bluuebunny/crossref_metadata_2025_split huggingface dataset:
E-Cadherin Deficiency Initiates Gastric Signet-Ring Cell Carcinoma in Mice and Man
Authors: Humar Bostjan , Blair Vanessa , Charlton Amanda , More Helen , Martin Iain , Guilford Parry 
Published: February 2009

Abstract
The importance of loss of the cell-cell adhesion molecule E-cadherin (encoded by CDH1) to tumor progression is well established. However, CDH1 germ-line mutations predispose to the cancer susceptibility syndrome hereditary diffuse gastric cancer (HDGC), suggesting a role for E-cadherin in tumor initiation. The earliest indications of cancer in the stomachs of CDH1 mutation carriers are microscopic foci of intramucosal signet-ring cell carcinoma (SRCC; designated “eHDGC”). Here, we used N-methyl-N-nitrosourea (MNU) to promote gastric carcinogenesis in wild-type (wt) and cdh1+/− mice. MNU induced a variety of gastric tumors; however, intramucosal SRCC developed with an 11 times higher incidence in cdh1+/− mice compared with wt mice. The murine SRCC resembled the human eHDGCs in that they were hypoproliferative, lacked nuclear β-catenin accumulation, and had reduced membrane localization of E-cadherin and its interacting junctional proteins. The down-regulation of E-cadherin in the murine SRCCs confirmed the importance of the second CDH1 hit to the initiation of diffuse gastric cancer. CDH1 promoter hypermethylation has been proposed to be a major second hit in advanced HDGC; however, its contribution to eHDGC was unknown. We thus examined a series of human eHDGC and detected CDH1 promoter methylation in 50% of foci. Promoter methylation was accompanied by reduced wt CDH1 mRNA levels in the foci and had a monoclonal pattern, consistent with an epigenetic initiation of disease. Together, these findings provide compelling evidence for a deficiency in cell-to-cell adhesion being sufficient to initiate diffuse gastric cancer in the absence of hyperproliferation and β-catenin activation. [Cancer Res 2009;69(5):2050–6]
Kinetic Preservation of Dual Specificity of Coprogrammed Minor Histocompatibility Antigen-Reactive Virus-Specific T Cells
Authors: van Loenen Marleen M. , Hagedoorn Renate S. , Kester Michel G.D. , Hoogeboom Manja , Willemze Roel , Falkenburg J.H. Frederik , Heemskerk Mirjam H.M. 
Published: February 2009

AbstractAdoptive transfer of antigen-specific T cells is an attractive strategy for the treatment of hematologic malignancies. It has been shown that T cells recognizing minor histocompatibility antigens (mHag) selectively expressed on hematopoietic cells mediate antileukemic reactivity after allogeneic stem cell transplantation. However, large numbers of T cells with defined specificity are difficult to attain. An attractive strategy to obtain large numbers of leukemia-reactive T cells is retroviral transfer of mHag-specific T-cell receptors (TCR). TCR transfer into T cells specific for persistent viruses may enable these T cells to proliferate both after encountering with viral antigens as well as mHags, increasing the possibility of in vivo survival. We analyzed whether the dual specificity of the TCR-transferred T cells after repetitive stimulation via either the introduced antileukemic HA-2-TCR or the endogenous cytomegalovirus (CMV) specific CMV-TCR was preserved. We show that after repetitive stimulation, T cells skew to a population predominantly expressing the triggered TCR. However, HA-2-TCR–transferred CMV-specific T cells with high antileukemic HA-2-TCR expression but low CMV-TCR expression were able to persist and proliferate after repetitive stimulation with pp65. Moreover, HA-2-TCR–transferred CMV-specific T cells remained dual specific after repetitive stimulation and TCR expression could be reverted after additional stimulation via the previously nonstimulated TCR, restoring high-avidity interactions. These data imply persistence of TCR-transferred virus-specific T cells with both antileukemic and antivirus reactivity in vivo. [Cancer Res 2009;69(5):2034–41]
Sustained Src Inhibition Results in Signal Transducer and Activator of Transcription 3 (STAT3) Activation and Cancer Cell Survival via Altered Janus-Activated Kinase–STAT3 Binding
Authors: Sen Banibrata , Saigal Babita , Parikh Nila , Gallick Gary , Johnson Faye M. 
Published: February 2009

Abstract
Locoregional and distant recurrence remains common and usually fatal for patients with advanced head and neck squamous cell carcinoma (HNSCC). One promising molecular target in HNSCC is the Src family kinases (SFK). SFKs can affect cellular proliferation and survival by activating the signal transducer and activator of transcription (STAT) family of transcription factors, especially STAT3. Surprisingly, sustained SFK inhibition resulted in only transient inhibition of STAT3. We investigated the mechanism underlying STAT3 activation and its biological importance. Specific c-Src knockdown with small interfering RNA (siRNA) resulted in STAT3 activation showing specificity, which was inhibited by Janus-activated kinase (JAK; TYK2 and JAK2) depletion with siRNA. Sustained SFK inhibition also resulted in recovered JAK-STAT3 binding and JAK kinase activity after an initial reduction, although JAK phosphorylation paradoxically decreased. To determine the biological significance of STAT3 activation, we combined specific STAT3 depletion with a pharmacologic SFK inhibitor and observed increased cell cycle arrest and apoptosis. Likewise, the addition of STAT3- or JAK-specific siRNA to c-Src–depleted cells enhanced cytotoxicity relative to cells incubated with c-Src siRNA alone. These results show that reactivation of STAT3 after sustained, specific c-Src inhibition is mediated through altered JAK-STAT3 binding and JAK kinase activity and that this compensatory pathway allows for cancer cell survival and proliferation despite durable c-Src inhibition. To our knowledge, this novel feedback pathway has never been described previously. Given that pharmacologic SFK inhibitors are currently being evaluated in clinical trials, these results have potential clinical implications for cancer therapy. [Cancer Res 2009;69(5):1958–65]
Neuronal Guidance Protein Netrin-1 Induces Differentiation in Human Embryonal Carcinoma Cells
Authors: Mancino Mario , Esposito Claudia , Watanabe Kazuhide , Nagaoka Tadahiro , Gonzales Monica , Bianco Caterina , Normanno Nicola , Salomon David S. , Strizzi Luigi 
Published: February 2009

AbstractPluripotent cells within embryonal carcinoma (EC) can differentiate in vivo or in vitro on treatment with specific agents. Differentiating EC cells express lower levels of stem cell–related genes, such as Cripto-1. We show that migration of human EC cells (NTERA/2 and NCCIT) can be reduced following treatment with the guidance molecule Netrin-1. Moreover, Netrin-1 treatment increased the levels of β-III tubulin, glial filament acidic protein, Nestin, and γ-aminobutyric acid and reduced the expressions of Cripto-1, Nanog, and Oct4 in EC cells. These Netrin-1–induced effects in the EC cells were mediated via binding of Netrin-1 to the Neogenin receptor and activation of SHP-2, resulting in increased levels of inactive phosphorylated c-src(Y527). These results suggest that Netrin-1 can induce neuroectodermal-like differentiation of human EC cells by affecting c-src signaling via SHP-2 activation and regulation of Nanog, Oct4, and Cripto-1 expressions. [Cancer Res 2009;69(5):1717–21]
Activation of Ribosomal RNA Transcription by Hepatitis C Virus Involves Upstream Binding Factor Phosphorylation via Induction of Cyclin D1
Authors: Raychaudhuri Santanu , Fontanes Vanessa , Barat Bhaswati , Dasgupta Asim 
Published: February 2009

Abstract
Hepatitis C virus (HCV) causes chronic infection in humans leading to liver cirrhosis and hepatocellular carcinoma. rRNA transcription, catalyzed by RNA polymerase I (Pol I), plays a critical role in ribosome biogenesis, and changes in Pol I transcription rate are associated with profound alterations in the growth rate of the cell. Because rRNA synthesis is intimately linked to cell growth and frequently up-regulated in many cancers, we hypothesized that HCV might have the ability to activate rRNA synthesis in infected cells. We show here that rRNA promoter–mediated transcription is significantly (10- to 12-fold) activated in human liver–derived cells following infection with type 2 JFH-1 HCV or transfection with the subgenomic type 1 HCV replicon. Further analysis revealed that HCV nonstructural protein 5A (NS5A) was responsible for activation of rRNA transcription. Both the NH2-terminal amphipathic helix and the polyproline motifs of NS5A seem to be essential for rRNA transcription activation. The NS5A-dependent activation of rRNA transcription seems to be due to hyperphosphorylation and consequent activation of upstream binding factor (UBF), a Pol I DNA binding transcription factor. We further show that hyperphosphorylation of UBF occurs as a result of up-regulation of both cyclin D1 and cyclin-dependent kinase 4 by the HCV NS5A polypeptide. These results suggest that the endoplasmic reticulum–associated NS5A is able to transduce signals into the nucleoplasm via UBF hyperphosphorylation leading to rRNA transcription activation. These results could, at least in part, explain a mechanism by which HCV contributes to transformation of liver cells. [Cancer Res 2009;69(5):2057–64]
Enhanced Immune Recognition of Cryptic Glycan Markers in Human Tumors
Authors: Newsom-Davis Thomas E. , Wang Denong , Steinman Lawrence , Chen Paul F-T. , Wang Lai-Xi , Simon A. Katharina , Screaton Gavin R. 
Published: February 2009

AbstractAbnormal glycosylation is one of the hallmarks of the cancer cell and is associated with tumor invasion and metastasis. The development of tumor-associated carbohydrate antigen (TACA) vaccines has been problematic due to poor immunogenicity. However, when appropriate targets can be identified, passive immunization with monoclonal antibodies (mAbs) directed against TACAs has been shown to have antitumor activity. Fas ligand (FasL) is a transmembrane protein that induces apoptosis in cells expressing its receptor, Fas. When grafted into mice, FasL-expressing tumor cells break immunologic tolerance to self-antigens and induce antibody-mediated tumor immunity. Here, five IgM mAbs were produced from mice vaccinated with FasL-expressing B16F10 mouse melanoma cells. They recognize various syngeneic and allogeneic murine tumor cell lines. One mAb, TM10, recognizes a range of human tumor cell lines, including melanoma, prostate, and ovarian cancer. It does not bind to untransformed cells. The epitopes recognized by all the mAbs were carbohydrates expressed on proteins. Using carbohydrate microarrays, the antigenic targets of TM10 were found to be high-mannose core structures of N-linked glycans. In normal cells, high-mannose clusters are hidden by extensive saccharide branching but they become exposed in cancer cells as a result of abnormal glycosylation pathways. Vaccination with FasL-expressing tumors therefore enables the immune system to break tolerance to self-antigens, allowing identification of novel TACAs that can form the basis of future humoral anticancer therapy. [Cancer Res 2009;69(5):2018–25]
Introducing Nanochemoprevention as a Novel Approach for Cancer Control: Proof of Principle with Green Tea Polyphenol Epigallocatechin-3-Gallate
Authors: Siddiqui Imtiaz A. , Adhami Vaqar M. , Bharali Dhruba J. , Hafeez Bilal B. , Asim Mohammad , Khwaja Sabih I. , Ahmad Nihal , Cui Huadong , Mousa Shaker A. , Mukhtar Hasan 
Published: February 2009

Abstract
Chemoprevention, especially through the use of naturally occurring phytochemicals capable of impeding the process of one or more steps of carcinogenesis process, is a promising approach for cancer management. Despite promising results in preclinical settings, its applicability to humans has met with limited success largely due to inefficient systemic delivery and bioavailability of promising chemopreventive agents. Here, we introduce the concept of nanochemoprevention, which uses nanotechnology for enhancing the outcome of chemoprevention. We encapsulated green tea polyphenol epigallocatechin-3-gallate (EGCG) in polylactic acid–polyethylene glycol nanoparticles and observed that encapsulated EGCG retains its biological effectiveness with over 10-fold dose advantage for exerting its proapoptotic and angiogenesis inhibitory effects, critically important determinants of chemopreventive effects of EGCG in both in vitro and in vivo systems. Thus, this study could serve as a basis for the use of nanoparticle-mediated delivery to enhance bioavailability and limit any unwanted toxicity of chemopreventive agents, such as EGCG. [Cancer Res 2009;69(5):1712–6]
HMGA Proteins Up-regulate CCNB2 Gene in Mouse and Human Pituitary Adenomas
Authors: De Martino Ivana , Visone Rosa , Wierinckx Anne , Palmieri Dario , Ferraro Angelo , Cappabianca Paolo , Chiappetta Gennaro , Forzati Floriana , Lombardi Gaetano , Colao Annamaria , Trouillas Jacqueline , Fedele Monica , Fusco Alfredo 
Published: February 2009

Abstract
The high mobility group As (HMGAs) belong to a family of nonhistone nuclear proteins that orchestrate the assembly of nucleoprotein complexes. Through a complex network of protein-DNA and protein-protein interaction, they play important roles in gene transcription, recombination, and chromatin structure. This protein family is involved, through different mechanisms, in both benign and malignant neoplasias. We have recently reported that transgenic mice carrying the Hmga1 or Hmga2 genes under transcriptional control of the cytomegalovirus promoter develop pituitary adenomas secreting prolactin and growth hormone. We have shown that the mechanism of the HMGA2-induced pituitary adenoma is based on the increased E2F1 activity. The expression profile of mouse normal pituitary glands and adenomas induced in HMGA transgenic mice revealed an increased expression of the ccnb2 gene, coding for the cyclin B2 protein, in the neoplastic tissues compared with the normal pituitary gland. Here, we show, by electrophoretic mobility shift assay and chromatin immunoprecipitation, a direct binding of HMGA proteins to the promoter of ccnb2 gene, whereas luciferase assays showed that HMGAs are able to up-regulate ccnb2 promoter activity. Finally, we report an increased CCNB2 expression in human pituitary adenomas of different histotypes that is directly correlated with HMGA1 and HMGA2 expression. Because cyclin B2 is involved in the regulation of the cell cycle, these results taken together indicate that HMGA-induced cyclin B2 overexpression gives an important contribution to experimental and human pituitary tumorigenesis. [Cancer Res 2009;69(5):1844–50]
Detection of Hepatocellular Carcinoma Using Glycomic Analysis
Authors: Goldman Radoslav , Ressom Habtom W. , Varghese Rency S. , Goldman Lenka , Bascug Gregory , Loffredo Christopher A. , Abdel-Hamid Mohamed , Gouda Iman , Ezzat Sameera , Kyselova Zuzana , Mechref Yehia , Novotny Milos V. 
Published: February 2009

Abstract
Purpose: Hepatocellular carcinoma (HCC) represents an increasing health problem in the United States. Serum α-fetoprotein, the currently used clinical marker, is elevated in only ∼60% of HCC patients; therefore, the identification of additional markers is expected to have significant public health impact. The objective of our study was to quantitatively assess N-glycans originating from serum glycoproteins as alternative markers for the detection of HCC.
Experimental Design: We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for quantitative comparison of 83 N-glycans in serum samples of 202 participants (73 HCC cases, 77 age- and gender-matched cancer-free controls, and 52 patients with chronic liver disease). N-glycans were enzymatically released from serum glycoproteins and permethylated before mass spectrometric quantification.
Results: The abundance of 57 N-glycans was significantly altered in HCC patients compared with controls. The sensitivity of six individual glycans evaluated for separation of HCC cases from population controls ranged from 73% to 90%, and the specificity ranged from 36% to 91%. A combination of three selected N-glycans was sufficient to classify HCC with 90% sensitivity and 89% specificity in an independent validation set of patients with chronic liver disease. The three N-glycans remained associated with HCC after adjustment for chronic viral infection and other known covariates, whereas the other glycans increased significantly at earlier stages of the progression of chronic viral infection to HCC.
Conclusion: A set of three identified N-glycans is sufficient for the detection of HCC with 90% prediction accuracy in a population with high rates of hepatitis C viral infection. Further evaluation of a wider clinical utility of these candidate markers is warranted.
MicroRNA-mediated Regulation of Ubc9 Expression in Cancer Cells
Authors: Wu Fangting , Zhu Shuomin , Ding Yanna , Beck William T. , Mo Yin-Yuan 
Published: February 2009

Abstract
Purpose: As an E2-conjugating enzyme for sumoylation, Ubc9 plays a critical role in sumoylation-mediated cellular pathways, ultimately impacting cell growth and cancer development. The aim of this study was to investigate the regulation of Ubc9 in cancer cells.
Experimental Design: Immunohistochemistry and Western blot were used to determine Ubc9 expression in paraffin-embedded tumor tissue and frozen specimens of the matched tumors from the same patient, respectively. To establish the causal relationship between miR-30e and Ubc9 expression, we overexpressed miR-30e and then determined the resultant effects on Ubc9 expression. To determine whether miR-30e directly targets Ubc9, we did luciferase assays using luciferase reporters carrying the 3′-untranslated region (3′-UTR) of the Ubc9 gene.
Results: We found that Ubc9 is up-regulated in breast, head and neck, and lung cancer specimens. In addition, an examination of eight pairs of matched breast tumor specimens by Western blot analysis revealed that, on average, the level of Ubc9 is 5.7-fold higher in tumor than in the matched normal breast tissue. Of interest, we present evidence that Ubc9 is subjected to posttranscriptional regulation by microRNA, and the miR-30 family, such as miR-30e, negatively regulates Ubc9 expression. In contrast to Ubc9, miR-30e is underexpressed in tumors. Moreover, ectopic expression of miR-30e suppresses cell growth, which can be partially reversed by Ubc9. Finally, using luciferase-Ubc9-3′-UTR reporters, we show that Ubc9 is a direct target for miR-30e by interactions with the putative miR-30e binding sites.
Conclusion: These results provide new insight into regulation of Ubc9 in cancer cells.
Tumor Suppressor BRCA1 Is Expressed in Prostate Cancer and Controls Insulin-like Growth Factor I Receptor (IGF-IR) Gene Transcription in an Androgen Receptor–Dependent Manner
Authors: Schayek Hagit , Haugk Kathy , Sun Shihua , True Lawrence D. , Plymate Stephen R. , Werner Haim 
Published: February 2009

Abstract
Purpose: The insulin-like growth factor (IGF) system plays an important role in prostate cancer. The BRCA1 gene encodes a transcription factor with tumor suppressor activity. The involvement of BRCA1 in prostate cancer, however, has not yet been elucidated. The purpose of the present study was to examine the functional correlations between BRCA1 and the IGF system in prostate cancer.
Experimental Design: An immunohistochemical analysis of BRCA1 was done on tissue microarrays comprising 203 primary prostate cancer specimens. In addition, BRCA1 levels were measured in prostate cancer xenografts and in cell lines representing early stages (P69 cells) and advanced stages (M12 cells) of the disease. The ability of BRCA1 to regulate IGF-I receptor (IGF-IR) expression was studied by coexpression experiments using a BRCA1 expression vector along with an IGF-IR promoter-luciferase reporter.
Results: We found significantly elevated BRCA1 levels in prostate cancer in comparison with histologically normal prostate tissue (P &lt; 0.001). In addition, an inverse correlation between BRCA1 and IGF-IR levels was observed in the androgen receptor (AR)–negative prostate cancer–derived P69 and M12 cell lines. Coexpression experiments in M12 cells revealed that BRCA1 was able to suppress IGF-IR promoter activity and endogenous IGF-IR levels. On the other hand, BRCA1 enhanced IGF-IR levels in LNCaP C4-2 cells expressing an endogenous AR.
Conclusions: We provide evidence that BRCA1 differentially regulates IGF-IR expression in AR-positive and AR-negative prostate cancer cells. The mechanism of action of BRCA1 involves modulation of IGF-IR gene transcription. In addition, immunohistochemical data are consistent with a potential survival role of BRCA1 in prostate cancer.
Utility of Incorporating Genetic Variants for the Early Detection of Prostate Cancer
Authors: Nam Robert K. , Zhang William W. , Trachtenberg John , Seth Arun , Klotz Laurence H. , Stanimirovic Aleksandra , Punnen Sanoj , Venkateswaran Vasundara , Toi Ants , Loblaw D. Andrew , Sugar Linda , Siminovitch Katherine A. , Narod Steven A. 
Published: February 2009

Abstract
Purpose: Several single nucleotide polymorphisms (SNP) have been associated with the risk of prostate cancer. The clinical utility of using SNPs in the early detection of prostate cancer has not been evaluated.
Experimental Design: We examined a panel of 25 SNPs from candidate genes and chromosomal regions in 3,004 unselected men who were screened for prostate cancer using serum prostate-specific antigen (PSA) and digital rectal examination. All underwent a prostate biopsy. We evaluated the ability of these SNPs to help predict the presence of prostate cancer at biopsy.
Results: Of the 3,004 patients, 1,389 (46.2%) were found to have prostate cancer. Fifteen of the 25 SNPs studied were significantly associated with prostate cancer (P = 0.02-7 × 10−8). We selected a combination of 4 SNPs with the best predictive value for further study. After adjusting for other predictive factors, the odds ratio for patients with all four of the variant genotypes compared with men with no variant genotype was 5.1 (95% confidence interval, 1.6-16.5; P = 0.006). When incorporated into a nomogram, genotype status contributed more significantly than PSA, family history, ethnicity, urinary symptoms, and digital rectal examination (area under the curve = 0.74). The positive predictive value of the PSA test ranged from 42% to 94% depending on the number of variant genotypes carried (P = 1 × 10−15).
Conclusions: SNP genotyping can be used in a clinical setting for the early detection of prostate cancer in a nomogram approach and by improving the positive predictive value of the PSA test.