bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclic AMP Suppression Is Sufficient to Induce Gliomagenesis in a Mouse Model of Neurofibromatosis-1
Authors: Warrington Nicole M. , Gianino Scott M. , Jackson Erin , Goldhoff Patricia , Garbow Joel R. , Piwnica-Worms David , Gutmann David H. , Rubin Joshua B. 
Published: June 2010

Abstract
Current models of oncogenesis incorporate the contributions of chronic inflammation and aging to the patterns of tumor formation. These oncogenic pathways, involving leukocytes and fibroblasts, are not readily applicable to brain tumors (glioma), and other mechanisms must account for microenvironmental influences on central nervous system tumorigenesis. Previous studies from our laboratories have used neurofibromatosis-1 (NF1) genetically engineered mouse (GEM) models to understand the spatial restriction of glioma formation to the optic pathway of young children. Based on our initial findings, we hypothesize that brain region–specific differences in cAMP levels account for the pattern of NF1 gliomagenesis. To provide evidence that low levels of cAMP promote glioma formation in NF1, we generated foci of decreased cAMP in brain regions where gliomas rarely form in children with NF1. Focal cAMP reduction was achieved by forced expression of phosphodiesterase 4A1 (PDE4A1) in the cortex of Nf1 GEM strains. Ectopic PDE4A1 expression produced hypercellular lesions with features of human NF1-associated glioma. Conversely, pharmacologic elevation of cAMP with the PDE4 inhibitor rolipram dramatically inhibited optic glioma growth and tumor size in Nf1 GEM in vivo. Together, these results indicate that low levels of cAMP in a susceptible Nf1 mouse strain are sufficient to promote gliomagenesis, and justify the implementation of cAMP-based stroma-targeted therapies for glioma. Cancer Res; 70(14); 5717–27. ©2010 AACR.
Wnt Inhibitor Dickkopf-1 as a Target for Passive Cancer Immunotherapy
Authors: Sato Nagato , Yamabuki Takumi , Takano Atsushi , Koinuma Junkichi , Aragaki Masato , Masuda Ken , Ishikawa Nobuhisa , Kohno Nobuoki , Ito Hiroyuki , Miyamoto Masaki , Nakayama Haruhiko , Miyagi Yohei , Tsuchiya Eiju , Kondo Satoshi , Nakamura Yusuke , Daigo Yataro 
Published: June 2010

Abstract
Dickkopf-1 (DKK1) is an inhibitor of Wnt/β-catenin signaling that is overexpressed in most lung and esophageal cancers. Here, we show its utility as a serum biomarker for a wide range of human cancers, and we offer evidence favoring the potential application of anti-DKK1 antibodies for cancer treatment. Using an original ELISA system, high levels of DKK1 protein were found in serologic samples from 906 patients with cancers of the pancreas, stomach, liver, bile duct, breast, and cervix, which also showed elevated expression levels of DKK1. Additionally, anti-DKK1 antibody inhibited the invasive activity and the growth of cancer cells in vitro and suppressed the growth of engrafted tumors in vivo. Tumor tissues treated with anti-DKK1 displayed significant fibrotic changes and a decrease in viable cancer cells without apparent toxicity in mice. Our findings suggest DKK1 as a serum biomarker for screening against a variety of cancers, and anti-DKK1 antibodies as potential theranostic tools for diagnosis and treatment of cancer. Cancer Res; 70(13); 5326–36. ©2010 AACR.
Pancreatic Cancers Epigenetically Silence SIP1 and Hypomethylate and Overexpress miR-200a/200b in Association with Elevated Circulating miR-200a and miR-200b Levels
Authors: Li Ang , Omura Noriyuki , Hong Seung-Mo , Vincent Audrey , Walter Kimberly , Griffith Margaret , Borges Michael , Goggins Michael 
Published: June 2010

Abstract
Aberrant DNA methylation and microRNA expression play important roles in the pathogenesis of pancreatic cancer. While interrogating differentially methylated CpG islands in pancreatic cancer, we identified two members of miR-200 family, miR-200a and miR-200b, that were hypomethylated and overexpressed in pancreatic cancer. We also identified prevalent hypermethylation and silencing of one of their downstream targets, SIP1 (ZFHX1B, ZEB2), whose protein product suppresses E-cadherin expression and contributes to epithelial mesenchymal transition. In a panel of 23 pancreatic cell lines, we observed a reciprocal correlation between miR-200, SIP1, and E-cadherin expression, with pancreatic cancer–associated fibroblasts showing the opposite expression pattern to most pancreatic cancers. In Panc-1 cells, which express SIP1, have low E-cadherin expression, and do not express miR-200a or miR-200b, treatment with miR-200a and miR-200b downregulated SIP1 mRNA and increased E-cadherin expression. However, most pancreatic cancers express miR-200a and miR-200b, but this expression does not affect SIP1 expression, as the SIP1 promoter is silenced by hypermethylation and in these cancers E-cadherin is generally expressed. Both miR-200a and miR-200b were significantly elevated in the sera of pancreatic cancer and chronic pancreatitis patients compared with healthy controls (P &lt; 0.0001), yielding receiver operating characteristic curve areas of 0.861 and 0.85, respectively. In conclusion, most pancreatic cancers display hypomethylation and overexpression of miR-200a and miR-200b, silencing of SIP1 by promoter methylation, and retention of E-cadherin expression. The elevated serum levels of miR-200a and miR-200b in most patients with pancreatic cancer could have diagnostic utility. Cancer Res; 70(13); 5226–37. ©2010 AACR.
Shedding of RANKL by Tumor-Associated MT1-MMP Activates Src-Dependent Prostate Cancer Cell Migration
Authors: Sabbota Aaron L. , Kim Hyeong-Reh Choi , Zhe Xiaoning , Fridman Rafael , Bonfil R. Daniel , Cher Michael L. 
Published: June 2010

Abstract
Membrane type 1 matrix metalloproteinase (MT1-MMP) plays an essential role in protease-mediated extracellular matrix (ECM) degradation, but it also functions as a sheddase releasing non-ECM substrates such as receptor activator of NF-κB ligand (RANKL), an osteoclastogenic factor typically confined to the surface of osteoblasts. We previously found high expression of MT1-MMP in skeletal metastasis of prostate cancer patients, in a pattern similar to RANKL expression. We also showed that overexpression of MT1-MMP in prostate cancer cells increases tumor growth and osteolysis in an intratibial mouse model of bone metastasis, and that soluble factor(s) shed by tumor-derived MT1-MMP enhance osteoclast differentiation in a RANKL-dependent manner. Recent evidence indicates that the cognate receptor for RANKL, RANK, is expressed in prostate cancer cells, suggesting the presence of an autocrine pathway. In this study, we show that MT1-MMP–expressing LNCaP prostate cancer cells display enhanced migration. Moreover, conditioned medium from LNCaP cells expressing both RANKL and MT1-MMP stimulates the migration of MT1-MMP–deficient C42b prostate cancer cells. This enhanced chemotaxis can be abrogated by osteoprotegerin (soluble decoy receptor of RANKL), MIK-G2 (a selective inhibitor for MT1-MMP), and PP2 (a Src inhibitor). These findings indicate that tumor-derived MT1-MMP enhances tumor cell migration through initiation of an autocrine loop requiring ectodomain shedding of membrane-bound RANKL in prostate cancer cells, and that Src is a key downstream mediator of RANKL-induced migration of prostate cancer cells. Cancer Res; 70(13); 5558–66. ©2010 AACR.
Extracellular ProteaseADAMTS9Suppresses Esophageal and Nasopharyngeal Carcinoma Tumor Formation by Inhibiting Angiogenesis
Authors: Lo Paulisally Hau Yi , Lung Hong Lok , Cheung Arthur Kwok Leung , Apte Suneel S. , Chan Kwok Wah , Kwong Fung Mei , Ko Josephine Mun Yee , Cheng Yue , Law Simon , Srivastava Gopesh , Zabarovsky Eugene R. , Tsao Sai Wah , Tang Johnny Cheuk On , Stanbridge Eric J. , Lung Maria Li 
Published: June 2010

AbstractADAMTS metalloprotease family member ADAMTS9 maps to 3p14.2 and shows significant associations with the aerodigestive tract cancers esophageal squamous cell carcinoma (ESCC) and nasopharyngeal carcinoma (NPC). However, the functional impact of ADAMTS9 on cancer development has not been explored. In this study, we evaluated the hypothesized antiangiogenic and tumor-suppressive functions of ADAMTS9 in ESCC and NPC, in stringent tumorigenicity and Matrigel plug angiogenesis assays. ADAMTS9 activation suppressed tumor formation in nude mice. Conversely, knockdown of ADAMTS9 resulted in clones reverting to the tumorigenic phenotype of parental cells. In vivo angiogenesis assays revealed a reduction in microvessel numbers in gel plugs injected with tumor-suppressive cell transfectants. Similarly, conditioned medium from cell transfectants dramatically reduced the tube-forming capacity of human umbilical vein endothelial cells. These activities were associated with a reduction in expression levels of the proangiogenic factors MMP9 and VEGFA, which were consistently reduced in ADAMTS9 transfectants derived from both cancers. Taken together, our results indicate that ADAMTS9 contributes an important function in the tumor microenvironment that acts to inhibit angiogenesis and tumor growth in both ESCC and NPC. Cancer Res; 70(13); 5567–76. ©2010 AACR.
Poly(ADP-Ribose) Polymerase Is Hyperactivated in Homologous Recombination–Defective Cells
Authors: Gottipati Ponnari , Vischioni Barbara , Schultz Niklas , Solomons Joyce , Bryant Helen E. , Djureinovic Tatjana , Issaeva Natalia , Sleeth Kate , Sharma Ricky A. , Helleday Thomas 
Published: June 2010

Abstract
Poly(ADP-ribose) (PAR) polymerase 1 (PARP1) is activated by DNA single-strand breaks (SSB) or at stalled replication forks to facilitate DNA repair. Inhibitors of PARP efficiently kill breast, ovarian, or prostate tumors in patients carrying hereditary mutations in the homologous recombination (HR) genes BRCA1 or BRCA2 through synthetic lethality. Here, we surprisingly show that PARP1 is hyperactivated in replicating BRCA2-defective cells. PARP1 hyperactivation is explained by the defect in HR as shRNA depletion of RAD54, RAD52, BLM, WRN, and XRCC3 proteins, which we here show are all essential for efficient HR and also caused PARP hyperactivation and correlated with an increased sensitivity to PARP inhibitors. BRCA2-defective cells were not found to have increased levels of SSBs, and PAR polymers formed in HR-defective cells do not colocalize to replication protein A or γH2AX, excluding the possibility that PARP hyperactivity is due to increased SSB repair or PARP induced at damaged replication forks. Resistance to PARP inhibitors can occur through genetic reversion in the BRCA2 gene. Here, we report that PARP inhibitor–resistant BRCA2-mutant cells revert back to normal levels of PARP activity. We speculate that the reason for the sensitivity of HR-defective cells to PARP inhibitors is related to the hyperactivated PARP1 in these cells. Furthermore, the presence of PAR polymers can be used to identify HR-defective cells that are sensitive to PARP inhibitors, which may be potential biomarkers. Cancer Res; 70(13); 5389–98. ©2010 AACR.
Exchange Protein Directly Activated by Cyclic AMP Increases Melanoma Cell Migration by a Ca2+-Dependent Mechanism
Authors: Baljinnyam Erdene , De Lorenzo Mariana S. , Xie Lai-Hua , Iwatsubo Mizuka , Chen Suzie , Goydos James S. , Nowycky Martha C. , Iwatsubo Kousaku 
Published: June 2010

Abstract
Melanoma has a poor prognosis due to its strong metastatic ability. Although Ca2+ plays a major role in cell migration, little is known about the role of Ca2+ in melanoma cell migration. We recently found that the exchange protein directly activated by cyclic AMP (Epac) increases melanoma cell migration via a heparan sulfate–related mechanism. In addition to this mechanism, we also found that Epac regulates melanoma cell migration by a Ca2+-dependent mechanism. An Epac agonist increased Ca2+ in several different melanoma cell lines but not in melanocytes. Ablation of Epac1 with short hairpin RNA inhibited the Epac agonist–induced Ca2+ elevation, suggesting the critical role of Epac1 in Ca2+ homeostasis in melanoma cells. Epac-induced Ca2+ elevation was negated by the inhibition of phospholipase C (PLC) and inositol triphosphate (IP3) receptor. Furthermore, Epac-induced cell migration was reduced by the inhibition of PLC or IP3 receptor. These data suggest that Epac activates Ca2+ release from the endoplasmic reticulum via the PLC/IP3 receptor pathway, and this Ca2+ elevation is involved in Epac-induced cell migration. Actin assembly was increased by Epac-induced Ca2+, suggesting the involvement of actin in Epac-induced cell migration. In human melanoma specimens, mRNA expression of Epac1 was higher in metastatic melanoma than in primary melanoma, suggesting a role for Epac1 in melanoma metastasis. In conclusion, our findings reveal that Epac is a potential target for the suppression of melanoma cell migration, and, thus, the development of metastasis. Cancer Res; 70(13); 5607–17. ©2010 AACR.
FOXO1A Is a Target for HER2-Overexpressing Breast Tumors
Authors: Wu Yanyuan , Shang Xiying , Sarkissyan Marianna , Slamon Dennis , Vadgama Jaydutt V. 
Published: June 2010

Abstract
Trastuzumab treatment has improved the overall survival of HER2-overexpressing breast cancer patients. However, many of these patients will eventually become resistant to treatment. The mechanisms that contribute to resistance to trastuzumab are unknown. In this study, we tested the hypothesis that targeting of the FKHR transcription factor FOXO1A in HER2-overexpressing breast tumor cells can overcome the trastuzumab resistance in vitro. We have shown that overexpression of HER2 leads to activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway and subsequent inactivation of FOXO1A in HER2-overexpressing breast cancer cells SKBR3, BT474, and MCF7-HER2. In wild-type SKBR3 and BT474 cells, trastuzumab downregulates active Akt and increases FOXO1A expression that leads to increase in p27kip1 and decrease in cyclin D1 and finally inhibits cell proliferation. In contrast, the effect of trastuzumab was eliminated by the reduction of FOXO1A in HER2-overexpressing cells with constitutively active Akt1 (SKBR3/AA28 and BT474/AA9). The downregulation of FOXO1A resulted in nuclear export of p27kip1. Blocking the constitutively active Akt by a specific Akt/protein kinase B signaling inhibitor-2 (API-2) significantly increased FOXO1A expression and rendered the cells more responsive to trastuzumab-induced growth inhibition. Reactivation of FOXO1A by stable or transient transfection also restored the growth-inhibitory effects of trastuzumab in SKBR3/AA28, BT474/AA9, and MCF7-HER2 cells. Knocking down FOXO1A by small interfering RNA resulted in reducing trastuzumab-induced growth inhibition. In summary, trastuzumab can inhibit proliferation of HER2-overexpressing breast cancer cells by reactivating FOXO1A through inhibition of the PI3K/Akt pathway. FOXO1A may therefore serve as a target for HER2-overexpressing breast tumors. Cancer Res; 70(13); 5475–85. ©2010 AACR.
Src Family Kinase Inhibitor Saracatinib (AZD0530) Impairs Oxaliplatin Uptake in Colorectal Cancer Cells and Blocks Organic Cation Transporters
Authors: Morrow Christopher J. , Ghattas Mohammad , Smith Christopher , Bönisch Heinz , Bryce Richard A. , Hickinson D. Mark , Green Tim P. , Dive Caroline 
Published: June 2010

Abstract
Elevated Src family kinase (SFK) activity is associated with tumor invasion and metastasis. The SFK inhibitor saracatinib (AZD0530) is currently in phase II trials in patients including those with colorectal cancer (CRC), where links between SFK activity and poor prognosis are particularly striking. Saracatinib is likely to be used clinically in combination regimens, specifically with 5-fluorouracil (5-FU) and oxaliplatin, in CRC. The aim of this study was to determine the effect of saracatinib on oxaliplatin and 5-FU efficacy in CRC cells. Saracatinib did not modulate 5-FU efficacy but antagonized oxaliplatin in a schedule-specific manner through reduced oxaliplatin uptake via an SFK-independent mechanism. Saracatinib resembles the pharmacophore of known organic cation transporter (OCT) inhibitors and reduced oxaliplatin efficacy maximally in cells overexpressing OCT2. These data suggest that oxaliplatin uptake in CRC is attenuated by saracatinib via inhibition of OCT2, a potential consideration for the clinical development of this SFK inhibitor. Cancer Res; 70(14); 5931–41. ©2010 AACR.
Matrix Metalloproteinase-1 Expression Can Be Upregulated through Mitogen-Activated Protein Kinase Pathway under the Influence of Human Epidermal Growth Factor Receptor 2 Synergized with Estrogen Receptor
Authors: Jung Hae Hyun , Park Yeon Hee , Jun Hyun Jung , Kong Jeehyun , Kim Jeong Hoon , Kim Jung A , Yun Jina , Sun Jong Mu , Won Young Woong , Lee Soohyeon , Kim Seung Tae , Ahn Jin Seok , Im Young-Hyuck 
Published: June 2010

AbstractIn our previous work, Ets-1 upregulates human epidermal growth factor receptor 2 (HER2) induced matrix metalloproteinase 1 (MMP-1) expression. Based on the above knowledge and result, we hypothesized that estrogen receptor (ER) and its signaling pathway may affect MMP-1 expression under the influence of HER2. In addition, we investigated how the HER2 pathway cross-talk with the ER signaling pathway in genomic and nongenomic action of ER using reverse transcription-PCR, Western blot analysis, and ELISA assay. The results showed that ER-α expression increased MMP-1 expression under the presence of HER2. These upregulatory effects were mediated mainly by mitogen-activated protein kinase pathway and were reversed by downregulation of HER2 and/or ER. Activator protein DNA binding activity was involved in the MMP-1 expression. In summary, our results showed that ER can upregulate MMP-1 expression under the influence of HER2 in MCF-7 cells. In addition, this upregulatory effect was found to be mediated by mitogen-activated protein kinase pathway. MMP-1 might be an assigned target in interaction between ER and HER2. Mol Cancer Res; 8(7); 1037–47. ©2010 AACR.
Quercetin Potentiates UVB-Induced c-Fos Expression: Implications for Its Use as a Chemopreventive Agent
Authors: Olson Erik R. , Melton Tania , Dickinson Sally E. , Dong Zigang , Alberts David S. , Bowden G. Tim 
Published: June 2010

AbstractQuercetin (Qu) is currently being investigated as a chemopreventive agent for several cancers, including nonmelanoma skin cancer induced by UV light. We previously reported that Qu degradation has important consequences on signaling and cell biology. In the current study, we report that Qu induces c-Fos mRNA and protein expression through activation of p38 and cAMP-responsive element binding protein (CREB), and Qu potentiates UVB-induced c-Fos expression. Inclusion of ascorbic acid (AA) in cell culture medium stabilizes Qu and completely prevents both Qu- and UVB-induced p38 and CREB activation, leading to a blockade of c-fos gene expression through reduced CREB/cAMP-responsive element binding. AA stabilizes c-Fos mRNA, increasing steady-state levels even when c-fos gene expression is suppressed, but this has no effect on c-Fos protein levels in either mock- or UVB-irradiated cells. We report that Qu blocks mammalian target of rapamycin signaling and inhibits c-Fos protein expression directly through this mechanism because cotreatment with Qu and AA resulted in the complete suppression of UVB-induced c-Fos protein expression even in the presence of significantly increased mRNA levels. We further confirmed that this was not due to increased protein turnover because inhibition of proteasome activity with MG-132 did not raise c-Fos protein levels in Qu+AA-treated cells. Together, these data indicate that although Qu has been reported to have some beneficial properties as a chemopreventive agent, it is also capable of inducing c-fos expression, a cellular event important for the promotion phase of tumor development, if it is not stabilized. Cancer Prev Res; 3(7); 876–84. ©2010 AACR.
Meat Consumption, Nonsteroidal Anti-Inflammatory Drug Use, and Mortality among Colorectal Cancer Patients in the California Teachers Study
Authors: Zell Jason A. , Ziogas Argyrios , Bernstein Leslie , Clarke Christina A. , Deapen Dennis , Largent Joan A. , Neuhausen Susan L. , Stram Daniel O. , Ursin Giske , Anton-Culver Hoda 
Published: June 2010

Abstract
A low-meat diet and regular use of nonsteroidal anti-inflammatory drugs (NSAID) have been associated with decreased mortality among colorectal cancer (CRC) patients. Here, we investigated the association between prediagnosis usual meat consumption and CRC-specific mortality, and whether meat consumption modifies the previously noted association between NSAID use and CRC-specific mortality among women in the California Teachers Study cohort. Women joining the California Teachers Study in 1995-1996 without prior CRC diagnosis, diagnosed with incident CRC during follow-up through December 2007, were eligible for inclusion. Meat intake (frequency and serving size) and NSAID use (aspirin or ibuprofen use) were ascertained via self-administered questionnaires before diagnosis. Vital status and cause of death were determined by linkage with mortality files. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios for death and 95% confidence intervals. Prediagnosis meat consumption was not associated with CRC-specific mortality among 704 CRC patients (and 201 CRC-specific deaths), comparing patients in the lowest consumption tertile (0-5.4 medium-sized servings/wk) to those in the higher consumption tertiles. Regular NSAID use (1-3 times/wk, 4-6 times/wk, daily) versus none was associated with decreased CRC-specific mortality among patients in the lowest meat consumption tertile (hazard ratio, 0.22; 95% CI, 0.06-0.82), but not among patients in the higher meat intake tertiles. The previously observed mortality risk reduction among female CRC patients associated with regular NSAID use was restricted to patients who reported low meat intake before diagnosis. These findings have implications for CRC survivorship and tertiary CRC prevention. Cancer Prev Res; 3(7); 865–75. ©2010 AACR.
Mediterranean Dietary Pattern Is Associated With Improved Cardiac Autonomic Function Among Middle-Aged Men
Authors: Dai Jun , Lampert Rachel , Wilson Peter W. , Goldberg Jack , Ziegler Thomas R. , Vaccarino Viola 
Published: June 2010

Background—Reduced heart rate variability (HRV), a measure of cardiac autonomic dysfunction, is a risk factor for coronary artery disease. Diet can influence HRV, but this association may be confounded by genetic and environmental factors.Methods and Results—We administered the Willett Food Frequency Questionnaire to 276 middle-aged male twins. We derived a score measuring the extent to which an individual's diet conformed to the Mediterranean diet following a published algorithm. The higher the score, the greater the similarity to the Mediterranean diet. All twins underwent 24-hour ambulatory ECG recording. Time and frequency domain measures of HRV were calculated. Mixed-effects regression was used to partition the association into between- and within-twin pair differences. After adjusting for energy intake, other nutritional factors, shared genes, and common environment, a 1-unit higher score was significantly associated with 3.9% to 13% higher time and frequency domain HRV parameters. Further controlling for known cardiovascular risk factors and use of fish oil supplements and medications did not substantially change the estimates.Conclusions—The Mediterranean dietary pattern is associated with higher HRV.
Paskuwatti’s Ritual: Remedy for Impotence or Antidote to Homosexuality?
Authors: Miller Jared L. 
Published: June 2010

AbstractThe Hittite composition known as Paskuwatti’s Ritual (CTH 406) has long been understood as a rite designed to help a man to overcome sexual impotence. The present paper, in contrast, attempts to demonstrate that it is more convincingly interpreted as an antidote to homosexual behavior, apparently seeking to cure its patient of his proclivity for passive sexual acquiescence and to replace it with an inclination toward normative male, i.e. penetrative behavior.