bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct Chromosomal Bias of Gene Expression Signatures in the Progression of Hepatocellular Carcinoma
Authors: Midorikawa Yutaka , Tsutsumi Shuichi , Nishimura Kunihiro , Kamimura Naoko , Kano Makoto , Sakamoto Hirohiko , Makuuchi Masatoshi , Aburatani Hiroyuki 
Published: September 2005

AbstractTo identify the chromosomal aberrations associated with the progression of liver cancer, we applied expression imbalance map analysis to gene expression data from 31 hepatocellular carcinomas and 19 noncancerous tissues. Expression imbalance map analysis, which detects mRNA expression imbalance correlated with chromosomal regions, showed that expression gains of 1q21-23 (74%), 8q13-21 (48%), 12q23-24 (41%), 17q12-21(48%), 17q25 (25%), and 20q11 (22%) and losses of 4q13 (48%), 8p12-21 (32%), 13q14 (32%), and 17p13 (29%) were significantly associated with hepatocellular carcinoma. Most regions with altered expression identified by expression imbalance map were also identified in previous reports using comparative genomic hybridization. We demonstrated chromosomal copy number gain in 1q21-23 and loss in 17p13 by genomic quantitative PCR, suggesting that gene expression profiles reflect chromosomal alterations. Furthermore, expression imbalance map analysis revealed that more poorly differentiated hepatocellular carcinoma contain more chromosomal alterations, which are accumulated in a stepwise manner in the course of hepatocellular carcinoma progression: expression imbalance of 1q, 8p, 8q, and 17p occur as early events in hepatocarcinogenesis, and 12q, 17q25 and 20q occur as later events. In particular, expression gain of 17q12-21 and loss of 4q were seen to accumulate constantly through the dedifferentiation process. Our data suggest that gene expression profiles are subject to chromosomal bias and that expression imbalance map can correlate gene expression to gene loci with high resolution and sensitivity.
Increased Progesterone Receptor Expression in Benign Epithelium of
BRCA1
-Related Breast Cancers
Authors: King Tari A. , Gemignani Mary L. , Li Weiwei , Giri Dilip D. , Panageas Kathy S. , Bogomolniy Faina , Arroyo Crispinita , Olvera Narciso , Robson Mark E. , Offit Kenneth , Borgen Patrick I. , Boyd Jeff 
Published: September 2005

Abstract
The study of pathologically normal breast epithelium of BRCA mutation carriers may yield insights into the early natural history of breast tumorigenesis. Hormone receptor expression was assessed in 24 cases of invasive breast cancer associated with a mutation in BRCA1 (n = 15) or BRCA2 (n = 9) and in 39 sporadic cases matched for patient age and tumor hormone receptor status. Expression of progesterone receptor was significantly (P = 0.0003) more common in normal breast epithelium adjacent to invasive breast carcinoma in BRCA1-linked cases compared with sporadic cases. The wild-type BRCA allele was retained in normal epithelium of all cases tested. We conclude that deregulation of progesterone receptor expression, as a result of BRCA1 haploinsufficiency, may represent an early event in BRCA1-linked breast tumorigenesis.
ATR Affecting Cell Radiosensitivity Is Dependent on Homologous Recombination Repair but Independent of Nonhomologous End Joining
Authors: Wang Hongyan , Wang Huichen , Powell Simon N. , Iliakis George , Wang Ya 
Published: September 2005

Abstract
ATR is one of the most important checkpoint proteins in mammalian cells responding to DNA damage. Cells defective in normal ATR activity are sensitive to ionizing radiation (IR). The mechanism by which ATR protects the cells from IR-induced killing remains unclear. DNA double-strand breaks (DSBs) induced by IR are critical lesions for cell survival. Two major DNA DSB repair pathways exist in mammalian cells: homologous recombination repair (HRR) and nonhomologous end joining (NHEJ). We show that the doxycycline (dox)-induced ATR kinase dead (ATRkd) cells have the similar inductions and rejoining rates of DNA DSBs compared with cells without dox induction, although the dox-induced ATRkd cells are more sensitive to IR and have the deficient S and G2 checkpoints. We also show that the dox-induced ATRkd cells have a lower HRR efficiency compared with the cells without dox induction. These results indicate that the effects of ATR on cell radiosensitivity are independent of NHEJ but are linked to HRR that may be affected by the deficient S and G2 checkpoints.
Increased Survival, Proliferation, and Migration in Metastatic Human Pancreatic Tumor Cells Expressing Functional CXCR4
Authors: Marchesi Federica , Monti Paolo , Leone Biagio Eugenio , Zerbi Alessandro , Vecchi Annunciata , Piemonti Lorenzo , Mantovani Alberto , Allavena Paola 
Published: September 2005

AbstractIn this study, we have evaluated 11 pancreatic tumor cell lines and tumor cells from surgical samples of patients with pancreatic adenocarcinoma for expression of the chemokine receptor CXCR4. Six of 11 cell lines expressed detectable mRNA of CXCR4, with three cell lines (AsPC1, Capan1, and Hs766T) having substantial amounts of transcripts. Expression was higher in lines derived from metastatic lesions compared with those derived from primary tumors. Different inflammatory cytokines did not modify expression, whereas IFN-γ down-regulated and hypoxia up-regulated CXCR4 transcripts. Transcript expression was associated with surface expression in pancreatic carcinoma cell lines. All surgical carcinoma samples tested expressed higher levels of CXCR4 than normal pancreatic ducts, which were used as reference tissue. The chemokine CXCL12 induced chemotaxis in CXCR4-positive pancreatic carcinoma cell lines, which was inhibited by anti-CXCR4 monoclonal antibody and by the antagonist AMD3100. Transendothelial migration, Matrigel invasion, and activation of matrix metalloproteases were also enhanced by CXCL12. In CXCR4-positive cell lines, CXCL12 stimulated cell proliferation. The cell line Hs766T produces high levels of CXCL12, and addition of the CXCR4 antagonist AMD3100 partially inhibited proliferation, indicating an autocrine loop. Moreover, the addition of exogenous CXCL12 inhibited apoptosis induced by serum starvation. These results indicate that the CXCR4 receptor is frequently expressed in metastatic pancreatic tumor cells. CXCR4 not only stimulates cell motility and invasion but also promotes survival and proliferation. Strategies to target CXCR4 expressed on tumor cells may be of benefit in patients with pancreatic cancer.
Class II-Associated Invariant Chain Peptide Expression on Myeloid Leukemic Blasts Predicts Poor Clinical Outcome
Authors: Chamuleau Martine E. D. , Souwer Yuri , van Ham S. Marieke , Zevenbergen Adri , Westers Theresia M. , Berkhof Johannes , Meijer Chris J. L. M. , van de Loosdrecht Arjan A. , Ossenkoppele Gert J. 
Published: September 2005

AbstractEffective antitumor responses need the activation of CD4+ T cells. MHC class II antigen presentation requires the release of class II-associated invariant chain peptide (CLIP) from the antigen-binding site. In antigen-presenting cells, human leukocyte antigen DM (HLA-DM; abbreviated DM in this article) catalyzes CLIP dissociation. In B cells, HLA-DO (DO) down-modulates DM function. Cell surface CLIP:HLA-DR (DR) ratio correlates to DO:DM ratio and the efficacy of antigen presentation. We examined 111 blood and bone marrow samples of patients with newly diagnosed acute myeloid leukemia (AML) for the expression of CLIP, DR, DM, and DO by flow cytometry. Patients with DR+/CLIP− blasts had a significant longer disease-free survival than patients with DR+/CLIP+ blasts. DO, until now believed to be restricted to lymphoid cells, could be demonstrated at protein level as well as by reverse transcription-PCR. DO:DM ratio correlated to CLIP:DR ratio, suggesting that, unlike in other antigen-presenting cells of the nonlymphoid cell type, both DO and DM mediate regulation of CLIP expression in AML blasts. We hypothesize that DR+/CLIP− AML blasts are able to present leukemia-specific antigens to CD4+ T helper cells initiating an effective and long-lasting antitumor response resulting in a prolonged disease-free survival.
Gonadotropin-Releasing Hormone (GnRH) Antagonists Promote Proapoptotic Signaling in Peripheral Reproductive Tumor Cells by Activating a Gαi-Coupling State of the Type I GnRH Receptor
Authors: Maudsley Stuart , Davidson Lindsay , Pawson Adam J. , Chan Raymond , de Maturana Rakel López , Millar Robert P. 
Published: September 2005

AbstractGonadotropin-releasing hormone (GnRH) receptor agonists are extensively used in the treatment of sex hormone-dependent cancers via the desensitization of pituitary gonadotropes and consequent decrease in steroid sex hormone secretion. However, evidence now points to a direct inhibitory effect of GnRH analogs on cancer cells. These effects appear to be mediated via the Gαi-type G protein, in contrast to the predominant Gαq coupling in gonadotropes. Unlike Gαq coupling, Gαi coupling of the GnRH receptor can be activated by both agonists and antagonists. This unusual pharmacology suggested that the receptor involved in the cancer cells may not be the classical gonadotrope type I GnRH receptor. However, we have previously shown that a functional type II GnRH receptor is not present in man. In the present study, we show that GnRH agonists and selective GnRH antagonists exert potent antiproliferative effects on JEG-3 choriocarcinoma, benign prostate hyperplasia (BPH-1), and HEK293 cells stably expressing the type I GnRH receptor. This antiproliferative action occurs through a Gαi-mediated activation of stress-activated protein kinase pathways, resulting in caspase activation and transmembrane transfer of phosphatidlyserine to the outer membrane envelope. Structurally related antagonistic GnRH analogs displayed divergent antiproliferative efficacies but demonstrated equal efficacies in inhibiting GnRH-induced Gαq-based signaling. Therefore the ability of GnRH receptor antagonists to exert an antiproliferative effect on reproductive tumors may be dependent on ligand-selective activation of the Gαi-coupled form of the type I GnRH receptor.
Role of Human Ku86 in Telomere Length Maintenance and Telomere Capping
Authors: Jaco Isabel , Muñoz Purificación , Blasco María A. 
Published: September 2005

Abstract
The role of Ku86 at telomeres has been extensively studied in various organisms; however, a role for Ku86 at human telomeres was unknown because Ku86 deletion is lethal for human cells. Here, we used small interference RNA to decrease Ku86 protein levels in human cells. An ∼50% reduction in the amount of Ku86 protein was achieved 72 hours after transfection with Ku86-specific small interference RNAs. This decrease in Ku86 levels resulted in a rapid loss of cell viability characterized by increased apoptosis and decreased mitotic index in the cell population. Importantly, Ku86 knockdown was concomitant with a significant loss of telomeric sequences and with increased chromosomal aberrations, including chromatid-type fusions involving telomeric sequences. These findings demonstrate a role for Ku86 in regulating telomere length and telomere capping in human cells, which, in turn, could impact on cancer and aging.
Gene Expression in the Lung of
p53
Mutant Mice Exposed to Cigarette Smoke
Authors: Izzotti Alberto , Cartiglia Cristina , Longobardi Mariagrazia , Bagnasco Maria , Merello Andrea , You Ming , Lubet Ronald A. , De Flora Silvio 
Published: September 2005

Abstract
We showed previously that p53 mutations play a role in cigarette smoke-related carcinogenesis not only in humans but also in A/J mice. In fact, (UL53–3 × A/J)F1 mice, carrying a dominant-negative germ-line p53 mutation, responded to exposure to environmental cigarette smoke more efficiently than their wild-type (wt) littermate controls in terms of molecular alterations, cytogenetic damage, and lung tumor yield. To clarify the mechanisms involved, we analyzed by cDNA array the expression of 1,185 cancer-related genes in the lung of the same mice. Neither environmental cigarette smoke nor the p53 status affected the expression of the p53 gene, but the p53 mutation strikingly increased the basal levels of p53 nuclear protein in the lung. Environmental cigarette smoke increased p53 protein levels in wt mice only. The p53 mutation enhanced the expression of positive cell cycle regulators in sham-exposed mice, which suggests a physiologic protective role of p53. In environmental cigarette smoke-exposed mice, the p53 mutation resulted in a lack of induction of proapoptotic genes and in overexpression of genes involved in cell proliferation, signal transduction, angiogenesis, inflammation, and immune response. Mutant mice and wt mice reacted to environmental cigarette smoke in a similar manner regarding genes involved in metabolism of xenobiotics, multidrug resistance, and protein repair. Irrespective of the p53 status, environmental cigarette smoke poorly affected the expression of oncogenes, tumor suppressor genes, and DNA repair genes. Taken together, these findings may explain the increased susceptibility of p53 mutant mice to smoke-related alterations of intermediate biomarkers and lung carcinogenesis.
Identification of Aberrantly Methylated Genes in Association with Adult T-Cell Leukemia
Authors: Yasunaga Jun-ichirou , Taniguchi Yuko , Nosaka Kisato , Yoshida Mika , Satou Yorifumi , Sakai Tatsunori , Mitsuya Hiroaki , Matsuoka Masao 
Published: September 2005

Abstract
In this study, we identified 53 aberrantly hypermethylated DNA sequences in adult T-cell leukemia (ATL) cells using methylated CpG island amplification/representational difference analysis method. We also observed a proportionate increase in the methylation density of these regions with disease progression. Seven genes, which were expressed in normal T cells, but suppressed in ATL cells, were identified near the hypermethylated regions. Among these silenced genes, Kruppel-like factor 4 (KLF4) gene is a cell cycle regulator and early growth response 3 (EGR3) gene is a critical transcriptional factor for induction of Fas ligand (FasL) expression. Treatment with 5-aza-2′-deoxycytidine resulted in the recovery of their transcription, indicating that their silencing might be associated with DNA hypermethylation. To study their functions in ATL cells, we transfected recombinant adenovirus vectors expressing KLF4 and EGR3 genes. Expression of KLF4 induced apoptosis of ATL cells whereas enforced expression of EGR3 induced the expression of FasL gene, resulting in apoptosis. Thus, suppressed expression of EGR3 enabled ATL cells to escape from activation-induced cell death mediated by FasL. Our results showed that the methylated CpG island amplification/representational difference analysis method allowed the isolation of hypermethylated DNA regions specific to leukemic cells and thus shed light on the roles of DNA methylation in leukemogenesis.
In vitro
and
In vivo
Models Analyzing von Hippel-Lindau Disease-Specific Mutations
Authors: Rathmell W. Kimryn , Hickey Michele M. , Bezman Natalie A. , Chmielecki Christie A. , Carraway Natalie C. , Simon M. Celeste 
Published: September 2005

Abstract
Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene cause tissue-specific tumors, with a striking genotype-phenotype correlation. Loss of VHL expression predisposes to hemangioblastoma and clear cell renal cell carcinoma, whereas specific point mutations predispose to pheochromocytoma, polycythemia, or combinations of hemangioblastoma, renal cell carcinoma, and/or pheochromocytoma. The VHL protein (pVHL) has been implicated in many cellular activities including the hypoxia response, cell cycle arrest, apoptosis, and extracellular matrix remodeling. We have expressed missense pVHL mutations in Vhl−/− murine embryonic stem cells to test genotype-phenotype correlations in euploid cells. We first examined the ability of mutant pVHL to direct degradation of the hypoxia inducible factor (HIF) subunits HIF1α and HIF2α. All mutant pVHL proteins restored proper hypoxic regulation of HIF1α, although one VHL mutation (VHLR167Q) displayed impaired binding to Elongin C. This mutation also failed to restore HIF2α regulation. In separate assays, these embryonic stem cells were used to generate teratomas in immunocompromised mice, allowing independent assessment of the effects of specific VHL mutations on tumor growth. Surprisingly, teratomas expressing the VHLY112H mutant protein displayed a growth disadvantage, despite restoring HIFα regulation. Finally, we observed increased microvessel density in teratomas derived from Vhl−/− as well as VHLY112H, VHLR167Q, and VHLR200W embryonic stem cells. Together, these observations support the hypothesis that pVHL plays multiple roles in the cell, and that these activities can be separated via discrete VHL point mutations. The ability to dissect specific VHL functions with missense mutations in a euploid model offers a novel opportunity to elucidate the activities of VHL as a tumor suppressor.
Radiation Sensitivity, H2AX Phosphorylation, and Kinetics of Repair of DNA Strand Breaks in Irradiated Cervical Cancer Cell Lines
Authors: Banáth Judit P. , MacPhail Susan H. , Olive Peggy L. 
Published: September 2005

Abstract
Six human cervical cancer cell lines [five human papillomavirus (HPV) positive, one HPV negative] for induction and rejoining of DNA strand breaks and for kinetics of formation and loss of serine 139 phosphorylated histone H2AX (γH2AX). X-rays induced the same level of DNA breakage for all cell lines. By 8 hours after 20 Gy, &lt;2% of the initial single-strand breaks remained and no double-strand breaks could be detected. In contrast, 24 hours after irradiation, γH2AX representing up to 30% of the initial signal still present. SW756 cells showed almost four times higher background levels of γH2AX and no residual γH2AX compared with the most radiosensitive HPV-negative C33A cells that showed the lowest background and retained 30% of the maximum level of γH2AX. Radiation sensitivity, measured as clonogenic-surviving fraction after 2 Gy, was correlated with the fraction of γH2AX remaining 24 hours after irradiation. A substantial correlation with γH2AX loss half-time measured over the first 4 hours was seen only when cervical cell lines were included in a larger series of p53-deficient cell lines. Interestingly, p53 wild-type cell lines consistently showed faster γH2AX loss half-times than p53-deficient cell lines. We conclude that cell line-dependent differences in loss of γH2AX after irradiation are related in part to intrinsic radiosensitivity. The possibility that the presence of γH2AX foci may not always signify the presence of a physical break, notably in some tumor cell lines, is also supported by these results.
Suppression of Human Prostate Tumor Growth in Mice by a Cytolytic d-, l-Amino Acid Peptide
Authors: Papo Niv , Braunstein Amir , Eshhar Zelig , Shai Yechiel 
Published: September 2005

Abstract
Gene-encoded host defense peptides are used as part of the innate immunity, and many of them act by directly lysing the cell membrane of the pathogen. A few of these peptides showed anticancer activity in vitro but could not be used in vivo because of their inactivation by serum. We designed a 15-amino acid peptide, composed of d- and l-amino acids (diastereomer), which targets both androgen-independent and androgen-dependent human prostate carcinoma cell lines (CL1, 22RV1, and LNCaP). Most importantly, we observed a complete arrest of growth in CL1 and 22RV1 xenografts treated intratumorally with the diastereomer. This was also accompanied by a lowering of prostate-specific antigen serum levels secreted by the 22RV1 xenograft. Furthermore, the diastereomer synergized with conventional chemotherapeutics. In contrast, the parental all l-amino acids peptide was highly active only in vitro and could not discriminate between tumor and nontumor cells. Fluorescent confocal microscopy, histopathologic examination, and cell permeability studies (depolarization of transmembrane potential and release of an encapsulated dye) suggest a necrotic mechanism of killing, after a threshold concentration of peptide has been reached. Its destructive killing effect and the simple sequence of the diastereomer make it an attractive chemotherapeutic candidate possessing a new mode of action, with potential to be developed additionally for the treatment of prostate carcinoma.
Intratumor Heterogeneity of Cancer/Testis Antigens Expression in Human Cutaneous Melanoma Is Methylation-Regulated and Functionally Reverted by 5-Aza-2′-deoxycytidine
Authors: Sigalotti Luca , Fratta Elisabetta , Coral Sandra , Tanzarella Silvia , Danielli Riccardo , Colizzi Francesca , Fonsatti Ester , Traversari Catia , Altomonte Maresa , Maio Michele 
Published: September 2005

Abstract
Cancer/testis antigens (CTA) are suitable targets for immunotherapy of human malignancies, and clinical trials are mainly focusing on MAGE-A3. However, the heterogeneous intratumor expression of CTA may hamper the effectiveness of CTA-directed vaccination through the emergence of CTA-negative neoplastic clones. We investigated the intratumor heterogeneity of CTA in human melanoma and the underlying molecular mechanism(s) at clonal level using 14 single cell clones generated from the melanoma lesion Mel 313. Reverse transcription-PCR revealed a highly heterogeneous expression of MAGE-A1, -A2, -A3, -A4, -A6, GAGE 1–6, SSX 1–5, and PRAME among melanoma clones. Only nine clones expressed MAGE-A3 and competitive reverse transcription-PCR identified relative differences in the number of mRNA molecules of up to 130-fold between clones 5 and 14. This clonal heterogeneity of MAGE-A3 expression correlated with the methylation status of specific CpG dinucleotides in MAGE-A3 promoter: i.e., hypomethylated CpG dinucleotides at positions −321, −151, −19, −16, −5, −2, +21, and +42 were found in clones expressing high but not low levels of MAGE-A3. Supporting the role of DNA methylation in generating the intratumor heterogeneity of CTA, the DNA hypomethylating agent 5-aza-2′-deoxycytidine (5-AZA-dCyd) invariably induced their expression in all CTA-negative clones. Furthermore, 5-AZA-dCyd–treatment reduced to 6 folds the differential expression of MAGE-A3 between clones 5 and 14, which became recognized to a similar extent by T cells specific for a MAGE-A–encoded peptide. These findings identify promoter methylation as directly responsible for the intratumoral heterogeneity of therapeutic CTA in melanoma and foresee the use of 5-AZA-dCyd to overcome the limitations set by their intratumor heterogeneous expression to CTA-based vaccine therapy.