellular carcinomas and therefore of major interest to cancer researchers. Activation of the Wnt/β-catenin pathway results in a variety of downstream biological effects and this functional diversity is reflected in gene expression changes. By utilizing Wnt3a stimulation and siRNA mediated β-catenin knockdown in 293H cells followed by gene expression profiling analysis, we identified a list of 64 genes whose expression was upregulated in response to Wnt3a and whose increased expression levels were diminished by treatment with β-catenin siRNA. These 64 Wnt/β-catenin response genes were further evaluated by real-time PCR with 11 samples from a panel of 10 different cell lines either stimulated with Wnt3a and LiCl and/or inhibited with β-catenin siRNA. Sixteen genes were identified as a specific panel of indicators for Wnt/β-catenin pathway regulation using a nearest shrunken centroid classifier method. To further verify the 16 gene signature, we applied the signature to 10 new samples from 9 different cell lines in which 5 samples were stimulated with Wnt3a or LiCl and the rest of them were from cells transfected with β-catenin siRNA. The 16 gene signature predicted the regulatory status of Wnt/β-catenin pathway in these 10 samples with an accuracy of 100%. Our study demonstrates the identification and initial verification of a gene expression signature that can potentially serve to monitor the regulatory status of cellular Wnt/β-catenin pathway activity.
The applications presented here are for research use only. Not for use in diagnostic procedures.
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 LB-10. doi:10.1158/1538-7445.AM2011-LB-10
Abstract LB-104: The histone deacetylase SIRT2 regulates the cell proliferation and tumorigenicity of glioblastoma cancer stem cells
Authors: Funato Kosuke , Nasu-Nishimura Yukiko , Echizen Kanae , Todo Tomoki , Ino Yasushi , Saito Nobuhito , Koyama-Nasu Ryo , Oda Takeaki , Akiyama Tetsu 
Published: June 2012

Abstract
Despite huge efforts, glioblastoma has remained one of the most intractable tumors. According to the cancer stem cell theory, the aggressive phenotype and poor prognosis of glioblastoma are attributed to the rare tumor cells called glioblastoma cancer stem cells (GSCs), which are poorly differentiated and share features with neural stem cells. However, the molecular mechanisms underlying the tumorigenicity and stemness of GSCs are still to be elucidated. In this study, we performed an RNA-interference (RNAi)-based screen and identified 29 genes that positively regulate the expression of CD133. Among these, we focused on the histone deacetylase SIRT2. When the function of SIRT2 was inhibited by RNAi or the specific inhibitor AGK2, sphere-forming capacity and cell proliferation were significantly decreased. In addition, knockdown of SIRT2 induced apoptosis in GSCs but not in “serum-differentiated” GSCs, suggesting a stem-cell specific function of SIRT2. Furthermore, GSCs in which SIRT2 expression was stably repressed by a specific small hairpin RNA (shRNA) showed impaired tumorigenicity when transplanted into immunocompromised mice. Taken together, these results imply that SIRT2 is a possible therapeutic target for glioblastoma and the existing SIRT2 inhibitors should be useful seed compounds for novel antitumor drugs.
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 LB-104. doi:10.1158/1538-7445.AM2011-LB-104
Abstract LB-112: SP1 suppression is associated with poor prognosis in intestinal-type gastric adenocarcinoma
Authors: Lee HunSeok , Erkin Özgür Cem , Oh Ensel , Kwon Mi Jeong , Shin Young Kee 
Published: June 2012

Abstract
Specificity protein 1 (SP1) is a DNA-binding protein that activates and regulates the transcription of multiple genes. Since aberrant expression of SP1 was known to be related to cancer development and progression, we focused on SP1 expression in gastric cancer and its correlation with disease outcomes. We discovered a different relationship between SP1 expression and patient survival in intestinal and diffuse-type gastric cancer. In diffuse-type gastric cancer, patient survival decreased as SP1 expression increased (P &lt; 0.05) in accordance with previously published papers, whereas the lack of SP1 expression in intestinal-type gastric cancer was correlated significantly with poor survival (P &lt; 0.05). Multivariate analysis demonstrated that SP1 downregulation is an independent negative prognostic factor in intestinal-type gastric cancer. When SP1 downreguation was forced in high SP1 expressor intestinal-type gastric cell line MKN28 with siRNA, both migration and invasion was increased but cell proliferation was decreased. In accordance with these results, microarray data in siRNA-transfected MKN28 showed that genes inhibiting migration were downregulated and the expression of genes negatively facilitating proliferation was increased. Both migration and invasion, however, in low SP1 expressor intestinal-type gastric cell line AGS was decreased by SP1 induction. In contrast to intestinal-type, in diffuse-type gastric cell line SNU484, high SP1 expressor, both migration and invasion were decreased by siRNA. Contrary to previous studies, which did not reflect differences between the 2 histological types, our results showed that weak SP1 expression is involved in cancer progression and metastasis, and leads to poor prognosis in intestinal-type gastric adenocarcinoma.
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 LB-112. doi:10.1158/1538-7445.AM2011-LB-112
Abstract LB-116: sLZIP induces migration and invasion of cervical cancer cells through expression of matrix metalloproteinase-9
Authors: Kang Hyereen , Jang Sung-Wuk , Ko Jesang 
Published: June 2012

Abstract
Extracellular proteolysis mediates tissue homeostasis. In cancer, altered proteolysis leads to abnormal tumor growth, inflammation, tissue invasion, and metastasis. Chronic infections and inflammation are major risk for various types of cancer. The matrix metalloproteinases (MMPs) represent the most prominent family of proteinases associated with inflammation and tumorigenesis. Matrix metalloproteinase-9 (MMP-9) is involved in a wide range of normal and pathologic conditions, including inflammation, tissue repair, tumor invasion, and metastasis. sLZIP is a member of the zinc-finger transcription factor family. However, role of sLZIP in MMPs expression is previously unknown. Our results showed that sLZIP increased the mRNA level and the proteolytic activity of MMP-9 in HeLa cells. sLZIP also increased the transcription activity of MMP-9 by binding to the CRE of the MMP-9 promoter region. The requirement for sLZIP in MMP-9 expression was further supported by the fact that HeLa cells expressing sLZIP siRNA was refractory to MMP-9 expression. Results from wound healing and invasion assays showed that sLZIP enhanced migration and invasion of cervical cancer cells. Increased migration and invasion of HeLa cells induced by sLZIP was restored by inhibition of the proteolytic activity of MMP-9. Our results indicate that sLZIP induces expression of MMP-9 and is probably involved in invasion and metastasis of cervical 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 LB-116. doi:10.1158/1538-7445.AM2011-LB-116