bluuebunny/crossref_metadata_2025_split huggingface dataset:
Promoter Hypermethylation of
FANCF
Authors: Narayan Gopeshwar , Arias-Pulido Hugo , Nandula Subhadra V. , Basso Katia , Sugirtharaj Dorcas D. , Vargas Hernan , Mansukhani Mahesh , Villella Jeannine , Meyer Larissa , Schneider Achim , Gissmann Lutz , Dürst Matthias , Pothuri Bhavana , Murty Vundavalli V. V. S. 
Published: September 2005

Abstract
Patients with advanced stage invasive cervical cancer (CC) exhibit highly complex genomic alterations and respond poorly to conventional treatment protocols. In our efforts to understand the molecular genetic basis of CC, we examined the role of Fanconi Anemia (FA)-BRCA pathway. Here, we show that FANCF gene is disrupted by either promoter hypermethylation and/or deregulated gene expression in a majority of CC. Inhibition of DNA methylation and histone deacetylases induces FANCF gene re-expression in CC cell lines. FANCF-deregulated CC cell lines also exhibit a chromosomal hypersensitivity phenotype after exposure to an alkylating agent, a characteristic of FA patients. We also show the involvement of BRCA1 gene by promoter hypermethylation or down-regulated expression in a small subset of CC patients. Thus, we have found inactivation of genes in the FA-BRCA pathway by epigenetic alterations in a high proportion of CC patients, suggesting a major role for this pathway in the development of cervical cancer. Thus, these results have important implications in understanding the molecular basis of CC tumorigenesis and clinical management in designing targeted experimental therapeutic protocols.
Estrogen-Related Receptor α in Human Breast Carcinoma as a Potent Prognostic Factor
Authors: Suzuki Takashi , Miki Yasuhiro , Moriya Takuya , Shimada Norihiro , Ishida Takanori , Hirakawa Hisashi , Ohuchi Noriaki , Sasano Hironobu 
Published: September 2005

Abstract
Estrogen-related receptor α (ERRα) was identified as a gene related to estrogen receptor α (ERα) and belongs to a class of nuclear orphan receptors. ERRα binds to estrogen responsive element(s) (ERE) and is considered to be involved in modulation of estrogenic actions. However, biological significance of ERRα remains largely unknown. Therefore, we examined the expression of ERRα in human breast carcinoma tissues using immunohistochemistry (n = 102) and real-time reverse transcription-PCR (n = 30). ERRα immunoreactivity was detected in the nuclei of carcinoma cells in 55% of breast cancers examined, and relative immunoreactivity of ERRα was significantly (P = 0.0041) associated with the mRNA level. Significant associations were detected between ERα and ERE-containing estrogen-responsive genes, such as pS2 (P &lt; 0.0001) and EBAG9/RCAS1 (P = 0.0214), in breast carcinoma tissues. However, no significant association was detected between ERα and pS2 (P = 0.1415) in the ERRα-positive cases (n = 56) or between ERα and EBAG9/RCAS1 (P = 0.8271) in the ERRα-negative group (n = 46). ERRα immunoreactivity was significantly associated with an increased risk of recurrence and adverse clinical outcome by both uni- (P = 0.0097 and P = 0.0053, respectively) and multi- (P = 0.0215 and P = 0.0118, respectively) variate analyses. A similar tendency was also detected in the group of breast cancer patients who received tamoxifen therapy after surgery. Results from our study suggest that ERRα possibly modulates the expression of ERE-containing estrogen-responsive genes, and ERRα immunoreactivity is a potent prognostic factor in human breast carcinoma.
RASSF1A Interacts with Microtubule-Associated Proteins and Modulates Microtubule Dynamics
Authors: Dallol Ashraf , Agathanggelou Angelo , Fenton Sarah L. , Ahmed-Choudhury Jalal , Hesson Luke , Vos Michele D. , Clark Geoffrey J. , Downward Julian , Maher Eamonn R. , Latif Farida 
Published: September 2005

Abstract
The candidate tumor suppressor gene RASSF1A is inactivated in many types of adult and childhood cancers. However, the mechanisms by which RASSF1A exerts its tumor suppressive functions have yet to be elucidated. To this end, we performed a yeast two-hybrid screen to identify novel RASSF1A-interacting proteins in a human brain cDNA library. Seventy percent of interacting clones had homology to microtubule-associated proteins, including MAP1B and VCY2IP1/C19ORF5. RASSF1A association with MAP1B and VCY2IP1/C19ORF5 was subsequently confirmed in mammalian cell lines. This suggested that RASSF1A may exert its tumor-suppressive functions through interaction with the microtubules. We demonstrate that RASSF1A associates with the microtubules, causing them to exist as hyperstabilized circular bundles. We found that two naturally occurring tumor-associated missense substitutions in the RASSF1A coding region, C65R and R257Q, perturb the association of RASSF1A with the microtubules. The C65R and R257Q in addition to VCY2IP1/C19ORF5 showed reduced ability to induce microtubule acetylation and were unable to protect the microtubules against the depolymerizing action of nocodazole. In addition, wild-type RASSF1A but not the C65R or the R257Q is able to block DNA synthesis. Our data identify a role for RASSF1A in the regulation of microtubules and cell cycle dynamics that could be part of the mechanism(s) by which RASSF1A exerts its growth inhibition on cancer cells.
Hypoxia Inhibits Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis by Blocking Bax Translocation
Authors: Kim Moonil , Park Sang-Youel , Pai Hyun-Sook , Kim Tae-Hyoung , Billiar Timothy R. , Seol Dai-Wu 
Published: September 2005

AbstractThe hypoxic environment in solid tumors results from oxygen consumption by rapid proliferation of tumor cells. Hypoxia has been shown to facilitate the survival of tumor cells and to be a cause of malignant transformation. Hypoxia also is well known to attenuate the therapeutic activity of various therapies in cancer management. These observations indicate that hypoxia plays a critical role in tumor biology. However, little is known about the effects of hypoxia on apoptosis, especially on apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent apoptosis inducer that has been shown to specifically limit tumor growth without damaging normal cells and tissues in vivo. To address the effects of hypoxia on TRAIL-induced apoptosis, HCT116 human colon carcinoma cells were exposed to hypoxic or normoxic conditions and treated with soluble TRAIL protein. Hypoxia dramatically inhibited TRAIL-induced apoptosis in HCT116 cells, which are highly susceptible to TRAIL in normoxia. Hypoxia increased antiapoptotic Bcl-2 family member proteins and inhibitors of apoptosis proteins. Interestingly, these hypoxia-increased antiapoptotic molecules were decreased by TRAIL treatment to the levels lower than those of the untreated conditions, suggesting that hypoxia inhibits TRAIL-induced apoptosis via other mechanisms rather than up-regulation of these antiapoptotic molecules. Additional characterization revealed that hypoxia significantly inhibits TRAIL-induced translocation of Bax from the cytosol to the mitochondria in HCT116 and A549 cells, with the concomitant inhibition of cytochrome c release from the mitochondria. Bax-deficient HCT116 cells were completely resistant to TRAIL regardless of oxygen content, demonstrating a pivotal role of Bax in TRAIL-induced apoptotic signaling. Thus, our data indicate that hypoxia inhibits TRAIL-induced apoptosis by blocking Bax translocation to the mitochondria, thereby converting cells to a Bax-deficient state.
Hath1, Down-Regulated in Colon Adenocarcinomas, Inhibits Proliferation and Tumorigenesis of Colon Cancer Cells
Authors: Leow Ching Ching , Romero Maria S. , Ross Sarajane , Polakis Paul , Gao Wei-Qiang 
Published: September 2005

Abstract
A striking feature of colon tumors is the significant reduction of goblet cells. Although targeted deletion of Math1 in mice leads to a loss of intestinal secretory cells, including goblet cells, the role of Hath1 in colon tumorigenesis remains unknown. Here we report that Hath1, the human ortholog of Math1, was dramatically down-regulated in colon tumor samples and colon cancer cell lines. Overexpression of Hath1 in HT29, an aggressive colon cancer cell line, resulted in a significant inhibition on cell proliferation, anchorage-independent growth in soft agar and, more importantly, growth of human colon cancer cell xenografts in athymic nude mice. Such inhibition was accompanied by altered expression of a goblet cell differentiation marker, MUC2, and cell cycle regulators cyclin D1 and p27kip1. Hath1 expression also was up-regulated on inhibition of the Wnt pathway, which has been well implicated in colon tumorigenesis. Hence, this study suggests that Hath1 may be a novel factor downstream of the Wnt pathway capable of suppressing anchorage-independent growth of colon cancer cell lines. More importantly, this study is the first to establish a link between down-regulation of Hath1 expression and colon tumorigenesis.
Deletion of Laminin-8 Results in Increased Tumor Neovascularization and Metastasis in Mice
Authors: Zhou Zhongjun , Doi Masayuki , Wang Jianming , Cao Renhai , Liu Baohua , Chan Kui Ming , Kortesmaa Jarkko , Sorokin Lydia , Cao Yihai , Tryggvason Karl 
Published: September 2005

Abstract
Laminin-8 (α4β1γ1) is one of the major laminin isoforms expressed in vascular endothelial basement membranes. Here we show that deletion of laminin-8 in mice affects angiogenesis under pathological conditions. Murine tumor models used in laminin α4-deficient mice results in hyperneovascularization and significant promotion of tumor growth and metastasis. The higher tumor growth rates in mutant mice correlate with decreased tumor cell apoptosis. Depletion of laminin α4 chain may alter the structure of vascular basement membranes, leading to increased angiogenesis. Our data suggest that the laminin-8 plays a critical role in the regulation of pathological angiogenesis.
Chemopreventive Effects of a Selective Nitric Oxide Synthase Inhibitor on Carcinogen-Induced Rat Esophageal Tumorigenesis
Authors: Chen Tong , Nines Ronald G. , Peschke Sarah M. , Kresty Laura A. , Stoner Gary D. 
Published: September 2005

AbstractThe inducible nitric oxide synthase (iNOS) generates a high concentration of nitric oxide (NO) in tissues. Increased NO production is associated with many disorders including esophageal cancer. Previous studies in our laboratory demonstrated an association between increased iNOS expression and the development of N-nitrosomethylbenzylamine (NMBA)-induced tumors in the rat esophagus. On the basis of these observations, we initiated a bioassay to evaluate the ability of S,S′-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBIT), a selective iNOS inhibitor, to prevent the progression of esophageal tumors in rats preinitiated with NMBA. Rats were given s.c. injections of NMBA (0.25 mg/kg body weight) three times per week for 5 weeks. One week later, they were fed a synthetic diet containing either 50 or 100 ppm PBIT until the end of the bioassay (25 weeks). PBIT reduced the incidence of esophageal cancer from 96% in NMBA-treated rats to 83% and 77% (P &lt; 0.05) in rats treated with 50 and 100 ppm PBIT, respectively. Tumor multiplicity was reduced from 3.64 ± 0.42 tumors per esophagus in NMBA-treated rats to 1.79 ± 0.25 (P &lt; 0.001) and 1.50 ± 0.24 (P &lt; 0.0001) in rats treated with 50 and 100 ppm PBIT, respectively. PBIT reduced the production of NO in NMBA-induced preneoplastic and papillomatous esophageal lesions when compared with comparable lesions in rats treated with NMBA only. iNOS mRNA expression was not modulated by PBIT. These observations suggest that iNOS plays a role in tumor development and that its selective inhibitor, PBIT, significantly inhibits esophageal tumor progression presumably through reducing the production of NO.
In vivo
Detection of Gastric Cancer in Rats by Electron Paramagnetic Resonance Imaging
Authors: Mikuni Tomiko , He Guanglong , Petryakov Sergey , Fallouh Mohanad M. , Deng Yuanmu , Ishihara Ryu , Kuppusamy Periannan , Tatsuta Masaharu , Zweier Jay L. 
Published: September 2005

Abstract
Electron paramagnetic resonance imaging (EPRI) enables noninvasive spatial mapping of free radical metabolism and has recently been shown to provide in vivo physiologic information regarding alterations in the redox state of tumors and neoplastic tissues. With the use of nitroxide spin probes, it has been shown that certain tumors possess a highly reduced state. To determine whether EPRI can be used for early detection and visualization of gastric carcinoma based on its altered redox metabolism, studies were performed in a rat gastric cancer model induced by 1-methyl-3-nitro-1-nitrosoguanidine. Using a specialized 750 MHz resonator and EPRI instrument, a technique was developed for imaging nitroxide radicals in the whole stomach. In vivo three-dimensional EPRI of the stomach of rats with continuous intravenous administration of nitroxide 3-carboxamido-2,2,5,5-tetramethylpyrrolidine-N-oxyl (3-carbamoyl-proxyl) [3-CP] was performed. Whereas electron paramagnetic resonance images from untreated controls provide a uniform visualization of the stomach mucosa and wall, in the treated rats with gastric cancer, holes were present in the image at the locations of tumors. With localized spectroscopy, it was confirmed that the tumor regions were devoid of signal, and this was largely due to the presence of a more reduced state with rapid reduction of nitroxide. Pharmacokinetic studies indicated that 3-CP in tumors was rapidly reduced to an undetectable level, whereas the 3-CP levels in normal stomach tissue persisted. Near-infrared reflectance measurements of indocyanine green dye uptake indicated that there were no significant differences in tumor versus normal mucosal perfusion. From these results, we concluded that gastric cancer tumors could be distinguished from normal tissue based primarily on the marked difference in their rate of radical metabolism. Because alterations in cellular redox state and radical metabolism are of critical importance in tumor biology and treatment, this methodology should provide an important new tool for the study and visualization of gastric carcinoma and may also be of use in other cancer models.
Diminished Hepatocellular Proliferation in Mice Humanized for the Nuclear Receptor Peroxisome Proliferator-Activated Receptor α
Authors: Cheung Connie , Akiyama Taro E. , Ward Jerrold M. , Nicol Christopher J. , Feigenbaum Lionel , Vinson Charles , Gonzalez Frank J. 
Published: September 2005

Abstract
Lipid-lowering fibrate drugs function as agonists for the nuclear receptor peroxisome proliferator-activated receptor α (PPARα). Sustained activation of PPARα leads to the development of liver tumors in rats and mice. However, humans appear to be resistant to the induction of peroxisome proliferation and the development of liver cancer by fibrate drugs. The molecular basis of this species difference is not known. To examine the mechanism determining species differences in peroxisome proliferator response between mice and humans, a PPARα-humanized mouse line was generated in which the human PPARα was expressed in liver under control of the tetracycline responsive regulatory system. The PPARα-humanized and wild-type mice responded to treatment with the potent PPARα ligand Wy-14643 as revealed by induction of genes encoding peroxisomal and mitochondrial fatty acid metabolizing enzymes and resultant decrease of serum triglycerides. However, surprisingly, only the wild-type mice and not the PPARα-humanized mice exhibited hepatocellular proliferation as revealed by elevation of cell cycle control genes, increased incorporation of 5-bromo-2′-deoxyuridine into hepatocyte nuclei, and hepatomegaly. These studies establish that following ligand activation, the PPARα-mediated pathways controlling lipid metabolism are independent from those controlling the cell proliferation pathways. These findings also suggest that structural differences between human and mouse PPARα are responsible for the differential susceptibility to the development of hepatocarcinomas observed after treatment with fibrates. The PPARα-humanized mice should serve as models for use in drug development and human risk assessment and to determine the mechanism of hepatocarcinogenesis of peroxisome proliferators.
Telomeric Recombination in Mismatch Repair Deficient Human Colon Cancer Cells after Telomerase Inhibition
Authors: Bechter Oliver E. , Zou Ying , Walker William , Wright Woodring E. , Shay Jerry W. 
Published: September 2005

Abstract
The majority of human malignancies use telomerase to maintain telomere homeostasis. Antitelomerase therapy is therefore a promising approach for a cancer-specific therapy. The alternative lengthening of telomeres pathway (ALT) is a recombination-based, telomerase-independent mechanism of telomere length control. It is widely believed that ALT could be engaged when cancer cells escape from telomerase inhibition. However, no reports exist that would support this concept of therapy resistance. We inhibited telomerase in a human cancer cell line with a mismatch repair defect and observed a telomerase-independent, ALT-like telomere elongation. This is the first report of inducing a telomerase-independent telomere elongation in human cancer cells when telomerase is inhibited, thus describing a novel mechanism of resistance to antitelomerase therapy.
Microtubule-Dependent Matrix Metalloproteinase-2/Matrix Metalloproteinase-9 Exocytosis
Authors: Schnaeker Eva-Maria , Ossig Rainer , Ludwig Thomas , Dreier Rita , Oberleithner Hans , Wilhelmi M. , Schneider Stefan W. 
Published: September 2005

Abstract
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that cleave and degrade a wide spectrum of extracellular matrix components. By enhancing turnover of extracellular matrix, MMP activity is also known to play a key role in tumor cell invasion. Because extracellular protease activity requires efficient release of these proteases to the cellular surface, we investigated storage, transport, and exocytosis of MMP-2 and MMP-9 in human melanoma cells using immunofluorescence, electrical, and biochemical techniques. Immunolabeling of melanoma cells with antibodies specific for MMP-2 and MMP-9 led to the identification of two distinct populations of small cytoplasmatic vesicles containing MMP-2 or MMP-9, respectively. In combination with α-tubulin–specific antibodies, both vesicle populations were found to be aligned along the microtubular network. Moreover, the molecular motor protein kinesin is shown to be localized on most of these vesicles, providing evidence that the identified vesicles are actively propelled along microtubules toward the plasma membrane. The functional relevance of these findings is demonstrated using low dosage (5.9 nmol/L) of paclitaxel to affect the microtubular function of melanoma cells. Although cell proliferation is not altered, paclitaxel treatment impairs secretion of MMP-2/MMP-9 and significantly reduces invasive activity in our new cell invasion assay. In conclusion, we demonstrate in melanoma cells that microtubule-dependent traffic of MMP-containing vesicles and exocytosis are critical steps for invasive behavior and therefore are potential targets for specific antitumor drugs.
Endogenous Galectin-3 Determines the Routing of CD95 Apoptotic Signaling Pathways
Authors: Fukumori Tomoharu , Takenaka Yukinori , Oka Natsuo , Yoshii Tadashi , Hogan Victor , Inohara Hidenori , Kanayama Hiro-omi , Kim Hyeong-Reh Choi , Raz Avraham 
Published: September 2005

Abstract
Studies of CD95 (APO-1/Fas), a member of the death receptor family, have revealed that it is involved in two primary CD95 apoptotic signaling pathways, one regulated by the large amount of active caspase-8 (type I) formed at the death-inducing signaling complex and the other by the apoptogenic activity of mitochondria (type II). To date, it is still unclear which pathway will be activated in response to an apoptotic insult. Here, we demonstrate that the antiapoptotic molecule galectin-3, which contains the four amino acid-anti-death-motif (NWGR) conserved in the BH1 domain of the Bcl-2 member proteins, is expressed only in type I cells. Transfection of galectin-3 cDNA into galectin-3 null cells (type II) resulted converting them to type I apoptotic phenotype. In addition, we show that galectin-3 is complexed with CD95 in vivo identifying galectin-3 as a novel CD95-binding partner that determines which of the CD95 apoptotic signaling pathways the cell will select.
Akt/Protein Kinase B Signaling Inhibitor-2, a Selective Small Molecule Inhibitor of Akt Signaling with Antitumor Activity in Cancer Cells Overexpressing Akt
Authors: Yang Lin , Dan Han C. , Sun Mei , Liu Qiyuan , Sun Xia-meng , Feldman Richard I. , Hamilton Andrew D. , Polokoff Mark , Nicosia Santo V. , Herlyn Meenhard , Sebti Said M. , Cheng Jin Q. 
Published: September 2005

Abstract
Accumulated studies have shown that activation of the Akt pathway plays a pivotal role in malignant transformation and chemoresistance by inducing cell survival, growth, migration, and angiogenesis. Therefore, Akt is believed to be a critical target for cancer intervention. Here, we report the discovery of a small molecule Akt pathway inhibitor, Akt/protein kinase B signaling inhibitor-2 (API-2), by screening the National Cancer Institute Diversity Set. API-2 suppressed the kinase activity and phosphorylation level of Akt. The inhibition of Akt kinase resulted in suppression of cell growth and induction of apoptosis in human cancer cells that harbor constitutively activated Akt due to overexpression of Akt or other genetic alterations such as PTEN mutation. API-2 is highly selective for Akt and does not inhibit the activation of phosphatidylinositol 3′-kinase, phosphoinositide-dependent kinase-1, protein kinase C, serum- and glucocorticoid-inducible kinase, protein kinase A, signal transducer and activators of transcription 3, extracellular signal-regulated kinase-1/2, or c-Jun NH2-terminal kinase. Furthermore, API-2 potently inhibited tumor growth in nude mice of human cancer cells in which Akt is aberrantly expressed/activated but not of those cancer cells in which it is not. These findings provide strong evidence for pharmacologically targeting Akt for anticancer drug discovery.
The Nuclear Receptor Coactivator AIB1 Mediates Insulin-like Growth Factor I-induced Phenotypic Changes in Human Breast Cancer Cells
Authors: Oh Annabell , List Heinz-Joachim , Reiter Ronald , Mani Aparna , Zhang Ying , Gehan Edmund , Wellstein Anton , Riegel Anna T. 
Published: September 2005

Abstract
The nuclear receptor coactivator AIB1 (amplified in breast cancer 1) is overexpressed in human breast cancers and is required for estrogen signaling. However, the role of AIB1 in breast cancer etiology is not known. Here, we show that AIB1 is rate-limiting for insulin-like growth factor I (IGF-I)-dependent phenotypic changes and gene expression in human breast cancer cells. Reduction of endogenous AIB1 levels by small interfering RNA in MCF-7 breast cancer cells prevented IGF-I–stimulated anchorage-independent growth by reducing IGF-I–dependent anti-anoikis. cDNA array and immunoblot analysis of gene expression revealed that reduction in AIB1 levels led to a significant decrease in the expression of several genes controlling the cell cycle and apoptosis. These AIB1-dependent changes were also observed in the presence of estrogen antagonist and were corroborated in the estrogen receptor-negative cell line MDA MB-231. AIB1 reduction decreased the expression of the IGF-I receptor and IRS-1 in MCF-7 but not in MDA MB-231 cells. IGF-I–stimulated activation of AKT was reduced by AIB1 small interfering RNA treatment, whereas mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2) activation by IGF-I was unaffected. We conclude that AIB1 is required for IGF-I–induced proliferation, signaling, cell survival, and gene expression in human breast cancer cells, independent of its role in estrogen receptor signaling.