bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Resveratrol Inhibits Proliferation and Survival of Epstein Barr Virus–Infected Burkitt's Lymphoma Cells Depending on Viral Latency Program
Authors: De Leo Alessandra , Arena Giuseppe , Stecca Claudia , Raciti Marisa , Mattia Elena
Published: April 2023

Abstract
Resveratrol (3,4′,5-trihydroxy-trans-stilbene), a polyphenolic natural product, shows chemopreventive properties against several cancers, heart diseases, inflammation, and viral infections. Epstein Barr virus (EBV), a γ-herpesvirus, contributes to the development of several human cancers including Burkitt's lymphoma (BL). In this study, we asked whether treatment with resveratrol would affect the viability of EBV-positive BL cells displaying different forms of latency. We report here that resveratrol, regardless of EBV status, induces caspase-dependent apoptosis by arresting cell-cycle progression in G1 phase. However, resveratrol strongly induced apoptosis in EBV(−) and latency I EBV(+) cells, whereas latency II and latency III EBV(+) BL cells showed a survival advantage that increased with the extent of the pattern of viral gene expression. Resveratrol-induced cell-cycle arrest and apoptosis occurred in association with induction of p38 MAPK phosphorylation and suppression of ERK1/2 signaling pathway. Moreover, NF-κB DNA-binding activity was inhibited in all BL lines except EBV(+) latency III cells.

LMP1 oncogene, which is expressed in latency III phenotype, is involved with the higher resistance to the antiproliferative effect of resveratrol because siRNA-mediated inhibition of LMP1 greatly increased the sensitivity of latency III BL cells as well as that of lymphoblastoid cell lines to the polyphenol. We propose that a combined resveratrol/siRNA strategy may be a novel approach for the treatment of EBV-associated B-cell malignancies in which the viral pattern of gene expression has been defined. Mol Cancer Res; 9(10); 1346–55. ©2011 AACR.
Data from Critical Role of Endogenous Heme Oxygenase 1 as a Tuner of the Invasive Potential of Prostate Cancer Cells
Authors: Gueron Geraldine , De Siervi Adriana , Ferrando Mercedes , Salierno Marcelo , De Luca Paola , Elguero Belen , Meiss Roberto , Navone Nora , Vazquez Elba S.
Published: April 2023

Abstract
Prostate cancer (PCa) is the second leading cause of cancer-associated death in men. Inflammation has been recognized as a risk factor for this disease. Heme oxygenase 1 (HO-1), the inducible isoform of the rate-limiting enzyme in heme degradation, counteracts oxidative and inflammatory damage. Here, we investigated the regulated expression of HO-1 and its functional consequences in PCa. We studied the effect of genetic and pharmacologic disruption of HO-1 in the growth, invasion, and migration in androgen-sensitive (MDA PCa2b and LNCaP) and androgen-insensitive (PC3) PCa cell lines. Our results show that HO-1 levels are markedly decreased in PC3 compared with MDA PCa2b and LNCaP. Hemin treatment increased HO-1 at both protein and mRNA levels in all cell lines and decreased cell proliferation and invasion. Furthermore, overexpression of HO-1 in PC3 resulted in markedly reduced cell proliferation and migration. Accordingly, small interfering RNA–mediated silencing of HO-1 expression in MDA PCa2b cells resulted in increased proliferation and invasion. Using reverse transcription-quantitative PCR–generated gene array, a set of inflammatory and angiogenic genes were upregulated or downregulated in response to HO-1 overexpression identifying matrix metalloprotease 9 (MMP9) as a novel downstream target of HO-1. MMP9 production and activity was downregulated by HO-1 overexpression. Furthermore, PC3 cells stably transfected with HO-1 (PC3HO-1) and controls were injected into nu/nu mice for analysis of in vivo tumor xenograft phenotype. Tumor growth and MMP9 expression was significantly reduced in PC3HO-1 tumors compared with control xenografts. Taken together, these results implicate HO-1 in PCa cell migration and proliferation suggesting its potential role as a therapeutic target in clinical settings. (Mol Cancer Res 2009;7(11):1745–55)
Data from JAG2 Induction in Hypoxic Tumor Cells Alters Notch Signaling and Enhances Endothelial Cell Tube Formation
Authors: Pietras Alexander , von Stedingk Kristoffer , Lindgren David , Påhlman Sven , Axelson Håkan
Published: April 2023

Abstract
Several studies have revealed links between hypoxia and activation of Notch in solid tumors. While most reports have focused on intracellular domain of the Notch1 receptor (icN1) stabilization by direct interaction with HIF proteins, little attention has been given to Notch ligand regulation during hypoxia. Here we show that the Notch ligand JAG2 is transcriptionally activated by hypoxia in a HIF-1α dependent manner. Hypoxic JAG2 induction resulted in elevated Notch activity in tumor cells, as was measured by increased icN1 levels and induction of the Notch target gene HEY1. In primary tumor material, JAG2 expression correlated with vascular development and angiogenesis gene signatures. In line with this, coculture experiments of endothelial cells with hypoxic breast cancer cells displayed a reduction in number of capillary-like tubes formed upon JAG2 siRNA treatment of the breast cancer cells. Together these results suggest that a hypoxic induction of JAG2 in tumor cells mediates a hypoxia-regulated cross-talk between tumor and endothelial cells. Mol Cancer Res; 9(5); 626–36. ©2011 AACR.
Data from Distinct Roles for Histone Methyltransferases G9a and GLP in Cancer Germ-Line Antigen Gene Regulation in Human Cancer Cells and Murine Embryonic Stem Cells
Authors: Link Petra A. , Gangisetty Omkaram , James Smitha R. , Woloszynska-Read Anna , Tachibana Makoto , Shinkai Yoichi , Karpf Adam R.
Published: April 2023

Abstract
The H3K9me2 histone methyltransferases G9a and GLP repress Mage-a class cancer germ-line (CG) antigen gene expression in murine embryonic stem (ES) cells, but the role of these enzymes in CG antigen gene regulation in human cancer cells is unknown. Here we show that whereas independent or dual knockdown of G9a and GLP in human cancer cells leads to reduced global and CG antigen promoter–associated H3K9me2 levels, it does not activate CG antigen gene expression. Moreover, CG antigen gene repression is maintained following pharmacologic targeting of G9a or treatment of G9a knockdown cells with the histone deacetylase inhibitor trichostatin A. However, G9a knockdown cells display increased sensitivity to CG antigen gene activation mediated by the DNA methyltransferase inhibitor decitabine. To account for these findings, we examined DNA methylation at CG antigen gene promoters in both cell types. We found robust DNA hypomethylation in G9a/GLP targeted murine ES cells but a lack of DNA methylation changes in G9a/GLP targeted human cancer cells; intriguingly, this distinction also extended to markers of global DNA methylation. These data reveal that G9a/GLP is required for DNA methylation of CG antigen genes and genomic DNA in murine ES cells, but not human cancer cells, and implicate DNA methylation status as the key epigenetic mechanism involved in CG antigen gene repression. (Mol Cancer Res 2009;7(6):851–62)
Data from The ARF Tumor Suppressor Inhibits Tumor Cell Colonization Independent of p53 in a Novel Mouse Model of Pancreatic Ductal Adenocarcinoma Metastasis
Authors: Muniz Viviane Palhares , Barnes J. Matthew , Paliwal Seema , Zhang Xuefeng , Tang Xiaoyun , Chen Songhai , Zamba Kokou D. , Cullen Joseph J. , Meyerholz David K. , Meyers Shari , Davis J. Nathan , Grossman Steven R. , Henry Michael D. , Quelle Dawn E.
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an incurable, highly metastatic disease that is largely resistant to existing treatments. A better understanding of the genetic basis of PDAC metastasis should facilitate development of improved therapies. To that end, we developed a novel mouse xenograft model of PDAC metastasis to expedite testing of candidate genes associated with the disease. Human PDAC cell lines BxPC-3, MiaPaCa-2, and Panc-1 stably expressing luciferase were generated and introduced by intracardiac injections into immunodeficient mice to model hematogenous dissemination of cancer cells. Tumor development was monitored by bioluminescence imaging. Bioluminescent MiaPaCa-2 cells most effectively recapitulated PDAC tumor development and metastatic distribution in vivo. Tumors formed in nearly 90% of mice and in multiple tissues, including normal sites of PDAC metastasis. Effects of p14ARF, a known suppressor of PDAC, were tested to validate the model. In vitro, p14ARF acted through a CtBP2-dependent, p53-independent pathway to inhibit MiaPaCa-2–invasive phenotypes, which correlated with reduced tumor cell colonization in vivo. These findings establish a new bioluminescent mouse tumor model for rapidly assessing the biological significance of suspected PDAC metastasis genes. This system may also provide a valuable platform for testing innovative therapies. Mol Cancer Res; 9(7); 867–77. ©2011 AACR.
Data from Mitotic Arrest, Apoptosis, and Sensitization to Chemotherapy of Melanomas by Methionine Deprivation Stress
Authors: Kokkinakis Demetrius M. , Brickner Anthony G. , Kirkwood John M. , Liu XiaoYan , Goldwasser Jason E. , Kastrama Anastasiya , Sander Cindy , Bocangel Dora , Chada Sunil
Published: April 2023

Abstract
Methionine deprivation stress (MDS) eliminates mitotic activity in melanoma cells regardless of stage, grade, or TP53 status, whereas it has a negligible effect on normal skin fibroblasts. In most cases, apoptosis accounts for the elimination of up to 90% of tumor cells from the culture within 72 hours after MDS, leaving a scattered population of multinucleated resistant cells. Loss of mitosis in tumor cells is associated with marked reduction of cyclin-dependent kinase (CDK) 1 transcription and/or loss of its active form (CDK1-P-Thr161), which is coincident with up-regulation of CDKN1A, CDKN1B, and CDKN1C (p21, p27, and p57). Expression of the proapoptotic LITAF, IFNGR, EREG, TNFSF/TNFRSF10 and TNFRSF12, FAS, and RNASEL is primarily up-regulated/induced in cells destined to undergo apoptosis. Loss of Aurora kinase B and BIRC5, which are required for histone H3 phosphorylation, is associated with the accumulation of surviving multinucleated cells. Nevertheless, noncycling survivors of MDS are sensitized to temozolomide, carmustin, and cisplatin to a much greater extent than normal skin fibroblasts possibly because of the suppression of MGMT/TOP1/POLB, MGMT/RAD52/RAD54, and cMET/RADD52, respectively. Sensitivity to these and additional genotoxic agents and radiation may also be acquired due to loss of cMET/OGG1, reduced glutathione reductase levels, and a G2-phase block that is a crucial step in the damage response associated with enhancement of drug toxicity. Although the genes controlling mitotic arrest and/or apoptosis in response to low extracellular methionine levels are unknown, it is likely that such control is exerted via the induction/up-regulation of tumor suppressors/growth inhibitor genes, such as TGFB, PTEN, GAS1, EGR3, BTG3, MDA7, and the proteoglycans (LUM, BGN, and DCN), as well as the down-regulation/loss of function of prosurvival genes, such as NFκB, MYC, and ERBB2. Although MDS targets several common genes in tumors, mutational variability among melanomas may decide which metabolic and signal transduction pathways will be activated or shutdown. (Mol Cancer Res 2006;4(8):575–89)
Data from Microarray Analysis of Bleomycin-Exposed Lymphoblastoid Cells for Identifying Cancer Susceptibility Genes
Authors: Cloos Jacqueline , de Boer Wim P.H. , Snel Mireille H.J. , van den IJssel Paul , Ylstra Bauke , Leemans C. René , Brakenhoff Ruud H. , Braakhuis Boudewijn J.M.
Published: April 2023

Abstract
The uncovering of genes involved in susceptibility to the sporadic cancer types is a great challenge. It is well established that the way in which an individual deals with DNA damage is related to the chance to develop cancer. Mutagen sensitivity is a phenotype that reflects an individual's susceptibility to the major sporadic cancer types, including colon, lung, and head and neck cancer. A standard test for mutagen sensitivity is measuring the number of chromatid breaks in lymphocytes after exposure to bleomycin. The aim of the present study was to search for the pathways involved in mutagen sensitivity. Lymphoblastoid cell lines of seven individuals with low mutagen sensitivity were compared with seven individuals with a high score. RNA was isolated from cells exposed to bleomycin (4 hours) and from unexposed cells. Microarray analysis (19K) was used to compare gene expression of insensitive and sensitive cells. The profile of most altered genes after bleomycin exposure, analyzed in all 14 cell lines, included relatively many genes involved in biological processes, such as cell growth and/or maintenance, proliferation, and regulation of cell cycle, as well as some genes involved in DNA repair. When comparing the insensitive and sensitive individuals, other differentially expressed genes were found that are involved in signal transduction and cell growth and/or maintenance (e.g., BUB1 and DUSP4). This difference in expression profiles between mutagen-sensitive and mutagen-insensitive individuals justifies further studies aimed at elucidating the genes responsible for the development of sporadic cancers. (Mol Cancer Res 2006;4(2):71–7)
Data from Genomic Analysis of a Spontaneous Model of Breast Cancer Metastasis to Bone Reveals a Role for the Extracellular Matrix1
Authors: Eckhardt Bedrich L. , Parker Belinda S. , van Laar Ryan K. , Restall Christina M. , Natoli Anthony L. , Tavaria Michael D. , Stanley Kym L. , Sloan Erica K. , Moseley Jane M. , Anderson Robin L.
Published: April 2023

Abstract
A clinically relevant model of spontaneous breast cancer metastasis to multiple sites, including bone, was characterized and used to identify genes involved in metastatic progression. The metastatic potential of several genetically related tumor lines was assayed using a novel real-time quantitative RT-PCR assay of tumor burden. Based on this assay, the tumor lines were categorized as nonmetastatic (67NR), weakly metastatic to lymph node (168FARN) or lung (66cl4), or highly metastatic to lymph node, lung, and bone (4T1.2 and 4T1.13). In vitro assays that mimic stages of metastasis showed that highly metastatic tumors lines were more adhesive, invasive, and migratory than the less metastatic lines. To identify metastasis-related genes in this model, each metastatic tumor was array profiled against the nonmetastatic 67NR using 15,000 mouse cDNA arrays. A significant proportion of genes relating to the extracellular matrix had elevated expression in highly metastatic tumors. The role of one of these genes, POEM, was further investigated in the model. In situ hybridization showed that POEM expression was specific to the tumor epithelium of highly metastatic tumors. Decreased POEM expression in 4T1.2 tumors significantly inhibited spontaneous metastasis to the lung, bone, and kidney. Taken together, our data support a role for the extracellular matrix in metastatic progression and describe, for the first time, a role for POEM in this process.
Data from A Dominant-Negative Form of the Major Human Abasic Endonuclease Enhances Cellular Sensitivity to Laboratory and Clinical DNA-Damaging Agents
Authors: McNeill Daniel R. , Wilson David M.
Published: April 2023

Abstract
Apurinic/apyrimidinic (AP) endonuclease 1 (APE1) is the primary enzyme in mammals for the repair of abasic sites in DNA, as well as a variety of 3′ damages that arise upon oxidation or as products of enzymatic processing. If left unrepaired, APE1 substrates can promote mutagenic and cytotoxic outcomes. We describe herein a dominant-negative form of APE1 that lacks detectable nuclease activity and binds substrate DNA with a 13-fold higher affinity than the wild-type protein. This mutant form of APE1, termed ED, possesses two amino acid substitutions at active site residues Glu96 (changed to Gln) and Asp210 (changed to Asn). In vitro biochemical assays reveal that ED impedes wild-type APE1 AP site incision function, presumably by binding AP-DNA and blocking normal lesion processing. Moreover, tetracycline-regulated (tet-on) expression of ED in Chinese hamster ovary cells enhances the cytotoxic effects of the laboratory DNA-damaging agents, methyl methanesulfonate (MMS; 5.4-fold) and hydrogen peroxide (1.5-fold). This MMS-induced, ED-dependent cell killing coincides with a hyperaccumulation of AP sites, implying that excessive DNA damage is the cause of cell death. Because an objective of the study was to identify a protein reagent that could be used in targeted gene therapy protocols, the effects of ED on cellular sensitivity to a number of chemotherapeutic compounds was tested. We show herein that ED expression sensitizes Chinese hamster ovary cells to the killing effects of the alkylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea (also known as carmustine) and the chain terminating nucleoside analogue dideoxycytidine (also known as zalcitabine), but not to the radiomimetic bleomycin, the nucleoside analogue β-d-arabinofuranosylcytosine (also known as cytarabine), the topoisomerase inhibitors camptothecin and etoposide, or the cross-linking agents mitomycin C and cisplatin. Transient expression of ED in the human cancer cell line NCI-H1299 enhanced cellular sensitivity to MMS, 1,3-bis(2-chloroethyl)-1-nitrosourea, and dideoxycytidine, demonstrating the potential usefulness of this strategy in the treatment of human tumors. (Mol Cancer Res 2007;5(1):61–70)
Data from Histone Deacetylase Inhibitors (HDI) Cause DNA Damage in Leukemia Cells: A Mechanism for Leukemia-Specific HDI-Dependent Apoptosis?
Authors: Gaymes Terry J. , Padua Rose Ann , Pla Marika , Orr Stephen , Omidvar Nader , Chomienne Christine , Mufti Ghulam J. , Rassool Feyruz V.
Published: April 2023

Abstract
Histone deacetylase inhibitors (HDI) increase gene expression through induction of histone acetylation. However, it remains unclear whether increases in specific gene expression events determine the apoptotic response following HDI administration. Herein, we show that a variety of HDI trigger in hematopoietic cells not only widespread histone acetylation and DNA damage responses but also actual DNA damage, which is significantly increased in leukemic cells compared with normal cells. Thus, increase in H2AX and ataxia telangiectasia mutated (ATM) phosphorylation, early markers of DNA damage, occurs rapidly following HDI administration. Activation of the DNA damage and repair response following HDI treatment is further emphasized by localizing DNA repair proteins to regions of DNA damage. These events are followed by subsequent apoptosis of neoplastic cells but not normal cells. Our data indicate that induction of apoptosis by HDI may result predominantly through accumulation of excessive DNA damage in leukemia cells, leading to activation of apoptosis. (Mol Cancer Res 2006;4(8):563–73)
Data from Identification and Validation of Colorectal Neoplasia–Specific Methylation Markers for Accurate Classification of Disease
Authors: Model Fabian , Osborn Neal , Ahlquist David , Gruetzmann Robert , Molnar Bela , Sipos Ferenc , Galamb Orsolya , Pilarsky Christian , Saeger Hans-Detlev , Tulassay Zsolt , Hale Kari , Mooney Suzanne , Lograsso Joseph , Adorjan Peter , Lesche Ralf , Dessauer Andreas , Kleiber Joerg , Porstmann Baerbel , Sledziewski Andrew , Lofton-Day Catherine
Published: April 2023

Abstract
Aberrant DNA methylation occurs early in oncogenesis, is stable, and can be assayed in tissues and body fluids. Therefore, genes with aberrant methylation can provide clues for understanding tumor pathways and are attractive candidates for detection of early neoplastic events. Identification of sequences that optimally discriminate cancer from other diseased and healthy tissues is needed to advance both approaches. Using well-characterized specimens, genome-wide methylation techniques were used to identify candidate markers specific for colorectal neoplasia. To further validate 30 of these candidates from genome-wide analysis and 13 literature-derived genes, including genes involved in cancer and others with unknown functions, a high-throughput methylation-specific oligonucleotide microarray was used. The arrays were probed with bisulfite-converted DNA from 89 colorectal adenocarcinomas, 55 colorectal polyps, 31 inflammatory bowel disease, 115 extracolonic cancers, and 67 healthy tissues. The 20 most discriminating markers were highly methylated in colorectal neoplasia (area under the receiver operating characteristic curve > 0.8; P < 0.0001). Normal epithelium and extracolonic cancers revealed significantly lower methylation. Real-time PCR assays developed for 11 markers were tested on an independent set of 149 samples from colorectal adenocarcinomas, other diseases, and healthy tissues. Microarray results could be reproduced for 10 of 11 marker assays, including eight of the most discriminating markers (area under the receiver operating characteristic curve > 0.72; P < 0.009). The markers with high specificity for colorectal cancer have potential as blood-based screening markers whereas markers that are specific for multiple cancers could potentially be used as prognostic indicators, as biomarkers for therapeutic response monitoring or other diagnostic applications, compelling further investigation into their use in clinical testing and overall roles in tumorigenesis. (Mol Cancer Res 2007;5(2):153–63)
Data from Targeting Bladder Tumor Cells In vivo and in the Urine with a Peptide Identified by Phage Display
Authors: Lee Seung-Min , Lee Eun-Ju , Hong Hai-Yan , Kwon Mi-Kyung , Kwon Tae-Hwan , Choi Je-Yong , Park Rang-Woon , Kwon Tae-Gyun , Yoo Eun-Sang , Yoon Gil-Suk , Kim In-San , Ruoslahti Erkki , Lee Byung-Heon
Published: April 2023

Abstract
Bladder cancer is one of the most common tumors of the genitourinary tract. Here, we use phage display to identify a peptide that targets bladder tumor cells. A phage library containing random peptides was screened for binding to cells from human bladder tumor xenografts. Phage clones were further selected for binding to a bladder tumor cell line in culture. Six clones displaying the consensus sequence CXNXDXRX/RC showed selective binding to cells from primary human bladder cancer tissue. Of these, the CSNRDARRC sequence was selected for further study as a synthetic peptide. Fluorescein-conjugated CSNRDARRC peptide selectively bound to frozen sections of human bladder tumor tissue, whereas only negligible binding to normal bladder tissue was observed. When the fluorescent peptide was introduced into the bladder lumen, in a carcinogen-induced rat tumor model, it selectively bound to tumor epithelium. Moreover, when the peptide was intravenously injected into the tail vein, it homed to the bladder tumor but was not detectable in normal bladder and control organs. Next, we examined whether the peptide can detect tumor cells in urine. The fluorescent peptide bound to cultured bladder tumor cells but not to other types of tumor cell lines. Moreover, it bound to urinary cells of patients with bladder cancer, while showing little binding to urinary cells of patients with inflammation or healthy individuals. The CSNRDARRC peptide may be useful as a targeting moiety for selective delivery of therapeutics and as a diagnostic probe for the detection of bladder cancer. (Mol Cancer Res 2007;5(1):11–19)
Data from Src Induces Urokinase Receptor Gene Expression and Invasion/Intravasation via Activator Protein-1/p-c-Jun in Colorectal Cancer
Authors: Leupold Jörg H. , Asangani Irfan , Maurer Gabriele D. , Lengyel Ernst , Post Stefan , Allgayer Heike
Published: April 2023

Abstract
The urokinase receptor [urokinase plasminogen activator receptor (u-PAR)] promotes invasion and metastasis and is associated with poor patient survival. Recently, it was shown that Src induces u-PAR gene expression via Sp1 bound to the u-PAR promoter region −152/−135. However, u-PAR is regulated by diverse promoter motifs, among them being an essential activator protein-1 (AP-1) motif at −190/−171. Moreover, an in vivo relevance of Src-induced transcriptional regulators of u-PAR–mediated invasion, in particular intravasation, and a relevance in resected patient tumors have not sufficiently been shown. The present study was conducted (a) to investigate if, in particular, AP-1–related transcriptional mediators are required for Src-induced u-PAR–gene expression, (b) to show in vivo relevance of AP-1–mediated Src-induced u-PAR gene expression for invasion/intravasation and for resected tissues from colorectal cancer patients. Src stimulation of the u-PAR promoter deleted for AP-1 region −190/−171 was reduced as compared with the wild-type promoter in cultured colon cancer cells. In gelshifts/chromatin immunoprecipitation, Src-transfected SW480 cells showed an increase of phospho–c-Jun, in addition to JunD and Fra-1, bound to region −190/−171. Src-transfected cells showed a significant increase in c-Jun phosphorylated at Ser73 and also Ser63, which was paralleled by increased phospho–c-jun-NH2-kinase. Significant decreases of invasion/in vivo intravasation (chorionallantoic membrane model) were observed in Src-overexpressing cells treated with Src inhibitors, u-PAR–small interfering RNA, and dominant negative c-Jun (TAM67). In resected tissues of 20 colorectal cancer patients, a significant correlation between Src activity, AP-1 complexes bound to u-PAR region −190/−171, and advanced pN stage were observed. These data suggest that Src-induced u-PAR gene expression and invasion/intravasation in vivo is also mediated via AP-1 region −190/−171, especially bound with c-Jun phosphorylated at Ser73/63, and that this pathway is biologically relevant for colorectal cancer patients, suggesting therapeutic potential. (Mol Cancer Res 2007;5(5):485–96)
Data from Sustained VEGF Blockade Results in Microenvironmental Sequestration of VEGF by Tumors and Persistent VEGF Receptor-2 Activation
Authors: Kadenhe-Chiweshe Angela , Papa Joey , McCrudden Kimberly W. , Frischer Jason , Bae Jae-O , Huang Jianzhong , Fisher Jason , Lefkowitch Jay H. , Feirt Nikki , Rudge John , Holash Jocelyn , Yancopoulos George D. , Kandel Jessica J. , Yamashiro Darrell J.
Published: April 2023

Abstract
Vascular endothelial growth factor (VEGF) blockade has been validated clinically as a treatment for human cancers, yet virtually all patients eventually develop progressive disease during therapy. In order to dissect this phenomenon, we examined the effect of sustained VEGF blockade in a model of advanced pediatric cancer. Treatment of late-stage hepatoblastoma xenografts resulted in the initial collapse of the vasculature and significant tumor regression. However, during sustained treatment, vessels recovered, concurrent with a striking increase in tumor expression of perlecan, a heparan sulfate proteoglycan. Whereas VEGF mRNA was expressed at the periphery of surviving clusters of tumor cells, both secreted VEGF and perlecan accumulated circumferential to central vessels. Vascular expression of heparanase, VEGF receptor-2 ligand binding, and receptor activation were concurrently maintained despite circulating unbound VEGF Trap. Endothelial survival signaling via Akt persisted. These findings provide a novel mechanism for vascular survival during sustained VEGF blockade and indicate a role for extracellular matrix molecules that sequester and release biologically active VEGF. (Mol Cancer Res 2008;6(1):1–9)
Data from Notch Signal Activates Hypoxia Pathway through HES1-Dependent SRC/Signal Transducers and Activators of Transcription 3 Pathway
Authors: Lee Jae Ho , Suk Jinkyu , Park Jinhwi , Kim Seung Beom , Kwak Sang Su , Kim Jin Woo , Lee Chan Hee , Byun Boohyeong , Ahn Jeong Keun , Joe Cheol O.
Published: April 2023

Abstract
We report a Notch signal–induced pathway that leads to transcriptional activation of HIF1-α gene. HeLa/rtTAA/TRE-N1-IC cell line capable of doxycycline-induced expression of human Notch1-IC was established. The induction of Notch signaling activates HIF1-α and its target gene expression in HeLa/rtTAA/TRE-N1-IC cells. Notch signaling enhanced signal transducers and activators of transcription 3 (STAT3) phosphorylation required for HIF1-α expression. SRC kinase was found to be responsible for the enhanced STAT3 phosphorylation in response to Notch signaling. Activation of SRC/STAT3 pathway by Notch signaling was dependent on the expression of Notch effector HES1 transcription factor. The induction of HES1 enhanced STAT3 phosphorylation at Tyr 705 as well as SRC phosphorylation at Tyr 416 in inducible HeLa/rtTAA/TRE-HES1 cells, which express HES1 in response to doxycycline treatment. However, the treatment of Trichostatin A that interferes with HES1 transcriptional regulation did not affect STAT3 phosphorylation, and the expression of dominant negative HES1 failed to interfere with HES1-dependnent SRC/STAT3 pathway. These observations have led us to the conclusion that HES1-dependent activation of SRC/STAT3 pathway is independent of HES1 transcription regulation. This study first reports HES1-dependent SRC/STAT3 pathway that provides a functional link between Notch signaling and hypoxia pathway. (Mol Cancer Res 2009;7(10):1663–71)
Data from Wwox Suppresses Prostate Cancer Cell Growth through Modulation of ErbB2-Mediated Androgen Receptor Signaling
Authors: Qin Haiyan R. , Iliopoulos Dimitrios , Nakamura Tatsuya , Costinean Stefan , Volinia Stefano , Druck Teresa , Sun Jin , Okumura Hiroshi , Huebner Kay
Published: April 2023

Abstract
The expression of the WWOX tumor suppressor gene is lost or reduced in a large fraction of various cancers, including prostate cancer. We previously reported that Wwox overexpression induced apoptosis and suppressed prostate cancer growth in vitro and in vivo. In this study, pathways through which Wwox contributes to control of prostate cancer cell growth have been investigated. We found that Wwox interacts with Ap2γ and prevents it from entering the nucleus to bind the ERBB2 promoter region to activate transcription of ERBB2, a mediator of androgen receptor activity and prostate cancer cell growth at limiting androgen concentration. Ectopic expression of Wwox reduced ErbB2 protein expression in vitro and expression of Wwox protein inversely correlated with expression of ErbB2 protein in prostate cancer tissues. Furthermore, Wwox suppressed Ap2γ/ErbB2–induced prostate cancer cell growth and suppressed prostate-specific antigen secretion through interaction with Ap2γ and down-modulation of ErbB2, an effect that required functional androgen receptor. (Mol Cancer Res 2007;5(9):957–65)
Data from Transcriptome Profile of Human Colorectal Adenomas
Authors: Sabates-Bellver Jacob , Van der Flier Laurens G. , de Palo Mariagrazia , Cattaneo Elisa , Maake Caroline , Rehrauer Hubert , Laczko Endre , Kurowski Michal A. , Bujnicki Janusz M. , Menigatti Mirco , Luz Judith , Ranalli Teresa V. , Gomes Vito , Pastorelli Alfredo , Faggiani Roberto , Anti Marcello , Jiricny Josef , Clevers Hans , Marra Giancarlo
Published: April 2023

Abstract
Colorectal cancers are believed to arise predominantly from adenomas. Although these precancerous lesions have been subjected to extensive clinical, pathologic, and molecular analyses, little is currently known about the global gene expression changes accompanying their formation. To characterize the molecular processes underlying the transformation of normal colonic epithelium, we compared the transcriptomes of 32 prospectively collected adenomas with those of normal mucosa from the same individuals. Important differences emerged not only between the expression profiles of normal and adenomatous tissues but also between those of small and large adenomas. A key feature of the transformation process was the remodeling of the Wnt pathway reflected in patent overexpression and underexpression of 78 known components of this signaling cascade. The expression of 19 Wnt targets was closely correlated with clear up-regulation of KIAA1199, whose function is currently unknown. In normal mucosa, KIAA1199 expression was confined to cells in the lower portion of intestinal crypts, where Wnt signaling is physiologically active, but it was markedly increased in all adenomas, where it was expressed in most of the epithelial cells, and in colon cancer cell lines, it was markedly reduced by inactivation of the β-catenin/T-cell factor(s) transcription complex, the pivotal mediator of Wnt signaling. Our transcriptomic profiles of normal colonic mucosa and colorectal adenomas shed new light on the early stages of colorectal tumorigenesis and identified KIAA1199 as a novel target of the Wnt signaling pathway and a putative marker of colorectal adenomatous transformation. (Mol Cancer Res 2007;5(12):1263–75)
Data from Visible Light Modulates the Expression of Cancer-Retina Antigens
Authors: Bazhin Alexandr V. , Schadendorf Dirk , Owen Robert W. , Zernii Evgeni Yu , Philippov Pavel P. , Eichmüller Stefan B.
Published: April 2023

Abstract
Proteins involved in the visual signaling cascade show light-dependent expression levels in photoreceptor cells. Recently, these proteins have been described to be expressed in neuroectodermal tumors and to function as cancer-retina antigens. Here, we show that light can down-regulate gene expression of rhodopsin, transducin, and cyclic guanosine 3′,5′-monophosphate phosphodiesterase 6 (PDE6) and up-regulate guanylyl cyclase 1, recoverin, and arrestin in human melanoma cells in vitro, comparable to physiologic changes earlier observed in photoreceptor cells. Similar modulation can be detected at the protein level in melanoma cells except for no changes in PDE6 protein levels. Two regulatory pathways have been identified: Sp1/Sp3/Sp4 proteins for rhodopsin and PDE6, and mitogen-activated protein kinases for recoverin and arrestin. The visual cascade and retinoic acid as its derivate do not play any role in this process. Putative explanations for light-dependent modulation of cancer-retina antigen expression in melanoma cells are discussed. (Mol Cancer Res 2008;6(1):110–8)
Data from Induction of Tumorigenesis and Metastasis by the Murine Orthologue of Tumor Protein D52
Authors: Lewis Jennifer D. , Payton Laura A. , Whitford Jill G. , Byrne Jennifer A. , Smith David I. , Yang LiBang , Bright Robert K.
Published: April 2023

Abstract
Expression studies have consistently identified tumor protein D52 (TPD52) overexpression in tumor cells. Murine TPD52 (mD52) shares 86% identity with the human orthologue. To study a possible role for TPD52 in transformation, 3T3 fibroblasts were transfected with the full-length cDNA for mD52. Expression of mD52 was confirmed by reverse transcription-PCR (RT-PCR), real-time PCR, and Western blot analysis compared with 3T3 and vector-transfected 3T3 (3T3.V), and the resultant cell line was designated 3T3.mD52. At 4 weeks, 3T3.mD52 gained a 2-fold increase in growth rate, lost contact inhibition, and exhibited a marked phenotype change. Further characterization revealed an acquired ability for anchorage-independent cell growth. To determine whether 3T3.mD52 had become tumorigenic, naïve, healthy, immunocompetent syngeneic mice were inoculated subcutaneously with varying cell doses. Tumors measuring >1 cm2 were detected 60 days postinoculation with 3T3.mD52, and a 50% subcutaneous tumor incidence was obtained with as few as 5 × 105 3T3.mD52 cells. Remarkably, when lungs from 3T3.mD52 tumor-bearing mice were analyzed, numerous tumor nodules were observed, ranging from nodules less than 10 to nodules too numerous to count (inoculation with 1 × 105 and 5 × 106 cells, respectively). Further support for the metastatic capacity of 3T3.mD52 was the demonstration that transforming growth factor (TGF)-βR1 (receptor) expression decreased and TGF-β1 secretion increased in 3T3.mD52 compared with 3T3 controls. cDNA microarray analysis showed a gene expression pattern that further supported mD52-induced transformation and metastasis. Together, these data suggest that mD52 expression in 3T3 cells initiated cellular transformation, tumorigenesis, and progression to metastasis. (Mol Cancer Res 2007;5(2):133–44)
Data from MUC4 Mucin Potentiates Pancreatic Tumor Cell Proliferation, Survival, and Invasive Properties and Interferes with Its Interaction to Extracellular Matrix Proteins
Authors: Chaturvedi Pallavi , Singh Ajay P. , Moniaux Nicolas , Senapati Shantibhushan , Chakraborty Subhankar , Meza Jane L. , Batra Surinder K.
Published: April 2023

Abstract
MUC4, a transmembrane mucin, is aberrantly expressed in pancreatic adenocarcinomas while remaining undetectable in the normal pancreas. Recent studies have shown that the expression of MUC4 is associated with the progression of pancreatic cancer and is inversely correlated with the prognosis of pancreatic cancer patients. In the present study, we have examined the phenotypic and molecular consequences of MUC4 silencing with an aim of establishing the mechanistic basis for its observed role in the pathogenesis of pancreatic cancer. The silencing of MUC4 expression was achieved by stable expression of a MUC4-specific short hairpin RNA in CD18/HPAF, a highly metastatic pancreatic adenocarcinoma cell line. A significant decrease in MUC4 expression was detected in MUC4-knockdown (CD18/HPAF-siMUC4) cells compared with the parental and scrambled short interfering RNA–transfected (CD18/HPAF-Scr) control cells by immunoblot analysis and immunofluorescence confocal microscopy. Consistent with our previous observation, inhibition of MUC4 expression restrained the pancreatic tumor cell growth and metastasis as shown in an orthotopic mouse model. Our in vitro studies revealed that MUC4-associated increase in tumor cell growth resulted from both the enhanced proliferation and reduced cell death. Furthermore, MUC4 expression was also associated with significantly increased invasiveness (P ≤ 0.05) and changes in actin organization. The presence of MUC4 on the cell surface was shown to interfere with the tumor cell-extracellular matrix interactions, in part, by inhibiting the integrin-mediated cell adhesion. An altered expression of growth- and metastasis-associated genes (LI-cadherin, CEACAM6, RAC1, AnnexinA1, thrombomodulin, epiregulin, S100A4, TP53, TP53BP, caspase-2, caspase-3, caspase-7, plakoglobin, and neuregulin-2) was also observed as a consequence of the silencing of MUC4. In conclusion, our study provides experimental evidence that supports the functional significance of MUC4 in pancreatic cancer progression and indicates a novel role for MUC4 in cancer cell signaling. (Mol Cancer Res 2007;5(4):309–20)
Supplementary Figures 1-4 from Long-term Epigenetic Therapy with Oral Zebularine Has Minimal Side Effects and Prevents Intestinal Tumors in Mice
Authors: Yoo Christine B. , Chuang Jody C. , Byun Hyang-Min , Egger Gerda , Yang Allen S. , Dubeau Louis , Long Tiffany , Laird Peter W. , Marquez Victor E. , Jones Peter A.
Published: April 2023

Supplementary Figures 1-4 from Long-term Epigenetic Therapy with Oral Zebularine Has Minimal Side Effects and Prevents Intestinal Tumors in Mice
Perspective from Finasteride Does Not Increase the Risk of High-Grade Prostate Cancer: A Bias-Adjusted Modeling Approach
Authors: Redman Mary W. , Tangen Catherine M. , Goodman Phyllis J. , Lucia M. Scott , Coltman Charles A. , Thompson Ian M.
Published: April 2023

Perspective from Finasteride Does Not Increase the Risk of High-Grade Prostate Cancer: A Bias-Adjusted Modeling Approach
Perspective on this Article from High-Dose Fenretinide in Oral Leukoplakia
Authors: William William N. , Lee J. Jack , Lippman Scott M. , Martin Jack W. , Chakravarti Nitin , Tran Hai T. , Sabichi Anita L. , Kim Edward S. , Feng Lei , Lotan Reuben , Papadimitrakopoulou Vassiliki A.
Published: April 2023

Perspective on this Article from High-Dose Fenretinide in Oral Leukoplakia
Perspective from Oral Epithelium as a Surrogate Tissue for Assessing Smoking-Induced Molecular Alterations in the Lungs
Authors: Bhutani Manisha , Pathak Ashutosh Kumar , Fan You-Hong , Liu Diane D. , Lee J. Jack , Tang Hongli , Kurie Jonathan M. , Morice Rodolfo C. , Kim Edward S. , Hong Waun Ki , Mao Li
Published: April 2023

Perspective from Oral Epithelium as a Surrogate Tissue for Assessing Smoking-Induced Molecular Alterations in the Lungs
Supplementary Table 1 from A Novel Derivative of the Natural Agent Deguelin for Cancer Chemoprevention and Therapy
Authors: Kim Woo-Young , Chang Dong Jo , Hennessy Bryan , Kang Hae Jin , Yoo Jakyung , Han Seung-Ho , Kim Yoo-Shin , Park Hyun-Ju , Geo Seung-Yong , Mills Gordon , Kim Kyu-Won , Hong Waun Ki , Suh Young-Ger , Lee Ho-Young
Published: April 2023

Supplementary Table 1 from A Novel Derivative of the Natural Agent Deguelin for Cancer Chemoprevention and Therapy
Supplementary Tables 1-2 from Taxifolin Suppresses UV-Induced Skin Carcinogenesis by Targeting EGFR and PI3K
Authors: Oi Naomi , Chen Hanyong , Ok Kim Myoung , Lubet Ronald A. , Bode Ann M. , Dong Zigang
Published: April 2023

PDF File - 32KB, Table 1. Shape similarity scores of 15 proteins Table 2. Docking score of each of the 4 taxifolin enantiomers against EGFR or PI3-K
Supplementary Figure Legend from Taxifolin Suppresses UV-Induced Skin Carcinogenesis by Targeting EGFR and PI3K
Authors: Oi Naomi , Chen Hanyong , Ok Kim Myoung , Lubet Ronald A. , Bode Ann M. , Dong Zigang
Published: April 2023

PDF file-67KB
Supplementary Figure 1 from Taxifolin Suppresses UV-Induced Skin Carcinogenesis by Targeting EGFR and PI3K
Authors: Oi Naomi , Chen Hanyong , Ok Kim Myoung , Lubet Ronald A. , Bode Ann M. , Dong Zigang
Published: April 2023

PDF file-22KB, Taxifolin suppresses SUV-induced COX-2 expression and PGE2 generation in JB6 P+ cells
Supplementary Tables 1-2 from A Pooled Analysis of Continued Prophylactic Efficacy of Quadrivalent Human Papillomavirus (Types 6/11/16/18) Vaccine against High-grade Cervical and External Genital Lesions
Authors: Kjaer Susanne K. , Sigurdsson Kristján , Iversen Ole-Erik , Hernandez-Avila Mauricio , Wheeler Cosette M. , Perez Gonzalo , Brown Darron R. , Koutsky Laura A. , Tay Eng Hseon , García Patricia , Ault Kevin A. , Garland Suzanne M. , Leodolter Sepp , Olsson Sven-Eric , Tang Grace W.K. , Ferris Daron G. , Paavonen Jorma , Lehtinen Matti , Steben Marc , Bosch F. Xavier , Dillner Joakim , Joura Elmar A. , Majewski Slawomir , Muñoz Nubia , Myers Evan R. , Villa Luisa L. , Taddeo Frank J. , Roberts Christine , Tadesse Amha , Bryan Janine , Maansson Roger , Lu Shuang , Vuocolo Scott , Hesley Teresa M. , Saah Alfred , Barr Eliav , Haupt Richard M.
Published: April 2023

PDF file - 284K
Perspective on this Article from Intravesical Delivery of Rapamycin Suppresses Tumorigenesis in a Mouse Model of Progressive Bladder Cancer
Authors: Seager Catherine M. , Puzio-Kuter Anna M. , Patel Trushar , Jain Shalini , Cordon-Cardo Carlos , Mc Kiernan James , Abate-Shen Cory
Published: April 2023

Perspective on this Article from Intravesical Delivery of Rapamycin Suppresses Tumorigenesis in a Mouse Model of Progressive Bladder Cancer
Related Article from Linking Epidemiology to Epigenomics—Where Are We Today?
Authors: Ulrich Cornelia M. , Grady William M.
Published: April 2023

Related Article from Linking Epidemiology to Epigenomics—Where Are We Today?
Related Article from The Great Escape: Microbiotal LPS Takes a Toll on the Liver
Authors: Weiss David S.
Published: April 2023

Related Article from The Great Escape: Microbiotal LPS Takes a Toll on the Liver
Supplementary Table 1 from Inhibition of 15-Hydroxyprostaglandin Dehydrogenase by Helicobacter pylori in Human Gastric Carcinogenesis
Authors: Ryu Yeon-Mi , Myung Seung-Jae , Park Young Soo , Yang Dong-Hoon , Song Ho June , Jeong Jin-Yong , Lee Sun Mi , Song Miyeoun , Kim Do Hoon , Lee Hyo-Jeong , Park Soo-Kyung , Fink Stephen P. , Markowitz Sandy D. , Jung Kee Wook , Kim Kyung-Jo , Ye Byong Duk , Byeon Jeong-Sik , Jung Hwoon-Yong , Yang Suk-Kyun , Kim Jin-Ho
Published: April 2023

PDF file - 40K, Sequences of the primers used for pyrosequencing
Related Article from Prevention of Tumorigenesis in p53-Null Mammary Epithelium by Rexinoid Bexarotene, Tyrosine Kinase Inhibitor Gefitinib, and Celecoxib
Authors: Medina Daniel , Kittrell Frances , Hill Jamal , Zhang Yun , Hilsenbeck Susan G. , Bissonette Reid , Brown Powel H.
Published: April 2023

Related Article from Prevention of Tumorigenesis in p53-Null Mammary Epithelium by Rexinoid Bexarotene, Tyrosine Kinase Inhibitor Gefitinib, and Celecoxib
Supplementary Figure Legend from Inhibition of 15-Hydroxyprostaglandin Dehydrogenase by Helicobacter pylori in Human Gastric Carcinogenesis
Authors: Ryu Yeon-Mi , Myung Seung-Jae , Park Young Soo , Yang Dong-Hoon , Song Ho June , Jeong Jin-Yong , Lee Sun Mi , Song Miyeoun , Kim Do Hoon , Lee Hyo-Jeong , Park Soo-Kyung , Fink Stephen P. , Markowitz Sandy D. , Jung Kee Wook , Kim Kyung-Jo , Ye Byong Duk , Byeon Jeong-Sik , Jung Hwoon-Yong , Yang Suk-Kyun , Kim Jin-Ho
Published: April 2023

PDF file - 150K
Supplementary Tables 1-4 from Interleukin-6 as a Potential Indicator for Prevention of High-Risk Adenoma Recurrence by Dietary Flavonols in the Polyp Prevention Trial
Authors: Bobe Gerd , Albert Paul S. , Sansbury Leah B. , Lanza Elaine , Schatzkin Arthur , Colburn Nancy H. , Cross Amanda J.
Published: April 2023

Supplementary Tables 1-4 from Interleukin-6 as a Potential Indicator for Prevention of High-Risk Adenoma Recurrence by Dietary Flavonols in the Polyp Prevention Trial
Supplementary Figure 2 from Inhibition of 15-Hydroxyprostaglandin Dehydrogenase by Helicobacter pylori in Human Gastric Carcinogenesis
Authors: Ryu Yeon-Mi , Myung Seung-Jae , Park Young Soo , Yang Dong-Hoon , Song Ho June , Jeong Jin-Yong , Lee Sun Mi , Song Miyeoun , Kim Do Hoon , Lee Hyo-Jeong , Park Soo-Kyung , Fink Stephen P. , Markowitz Sandy D. , Jung Kee Wook , Kim Kyung-Jo , Ye Byong Duk , Byeon Jeong-Sik , Jung Hwoon-Yong , Yang Suk-Kyun , Kim Jin-Ho
Published: April 2023

PDF file - 1040K, 15-PGDH expression had no difference in LPS treated AGS cells
Supplementary Figure 1 from Inhibition of 15-Hydroxyprostaglandin Dehydrogenase by Helicobacter pylori in Human Gastric Carcinogenesis
Authors: Ryu Yeon-Mi , Myung Seung-Jae , Park Young Soo , Yang Dong-Hoon , Song Ho June , Jeong Jin-Yong , Lee Sun Mi , Song Miyeoun , Kim Do Hoon , Lee Hyo-Jeong , Park Soo-Kyung , Fink Stephen P. , Markowitz Sandy D. , Jung Kee Wook , Kim Kyung-Jo , Ye Byong Duk , Byeon Jeong-Sik , Jung Hwoon-Yong , Yang Suk-Kyun , Kim Jin-Ho
Published: April 2023

PDF file - 1133K, Pylori infection decreases the 15-PGDH protein expression in AGS cells
Supplementary Figure Legends 1-5 from Cryptotanshinone Activates p38/JNK and Inhibits Erk1/2 Leading to Caspase-Independent Cell Death in Tumor Cells
Authors: Chen Wenxing , Liu Lei , Luo Yan , Odaka Yoshinobu , Awate Sanket , Zhou Hongyu , Shen Tao , Zheng Shizhong , Lu Yin , Huang Shile
Published: April 2023

PDF file - 70K
Supplementary Figure 5 from Cryptotanshinone Activates p38/JNK and Inhibits Erk1/2 Leading to Caspase-Independent Cell Death in Tumor Cells
Authors: Chen Wenxing , Liu Lei , Luo Yan , Odaka Yoshinobu , Awate Sanket , Zhou Hongyu , Shen Tao , Zheng Shizhong , Lu Yin , Huang Shile
Published: April 2023

PDF file - 286K
Supplementary Figure 4 from Cryptotanshinone Activates p38/JNK and Inhibits Erk1/2 Leading to Caspase-Independent Cell Death in Tumor Cells
Authors: Chen Wenxing , Liu Lei , Luo Yan , Odaka Yoshinobu , Awate Sanket , Zhou Hongyu , Shen Tao , Zheng Shizhong , Lu Yin , Huang Shile
Published: April 2023

PDF file - 554K
Related Articles from A Proposed Unified Mechanism for the Reduction of Human Breast Cancer Risk by the Hormones of Pregnancy
Authors: Jacobson Herbert I. , Lemanski Nicole , Agarwal Anu , Narendran Amithi , Turner Kelvin E. , Bennett James A. , Andersen Thomas T.
Published: April 2023

Related Articles from A Proposed Unified Mechanism for the Reduction of Human Breast Cancer Risk by the Hormones of Pregnancy
Supplementary Figure 3 from Cryptotanshinone Activates p38/JNK and Inhibits Erk1/2 Leading to Caspase-Independent Cell Death in Tumor Cells
Authors: Chen Wenxing , Liu Lei , Luo Yan , Odaka Yoshinobu , Awate Sanket , Zhou Hongyu , Shen Tao , Zheng Shizhong , Lu Yin , Huang Shile
Published: April 2023

PDF file - 43K