bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1429: Apc heterozygosity in the C57BL/6J-Min/+ mouse produces an abnormal exuberant proliferative response in excisional wound healing
Authors: Heit Yvonne , Carothers Adelaide M. , Ross Eric , Rivzi Hira , Orgill Dennis , Bertagnolli Monica M. 
Published: June 2012

Abstract
The Min mouse is a model for intestinal tumor formation. Previously, we showed that the ApcMin allele produces a dominant-negative effect on enterocyte migration and stromal interaction in vivo. Tumorigenesis is driven by features of epithelial-mesenchymal interaction that are observed in wound healing, therefore we hypothesized that the Min phenotype also involved abnormalities in the wounding response program. We performed excisional wound assays on female Min mice (10 or 20-week old), comparing response to that of female age-matched Apc+/+ (WT) mice. The healing kinetics of full thickness dorsum wounds were quantified by digital planimetry. Histological cross sections on post-operative day 7 were used to measure granulation tissue thickness, nascent blood vessel density, and cell proliferation. Western blotting was performed using granulation tissue lysates to compare the expression of adhesion and extracellular matrix proteins, as well as α-smooth muscle actin, a marker for the presence of contractile cells. Immunofluorescent histochemistry was performed to detect the co-expression and quantitation of αSMA+, vimentin+, SM22+, desmin− myofibroblasts at wound edges. Wound closure was faster in Min mice relative to WT mice, 88.85% versus 68.86% (P&lt;0.01). Min mice also showed the strongest induction of granulation tissue formation; the relative granulation tissue thickness in the centre of wounds was 171.15±47.53 and 147.96±16 mm (P&lt;0.01) in Min and WT, respectively. Blood vessel density, measured by counting the number of CD31+ cells/high power field, was increased (40.72 + 22.6) in Min mice when compared to WT (19.03 ± 17.6, P&lt;0.01). The number of proliferating cells in granulation tissue (Ki67+ nuclei/all) in Min mice (63.72±16.83) was greater than in WT (41.58±23.46) (P&lt;0.01). Masson's stain demonstrated that more collagen deposition was present in wounds of Min/+ relative to WT. In conclusion, this study showed that wound healing was accelerated in Min/+ mice relative to WT. Therefore, even before the loss of the WT allele, Apc heterozygosity likely promotes tumor formation because it affects wound-induced invasive, homing, and engraftment responses of the epithelial stroma.
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 1429. doi:10.1158/1538-7445.AM2011-1429
Abstract 1445: The metastasis suppressor NM23-H1 promotes genomic stability through its 3’-5’ exonuclease and nucleoside diphosphate kinase activities following UV irradiation
Authors: Jarrett Stuart G. , Novak Marian , Harris Nathan , Mellon Isabel , Slominski Andrezj , Arnaud-Dabernat Sandrine , Daniel Jean-Yves , Kaetzel David M. 
Published: June 2012

Abstract
NM23-H1 is a metastasis suppressor whose reduced expression is associated with aggressive forms of melanoma, hepatoma, and carcinomas of the breast, stomach and colon. The current study has identified NM23-H1 (termed H1 isoform in human, M1 in mouse) and two of its attendant enzymatic activities, the 3’-5’ exonuclease and nucleoside diphosphate kinase (NDPK), as novel participants in the response to UV-induced DNA damage. Kinetics of repair for total DNA polymerase-blocking lesions and nucleotide excision pathway-mediated repair of 6-4 photoproducts were significantly compromised in different cellular settings of NM23-H1-deficiency. These included the human melanoma cell line WM793 and embryo fibroblasts (MEFs) derived from mouse strains rendered deficient in either NM23-M1 alone or both the M1 and M2 isoforms in tandem. The NDPK activity of NM23-H1 was critical for early repair of both polychromatic UVB/UVA (275-400 nm)- and UVC (254 nm)-induced DNA damage. Elevated rates of spontaneous and UV-induced mutations were observed in WM793 cells and NM23-deficient MEFs. The mutational spectra reflected aberrant repair of 6-4 photoproducts and oxidatively-induced DNA damage, with the 3’-5’ exonuclease being the principal enzymatic activity required to reduce UV-induced mutagenesis. This study has provided the first evidence for an essential role of mammalian NM23 isoforms in maintaining genomic stability. This novel anti-mutator function appears relevant not only to the metastasis suppressor activity of NM23-H1, but also possibly resistance to UV-induced carcinogenesis.
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 1445. doi:10.1158/1538-7445.AM2011-1445
Abstract 1452: The estrogen receptor β and its splice variant estrogen receptor β2 inhibits expression of Runx2, a key regulator of bone metastasis while only estrogen receptor β inhibits proliferation of the prostate cancer cell line PC3
Authors: dey Prasenjit , Gustafsson Jan-Ake , Strom Anders 
Published: June 2012

Abstract
Prostate cancer often metastases to bone in its later stages of tumor progression. We wanted to investigate if estrogen receptor β (ERβ) and/or its splice variant estrogen receptor β2 (ERβ2) are affecting signaling pathways involved in bone metastasis of prostate cancer. ERβ is progressively lost during prostate cancer progression while the splice variant ERβ2 is still expressed in advanced prostate cancer. ERβ2 is a 495 amino acid long splice variant of estrogen receptor ERβ. Using prostate cancer cell line, PC3 stably expressing ERβ or ERβ2, we found that both receptors inhibit migration in wound healing assays and are furthermore, repressing the expression of the bone metastasis regulator Runx2 and its target genes Slug and MMP9. In addition, we found by assaying the TCF/LEF reporter (TopGlow), that ERβ represses β-catenin signaling and it is also known that Runx2's expression is dependent on β-catenin activity. This gives a possible mechanism, by which ERβ represses Runx2 expression, is by inhibiting β-catenin signaling. This opens up a new pathway for the regulation of Runx2 by ERβ. On the other hand, we found that only ERβ and not ERβ2 inhibits proliferation and expression of the proliferation marker Skp2, which we have previously found to be a target gene of ERβ. The lack of antiproliferative activity of ERβ2 suggest that this splice variant could still be expressed in highly proliferative prostate cancer while at the same time inhibiting bone metastasis. In conclusion we found that both ERβ and ERβ2 are good targets for treatment of prostate cancer that might metastasize to the bone.
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 1452. doi:10.1158/1538-7445.AM2011-1452
Abstract 1457: Raf kinase inhibitor protein (RKIP) negatively regulates melanoma differentiation associated gene-9/syntenin-mediated melanoma metastasis
Authors: Das Swadesh K. , Sarkar Devanand , Fisher Paul B. 
Published: June 2012

Abstract
Melanoma differentiation associated gene-9 (mda-9/syntenin) functions as a positive regulator of melanoma progression and metastasis by physically interacting with c-Src and promoting the formation of an active FAK/c-Src signaling complex leading to NFκB and matrix metalloproteinase (MMP) activation. In contrast, Raf Kinase Inhibitor Protein (RKIP), an inhibitor of RAF-mediated activation of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEKK), is strongly downregulated in metastatic melanoma cells suggesting a possible inverse relationship between expression of mda-9/syntenin and RKIP. We have now genetically modulated expression of mda-9/syntenin and RKIP in melanocytes and melanoma cells and evaluated biological consequences using invasion, anchorage-independent growth, Western blotting, immunoprecipitation and in vivo confocal imaging assays. These studies confirm an inverse correlation between mda-9/syntenin and RKIP expression. This reciprocal relationship was also documented in vivo using a chick embryo chorioallantoic membrane (CAM) model, which monitors spontaneous intravasation of cells from the upper to the lower layer by polymerase chain reaction (PCR) amplification of human Alu genomic DNA. Using tissue microarrays and a series of cell lines we confirmed a higher expression of MDA-9/syntenin and absence of RKIP in both malignant melanoma tumor sections and cell lines. We also established through gain-of-function and loss-of-function experiments that mda-9/syntenin transcriptionally downregulates RKIP, providing evidence for crosstalk between these two proteins. Moreover, transient overexpression of RKIP in metastatic melanoma cells overrides mda-9/syntenin-mediated signaling resulting in decreased cell invasion, anchorage-independent growth and spontaneous tumor cell dissemination in the CAM assay. RKIP through its RAF1 binding site (amino acids 77-108) physically interacts with MDA-9/syntenin and this interaction inversely correlates with downregulation of FAK and c-Src phosphorylation, crucial steps necessary for forming a stable FAK/c-Src complex and initiating a signaling cascade leading to an MDA-9/syntenin-mediated metastatic phenotype in melanoma cells. These provocative findings highlight a potential therapeutic role of RKIP in melanoma metastasis through its interaction with MDA-9/syntenin.
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 1457. doi:10.1158/1538-7445.AM2011-1457
Abstract 1468: MTA2 enhances breast cancer metastasis via regulation of the cytoskeleton and rho signaling pathways
Authors: Covington Kyle R. , Brusco Lauren , Beyer Amanda , Cai Weiyan , Corona-Rodriguez Arnoldo , Fuqua Suzanne A.W. 
Published: June 2012

Abstract
Metastasis tumor associated (MTA) 2 is a component of the nucleosome remodeling and histone deacetylation complex and is implicated in regulating gene expression through its associated histone deacetylase activity. We have previously found that MTA2 enhanced the anchorage independent growth phenotype of estrogen receptor alpha (ER)-positive cells, implicating a potential role in metastasis. As MTA2-overexpression in these cells also resulted in an estrogen independent phenotype, we hypothesized that MTA2-overexpression may similarly enhance the aggressiveness of ER-negative cells.
We found that MTA2-overexpressing MDA-MB-231 cells were more invasive through Matrigel, had enhanced soft-agar colony formation activity compared with vector controls, and demonstrated increased migration in wound healing assays. Furthermore, we found that MTA2 overexpression resulted in rapid systemic metastases when grown as orthotopic xenografts, while vector control cells failed to form metastases, in the same time period. Microarray analysis revealed enrichment for genes regulating the cytoskeleton and cell-environment interactions, which was validated using a previously published microarray dataset. We found that the negative regulator of the Rho pathway, Rho GDP dissociation inhibitor alpha (RhoGDI-alpha), was also decreased in expression at the protein level in the MTA2-overexpressing MDA-MB-231 cells. We found that blocking signaling through the Rho pathway by either using a Rho Kinase inhibitor or by overexpressing RhoGDI-alpha significantly reduced the soft-agar colony forming ability of MTA2-overexpressing cells. We examined the effect of MTA2 and RhoGDI-alpha expression in a retrospective breast cancer microarray dataset and found that patients classified as MTA2-high and RhoGDI-alpha-low had significantly earlier recurrence compared with all other patients.
These data indicate that MTA2-overexpression results in an increase in the metastatic potential of breast cancer cells. These results have potential clinical implications as patients who have the MTA2-high/RhoGDI-alpha-low phenotype are at increased risk for early recurrence. In conclusion, our data show that MTA2 and RhoGDI-alpha enhances breast cancer metastasis possibly by promoting invasiveness and anchorage independent growth and survival.
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 1468. doi:10.1158/1538-7445.AM2011-1468
Abstract 1479: IKK-epsilon contributes to the malignant progression of ovarian cancer
Authors: Annunziata Christina M. , Hsu Sarah , Hernandez Lidia , Kohn Elise , Davidson Ben 
Published: June 2012

Abstract
Background and significance: The mechanism through which the NF-κB pathway affects the initiation, propagation and dissemination of ovarian cancer is unknown. I-κB kinases (IKKs) are key regulators of NF-κB signaling. Three IKK isoforms – α, β and ∈ – have been linked to oncogenesis, yet the precise components of NF-κB signaling mechanisms in ovarian cancer have not yet been dissected. IKK∈ was identified as an oncogene in breast cancer and has been associated with poor clinical outcome in ovarian cancer. This IKK isoform can regulate the innate immune response via activation of interferon-response factors, or can signal through classical NF-κB mechanisms by inactivating CYLD, a negative regulator of the pathway. Therefore, the molecular context is key to determining which oncogenic pathway is activated and how the signals will ultimately affect the cancer cel We hypothesized that IKK∈ drives ovarian cancer growth and metastasis.
Methods: The expression of IKKe was determined in primary ovarian cancer specimens and human ovarian cancer cell lines. Ovarian cancer cell lines were depleted of IKKe using RNA interference and tested in functional assays, including anchorage-independent growth, basement membrane invasion, and heterotypic cell adhesion. Orthotopic xenograft mouse models were used to determine the role of IKKe in metastasis in vivo. Gene expression microarrays established an IKKe-specific signature in ovarian cancer.
Results: We surveyed 120 ovarian cancer specimens (42 primary carcinomas, 78 solid metastases) for IKK∈ expression. Notably, cytoplasmic expression was elevated in metastatic lesions relative to primary tumor sites (p=0.03). RNA interference targeting IKK∈ in a panel of 5 metastatic ovarian cancer cell lines inhibited cell growth and prevented colony formation in soft agar. An ovarian cancer-specific IKK∈-regulated gene expression signature was identified using stably expressed shRNA targeting IKK∈. Pathway analysis of the signature indicated that IKK∈ regulates the expression of genes essential to diverse processes known to contribute to the malignancy of ovarian cancer, including TGFb and HIF1a pathways. Orthotopic xenograft experiments in mice demonstrated decreased aggressiveness of IKK∈-depleted ovarian cancer cells.
Conclusion: These data provide evidence that IKK∈ plays a key role in ovarian cancer metastasis. Understanding IKK∈-regulated signaling in ovarian cancer will identify novel pathway interactions for context-specific therapeutics in the poor prognostic group of women whose ovarian cancers over-express IKK∈.
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 1479. doi:10.1158/1538-7445.AM2011-1479
Abstract 149: Antisense inhibition of microRNA-21 and -221 in tumor-initiating stem-like cells modulates biological functions of pancreatic cancer including tumorigenesis, metastasis, and chemoresistance
Authors: Ischenko Ivan , Camaj Peter , Jauch Karl-Walter , Bruns Christiane J. 
Published: June 2012

Abstract
Introduction. Our preliminary studies identified a small population of pancreatic cancer cells with stem-like properties. These cells, called Side Population (SP) cells, were able to induce fast and aggressive tumor formation in nude mice. Cultured SP were able to differentiate into daughter SP or non-SP cells and were found to be highly chemoresistant. Furthermore, performed gene expression analysis showed a significant difference in the expression of more than 1300 genes in SP cells, among which the difference in microRNA expression between SP and non-SP cells was identified as the most interesting candidate for our further studies.
Methods. Pancreatic cancer stem-like cells from highly metastatic cell line L3.6pl were identified and characterized by flow cytometry using Hoechst 33342 dye staining. The gene expression was assessed by Affymetrix and the results were further confirmed by quantitative RT-PCR. The antagomir transfection was performed using microRNA-21 and -221 oligonucleotide antisense. Tumor cell apoptosis, cell cycle progression, chemoresistance, and invasion were quantitated by propidium iodide staining and Boyden chamber assay, respectively.
Results. In our study, some microRNAs, including miR-21, miR-221, miR-211, and miR-30c-2 were significantly upregulated in stem-like SP from L3.6pl cells. Interestingly, in these cells both miR-21 and miR-221 were involved in the modulation of expression of more than 200 genes, including RASSF6, RAB2B, TP63, TP53INP1, TP53INP2, TET1, MAPK10, MAP2K6, CDK6, TNFRSF11B, SOCS6, STK33, and SMAD7. The administration of antagomir-21 and -221 significantly reduced the SP fracture, decreased SP cell differentiation, positively affected L3.6pl cell proliferation, invasion, and chemoresistance against gemcitabine and 5-Fluorouracil.
Conclusion. Our results demonstrate the significance of both microRNA-21 and -221 in tumor-initiating capability of stem-like tumor cells in pancreatic cancer. Both microRNAs contribute to the most important biological functions of pancreatic cancer including apoptosis, metastasis, and chemoresistance, and may further serve as a potential target for pancreatic 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 149. doi:10.1158/1538-7445.AM2011-149
Abstract 150: Regulation of TGFB receptor by miR21 in Sezary syndrome
Authors: Narducci Maria Grazia , Arcelli Diego , Lazzeri Cristina , Pagani Elena , Picchio Maria Cristina , Cristofoletti Cristina , Tocco Valeria , Ferracin Manuela , Sampogna Francesca , Frontani Marina , Lombardo Giuseppe Alfonso , Scala Enrico , Negrini Massimo , Caprini Elisabetta , Russo Giandomenico 
Published: June 2012

Abstract
Sezary syndrome (SS) represents a very aggressive form of Cutaneous T Cell Lymphomas with a median overall survival of 5.1 years (range, 0.4-18.6 years). As it appears evident there are in this disease either short survivors than long survivors. Previous studies of prognostic indicators in SS showed that circulating Sézary cell count, high CD4/CD8 ratio, advanced age, high lactate dehydrogenase serum level and a high white blood cell count were associated with an unfavorable outcome. Up to now, few data have been provided concerning possible associations between immunological and genetic markers, who might provide also clues on tumor progression in this disease. In the last 10 years we have observed more than 50 Sezary Syndromes in our Institute and phenotyped them with new immunologic markers. We have also performed genetic analysis with Single Nucleotide polymorphysms (SNPs) for evaluation of genomic imbalances, mRNA expression and lately microRNA(miRNA) expression profiling. In this study we have analyzed the expression profile of 470 miRNAs using Agilent platform array in 22 SS patients. We investigated the relationship between the expression level of miRNAs and the clinical outcome of SS patients by Kaplan-Meier method and risk assessment by multivariate analysis. We also functionally investigated the role of miR-21, mapping in one of the region more frequently amplified in SS and some of its targets. We identified 45 miRNAs differentially expressed between SS and healthy controls. Using predictive analysis, a list of 19 miRNAs, including miR-21 and miR-18a, miR-342, miR-31 and let-7 members were also found. Moreover, we defined a signature of 14 miRNAs able to discriminate patients with unfavorable and favorable outcome. We show that miR-21 knockdown increases apoptosis and modulates TGF beta receptor 2 expression in vitro. The antipoptotic effect appears to be regulated through PTEN. Conversely, we were not able to observe a direct miR-21 regulation on PDCD4 gene mapping to chromosome 10q24, a frequently imbalanced region in SS. In conclusion we have identified a new prognostic miRNAs signature in SS and characterized the role of miR-21, one of the most involved in cancer, recognized as a disease and prognostic classifier in this disease.
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 150. doi:10.1158/1538-7445.AM2011-150