bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1053: Mouse Kremen 1 negatively regulates Wnt/β-catenin signaling in human breast cancer MDA-MB-231 cells
Authors: King Taj , Li Yonghe 
Published: June 2012

Abstract
The canonical Wnt/β-catenin signaling pathway is a major developmental pathway that regulates embryonic development, cell motility, polarity, growth, and progression. Wnts are secreted glycoproteins that bind to the low-density lipoprotein receptor-related protein 5/6 (LRP5/6) and Frizzled, a seven pass transmembrane receptor protein, which increase cytosolic β-catenin levels and subsequent β-catenin transcriptional activity via the inhibition of glycogen synthase kinase-3β. Kremen receptors are single-pass transmembrane proteins that consist of two isoforms (Kremen 1 and 2) in mammals. Dickkopf (Dkk) proteins are secreted glycoproteins that inhibit Wnt signaling. Kremen antagonizes Wnt signaling by forming a ternary complex with Dkk1 and LRP5/6, while Kremen alone is able to promote LRP6 cell-surface localization and stimulate LRP6 signaling. Previous studies have shown that aberrant Wnt/β-catenin signaling promotes tumorigenesis in breast cancer and that LRP6 is an important mediator in mammary gland development and in breast cancer tumorigenesis. In the present studies, we found that breast cancer MDA-MB-231 cells express LRP6 and Dkk1, but not Kremen 1 and 2. Therefore, MDA-MB-231 breast cancer cells were used to make stable cell lines that conditionally express mouse Kremen 1 in the presence of doxycycline. We found that doxycycline-induced Kremen 1 expression resulted in the down-regulation of endogenous LRP6 expression and inhibition of Wnt/β-catenin signaling in MDA-MB-231 cells. Furthermore, we demonstrated that Kremen 1 expression blocked Wnt-3a-indced activation of Wnt/β-catenin signaling in MDA-MB-231 cells. Future studies will focus on the effects of Kremen 1 on tumor progression in vitro and in vivo.
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 1053. doi:10.1158/1538-7445.AM2011-1053
Abstract 1054: S100B affects cell signaling in malignant melanoma
Authors: Gianni Kira , Vitolo Michele I. , Wilder Paul T. , Martin Stuart S. , Weber David J. 
Published: June 2012

Abstract
Establishing the mechanism by which S100B effects ERK and its downstream proteins will provide valuable insight into the role of S100B in the progression of melanoma and potentially aid in developing new pharmacological drugs. S100B is a 21.5 kDa symmetric homodimer that is highly conserved and expressed in a number of tissues and cell lines, including melanocytes. Generally, low levels of S100B have trophic effects, while higher levels are problematic, as is the case in human malignant melanoma. S100B is an effective and widely used prognostic marker for malignant melanoma, with increased levels of serum S100B being predictive of disease stage, increased recurrence, and low overall survival. It has previously been found that S100B directly interacts with the tumor suppressor protein p53, down-regulating its protein levels, thereby allowing damaged cells to proliferate and mutations to propagate. S100B has also been implicated in several other signaling pathways, including the MAPK pathway (BRAF-MEK-ERK). The initial hypothesis tested was that S100B inhibits the phosphorylation of ERK targets in a calcium-dependent manner. To evaluate the significance of S100B in melanoma cell lines, stable S100B knock-down clones were created using lentiviral shRNA particles. The extent of the knock-down varies among the clones and shows a correlation between the level of remaining S100B and the level of phosphorylated ERK, where the clone with the least amount of S100B also has the lowest level of phosphorylated ERK. The clones also display a decreased rate of proliferation measured with both an MTT based assay, as well as with electrical impedance. Over-expression studies were also conducted where normal human S100B, but not a mutant S100B incapable of binding calcium, results in increased phosphorylated ERK, but decreased phosphorylated RSK at Thr573. To determine if S100B was interacting with RSK directly, pull-down assays were performed, and RSK was detected in S100B pull-downs in the presence of calcium; however, it was not detected in the presence of the calcium chelator EDTA. In conclusion, we demonstrate that the calcium-binding protein S100B affects the MAPK pathway by simultaneously increasing phosphorylated ERK and decreasing phosphorylated RSK, together which are consistent with the increased growth rates and cancer progression.
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 1054. doi:10.1158/1538-7445.AM2011-1054
Abstract 106: Epigenetic regulation of snoRNAs in cancer
Authors: Ferreira Humberto , Heyn Holger , Balint Balazs , Martin-Subero Jose Ignacio , Esteller Manel 
Published: June 2012

Abstract
Cancer has been associated with epigenetic abnormalities leading to deregulated expression of both coding and non-coding RNAs (ncRNAs) involved in oncogenesis. Among these ncRNAs, microRNAs (miRNAs) were identified acting as oncogenes or tumor suppressors by repressing the expression of cancer related genes. In addition, other studies suggest that other ncRNAs are similarly involved in tumorigenesis, including long non-coding RNAs (lncRNAs) and transcribed Ultraconserved Regions (t-UCRs) by different mechanisms.
Recent studies have shown the impact of small nucleolar RNAs (snoRNAs) in the onset or progression of cancer. SnoRNAs encoded by the ncRNA GAS5 that is repressed in breast cancer or the snoRNA U50, which is mutated in breast and prostate cancer, are examples of the connection between snoRNAs and cancer. It is also known that some snoRNAs are differentially expressed in cancer in comparison with the correspondent matched tissue, indicating their possible role in this disease.
This study focuses in the analysis of the DNA methylation profile associated with the differentially expression of snoRNAs in cancer considering a host gene dependent or independent regulation. To select snoRNAs regulated by DNA methylation we used two different epigenetic approaches: snoRNA expression arrays upon DNA methylation inhibition and global genomic DNA methylation arrays. Herein, we were able to indentify snoRNAs with different DNA methylation that might be involved in 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 106. doi:10.1158/1538-7445.AM2011-106
Abstract 1062: Identification of flotilin-1 as an H-Ras-interacting lipid raft protein: Its implications in breast epithelial cell invasion
Authors: Yong Hae-Young , Son Hwajin , Kim Eun-Sook , Hwang Jin-Sun , Kim Myeong-Ok , Choi Wahn Soo , Noh Dong-Young , Hwang Ki-Tae , Kim Hyeong-Reh Choi , Kim Ki-Bum , Choi Yoomi , Kim Eun Joo , Park So Yeon , Moon Aree 
Published: June 2012

Abstract
Metastatic spread is the major cause of death from breast cancer. We previously showed that H-Ras, but not N-Ras, induces invasive/migratory phenotypes of MCF10A human breast epithelial cells, while both H-Ras and N-Ras induce proliferation/transformation. Here, we identified flotillin-1 as an H-Ras-induced lipid raft protein through comparative proteome profiling of lipid raft proteins. Flotillin-1 interacts with H-Ras in lipid raft at a higher affinity than with N-Ras, elucidating a molecular nature of the crucial link between lipid rafts and the function of H-Ras. Small interfering RNA (siRNA)-mediated flotillin-1 knockdown significantly reduced H-Ras activation and H-Ras-mediated motility/invasion in MCF10A cells engineered to express H-Ras and in highly invasive human breast carcinoma Hs578T cells that express endogenous H-Ras. These results suggest a positive signal amplification loop between flotillin-1 and H-Ras for the invasive signaling program in breast epithelial cells. Importantly, tissue microarrays of 289 patients with invasive breast cancer revealed that flotillin-1 expression positively correlates with lymph node metastases (p=0.027), HER2/neu oncogene expression (p&lt;0.001), and high histologic grade (p=0.014). Although infrequent, the membranous flotillin-1 expression is significantly associated with poor disease-free survival of patients (p=0.005), suggesting the clinical importance of predicting the characteristics of a small subpopulation of malignant breast cancer. Taken together, our findings provide new insight into the molecular basis of the Ras isoform-specific signaling mechanism that depends on the lipid-based sorting platforms. [This work was supported by the Korea government (Nos.ROA-2008-000-20070-0)]
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 1062. doi:10.1158/1538-7445.AM2011-1062
Abstract 1066: ERK/RSK and JNK signaling cooperatively mediate oncogenic Ras-induced death receptor 5 expression through enhancing CHOP, Elk1 and c-Jun-dependent transcription
Authors: Oh You-Take 
Published: June 2012

Abstract
Oncogenic mutation of Ras frequently occurs in many types of cancers and plays a critical role in cell transformation and oncogenesis. Interestingly, the oncogenic Ras has been documented to induce the expression of death receptor 5 (DR5), a pro-apoptotic death domain-containing cell surface receptor for TRAIL, through currently undefined mechanisms. The current study attempted to address the mechanisms by which the oncogenic Ras induces DR5 expression. Enforced expression of the oncogenic H-Ras or K-Ras (e.g., RasV12) increased DR5 promoter activity and DR5 expression. This was also accompanied by activation of both ERK/RSK and JNK signaling pathways as evidenced by increased levels of p-ERK, p-RSK, p-JNK and p-c-Jun as well as their downstream proteins, CHOP, Elk1 and c-Jun. Gene silencing-mediated inhibition of either ERK, RSK or JNK activation blocked RasV12-induced DR5 expression. Moreover, knockdown of CHOP, Elk1 or c-Jun abrogated RasV12-induced DR5 expression as well. These data collectively indicate that both ERK/RSK and JNK signaling pathways are required for RasV12-induced DR5 expression. Triple gene (CHOP, Elk1 and c-Jun) co-expressed resulted in the highest DR5 promoter transactivation and protein expression in comparison to single or double gene expression. Consistently, oligonucleotide pull-down assay could detect Elk1, CHOP and c-Jun proteins bound to the DR5 promoter in cells co-transfected with CHOP, Elk1 and c-Jun genes or transfected with Ras-V12 gene, indicating that these proteins together bind to the DR5 promoter region. Thus we suggest that these three proteins cooperatively participate in RasV12-induced DR5 expression by enhancing its transcription. Importantly, we found that RasV12-transformed human ovarian cells were more sensitive than their non-transformed counterparts to undergo TRAIL-induced apoptosis. In summary, this study demonstrated that oncogenic Ras induces DR5 expression through activation of both ERK/RSK and JNK signaling pathways and subsequent CHOP, Elk1 and c-Jun-mediated gene transactivation. Cancers with Ras mutation may be suitable for TRAIL-based 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 1066. doi:10.1158/1538-7445.AM2011-1066
Abstract 1067: SPROUTY-2 represses E-cadherin expression and vitamin D action in colorectal cancer
Authors: Barbachano Antonio , Ordonez-Moran Paloma , Pereira Fabio , Sanchez Agustin , Rojas Jose Maria , Munoz Alberto 
Published: June 2012

Abstract
Introduction: Colorectal cancer (CRC) is one of the highest in prevalence and mortality worldwide. Epidemiological and preclinical studies indicate that 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), the most active metabolite of vitamin D, and several analogs have protective effects against CRC. Previously we have reported that 1,25(OH)2D3 inhibits the proliferation and promotes the differentiation of human colon cancer cells at least in part by the induction of the adhesion molecule E-cadherin and the antagonism of the Wnt/β-catenin pathway (Pálmer et al., J. Cell Biol., 2001; Aguilera et al., Carcinogenesis, 2007). A transcriptomic analysis revealed a decrease in the RNA level of SPROUTY-2 (SPRY2), a gene that modulates signaling mediated by several tyrosine kinase receptors following treatment of human SW480-ADH cells with 1,25(OH)2D3 (5.6-fold at 4 h post-treatment; Pálmer et al., Cancer Res., 2003).
Methods: Protein expression in cell lines were done by Western blot analysis. RNA expression were performed by quantitative RT-PCR. To knock-down gene expression, cells were infected with lentiviral particles containing a U6 promoter driving an shRNA targeting the respective RNA. Protein expression in human colon tumors were performed by immunofluorescence. Cell proliferation was measure by MTT assay.
Results: In this study, we show that the expression of SPRY2 is inhibited by 1,25(OH)2D3 in colon cancer cells by E-cadherin-dependent and -independent mechanisms. In turn, ectopic expression of SPRY2 in SW480-ADH cells inhibits both basal and 1,25(OH)2D3-induced E-cadherin expression. SPRY2 induces ZEB-1 RNA and protein, a transcriptional repressor of CDH1/E-cadherin, and prevents the induction of an adhesive phenotype by 1,25(OH)2D3. A study of the mutual repression between SPRY2 and E-cadherin proteins revealed that their expression levels are inversely correlated in colon cancer cell lines and in xenografted tumors. In colon cancer patients, SPRY2 expression correlates also inversely with that of E-cadherin and is upregulated in invasive areas and high grade tumors. In addition, the ectopic expression of SPRY2 precludes other 1,25(OH)2D3 actions such as the antagonism of Wnt/beta-catenin signaling and the inhibition of cell proliferation. Conclusions: Our data indicate that SPRY2 is a negative regulator of E-cadherin and 1,25(OH)2D3 action and has a putative tumorigenic action in colorectal 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 1067. doi:10.1158/1538-7445.AM2011-1067
Abstract 1069: Clinicopathological significance of CARD10 alterations in Middle Eastern colorectal cancer
Authors: Abubaker Jehad , Bavi Prashant , Jehan Zeenath , Ahmed Maqbool , Al-Haqawi Wael , Sultana Mehar , Prabhakaran Sarita , Al-Sanea Nasser , Abduljabbar Alaa , Ashari Luai H. , Alhomoud Samar , Al-Dayel Fouad , Uddin Shahab , Al-Kuraya Khawla S. 
Published: June 2012

Abstract
The incidence of Colorectal Carcinoma (CRC) in Saudi Arabia is rising and CRC is among the top 3 Saudi cancers in both men and women. NF-κB gene plays a role in tumorgenesis through the transcriptional activation of genes associated with cell proliferation, angiogenesis, metastasis, tumor promotion, inflammation and suppression of apoptosis. NF-κB protein activation, defined as nuclear expression of NF-kB by immunohistochemistry was seen in 43.2% (164/380) CRC and was an independent prognostic marker for poor survival. CARD10 and A20 genes are known positive and negative regulators of the NF-kB activation pathway and can activate the NF-kB activity. CARD10 is an enzyme that is encoded by the CARD10 gene and it associates with IKK complex resulting in NF-κB activation. CARD11 which shares a high degree of structure, domain and functional homology to CARD10 is oncogenic in diffuse large B cell lymphoma and results in activation of NF-κB. Considering the potential therapeutic utility of targeting NF-kB and its key modulators, we studied CARD10 genetic alterations (mutations and amplifications) and immunohistochemical expression of CARD10 in over 300 CRC cases and 13 colon cell lines. We detected missense mutations in 5.2 % (15/288) and 2 colon cell lines. Our results showed that CARD10 protein is widely expressed in CRC (67.7%) and expression levels of CARD10 progressively increase from normal colorectal mucosa to pre-malignant colorectal adenomas to CRC. CARD10 protein expression associated significantly with NF-KB activation (P = 0.0313). Interestingly, there was a mutual exclusivity between CARD10 protein overexpression and A20 loss of expression which might suggest that NFKB can be activated by alteration in one of these genes in CRC. Furthermore, CARD10 amplification (15.3%) was significantly associated with CARD10 protein expression and presence of distance metastasis (p=0.0487) Interestingly CARD10 mutations were detected in 21.4% of MSI CRC and only 78.6% of MSS CRC (p=0.0251), suggesting that CARD10 mutations play a role in both subsets of CRC but might represent more important oncogenic event for the development/progression of MSI CRC than MSS CRC. Our study highlights for the first time the role of CARD10 protein overexpression as a novel mechanism for NF-kB activation and demonstrates clinico-pathological significance of CARD10 alterations in Middle Eastern CRC.
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 1069. doi:10.1158/1538-7445.AM2011-1069
Abstract 1075: STAT3 signaling in thyroid cancer
Authors: Silva Joana , Soares Paula , Knauf Jeffrey , Fagin James , Sobrinho-Simoes Manuel , Ghossein Ronald , Bromberg Jacqueline F. 
Published: June 2012

Abstract
Here, we examined the contribution of STAT3 activation in papillary thyroid carcinoma (PTC), which constitutes 80% of all thyroid malignancies. We initially examined STAT3 activation (i.e. Y705 phosphorylation) by IHC in 80 primary PTCs. Approximately 50% of the tumors expressed nuclear pSTAT3. In general, positive cancer cells were found on the edge of the tumor and in association with the stroma (also strongly pSTAT3 positive). The inner part of the tumor was generally negative, as well as all solid PTCs. Additionally, we examined human thyroid cancer derived cell lines and determined that STAT3 was phosphorylated in ∼50% and was regulated by the IL-6/gp130/JAK pathway, similarly to what has been described in breast and lung cancers.
To assess STAT3's role in thyroid cancer, we evaluated the effects of STAT3 under-expression in two models: thyroid cancer derived cell lines where STAT3 levels were reduced using a short hairpin and a transgenic model of PTC lacking STAT3. We observed no significant effects on in vitro growth, migration and invasion as a consequence of reduced STAT3 levels in cancer cell lines. However, in vivo (xenografts in nude mice) the tumors with low STAT3 were significantly larger compared to control (STAT3 expressing) tumors. Similarly, in a transgenic model of PTC lacking STAT3, tumors were larger, more cellular with evidence of increased proliferation compared to the STAT3 expressing cancers. RNA expression analysis of the human xenografts suggested that tumors deficient in STAT3 have downregulated death-promoting genes. In conclusion, our data suggests that in thyroid cancer STAT3 can function as a tumor suppressor, contrary to the current dogma where STAT3 is considered to be oncogenic. We are currently determining whether STAT3's effect on tumorigenesis is dependent on “activated” or total STAT3 and hope to identify the specific molecular pathways involved.
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 1075. doi:10.1158/1538-7445.AM2011-1075
Abstract 108: FGF-2 regulates cell proliferation, migration and angiogenesis through a novel NDY1/KDM2B-miR101-EZH2 pathway
Authors: Kottakis Filippos , Polytarchou Christos , Kampranis Sotirios , Tsichlis Philip N. 
Published: June 2012

Abstract
The histone H3K27 methyltransferase EZH2 plays an important role in oncogenesis, by mechanisms that are incompletely understood. Here we show that NDY1/KDM2B, a JmjC domain-containing histone H3K36me2, H3K36me1 and H3K4me3 demethylase synergizes with EZH2 to silence the EZH2 inhibitor miR-101. NDY1/KDM2B and EZH2 repress miR-101 by binding its promoter in concert via a process that is activated by upregulation of NDY1/KDM2B. EZH2 does not bind the miR-101 promoter when overexpressed in the absence of NDY1/KDM2B, while NDY1/KDM2B binds the miR-101 promoter when overexpressed in the absence of EZH2, but fails to repress transcription. The concerted action of NDY1/KDM2B and EZH2, triggered by the upregulation of NDY1/KDM2B, promotes the initial upregulation of EZH2 and initiates a feedforward loop that results to the gradual upregulation of EZH2 and other miR-101 targets. NDY1/KDM2B expression was induced by FGF-2 and to a lesser degree by VEGF, via CREB phosphorylation and activation, downstream of the DYRK1A kinase. The FGF-2-NDY1-miR-101-EZH2 axis was documented in primary fibroblasts in culture, and in a set of human tumor cell lines, and it was shown to be responsible for the FGF-2 and EZH2 effects on cell proliferation, migration and angiogenesis. The axis appeared to also be active in a set of transitional cell bladder carcinomas, in which NDY1/KDM2B and FGF-2 were overexpressed in concert and their upregulation correlated with the repression of miR-101 and the upregulation of EZH2. These data delineate a novel pathway that links FGF-2 signaling with the functional and transcriptional regulation of EZH2 via NDY1/KDM2B and miR-101, and contributes to oncogenesis.
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 108. doi:10.1158/1538-7445.AM2011-108