bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Profiling of Epithelial Cells Expressing E-Cadherin Repressors Reveals a Distinct Role for Snail, Slug, and E47 Factors in Epithelial-Mesenchymal Transition
Authors: Moreno-Bueno Gema , Cubillo Eva , Sarrió David , Peinado Héctor , Rodríguez-Pinilla Socorro María , Villa Sonia , Bolós Victoria , Jordá Mireia , Fabra Angels , Portillo Francisco , Palacios José , Cano Amparo 
Published: October 2006

AbstractThe transcription factors Snail, Slug, and bHLH E47 have been recently described as direct repressors of E-cadherin and inducers of epithelial-mesenchymal transition (EMT) and invasion when overexpressed in epithelial cells. Although a role of those factors in tumor progression and invasion has been proposed, whether the different repressors play distinct or redundant roles in the tumorigenic process has not been established. To further investigate this important issue, we have analyzed the gene expression profiling of Madin-Darby canine kidney (MDCK) epithelial cells expressing the different repressors (MDCK-Snail, MDCK-Slug, and MDCK-E47 cells) versus control MDCK cells by cDNA microarrays. A total of 243 clones (228 genes and 15 expressed sequence tags) were found to be differentially expressed between either of the three MDCK-derived cell lines and control MDCK cells. Twenty two of the candidate genes were validated by Northern blot, Western blot, immunofluorescence, and promoter analyses in cell lines and by immunohistochemistry in xenografted tumors. Gene clustering analysis indicated that about a third of the 243 candidate genes were common to MDCK cells expressing Snail, Slug, or E47 factors, whereas the rest of the genes were regulated in only one or two cell types. Differentially regulated genes include those related to EMT (45 genes), transcriptional regulation (18 genes), cell proliferation and signaling (54 genes), apoptosis (12 genes), and angiogenesis (9 genes). These results indicate that Snail, Slug, and E47 transcription factors induce common and specific genetic programs, supporting a differential role of the factors in tumor progression and invasion. (Cancer Res 2006; 66(19): 9543-56)
Enhanced Killing of Melanoma Cells by Simultaneously Targeting Mcl-1 and NOXA
Authors: Qin Jian-Zhong , Xin Hong , Sitailo Leonid A. , Denning Mitchell F. , Nickoloff Brian J. 
Published: October 2006

Abstract
By deciphering the dysregulation of apoptosis in melanoma cells, new treatment approaches exploiting aberrant control mechanisms regulating cell death can be envisioned. Among the Bcl-2 family, a BH3-only member, NOXA, functions in a specific mitochondrial-based cell death pathway when melanoma cells are exposed to a proteasome inhibitor (e.g., bortezomib). Some therapeutic agents, such as bortezomib, not only induce proapoptotic Bcl-2 family members and active conformational changes in Bak and Bax but also are associated with undesirable effects, including accumulation of antiapoptotic proteins, such as Mcl-1. To enhance the bortezomib-mediated killing of melanoma cells, the apoptotic pathway involving NOXA was further investigated, leading to identification of an important target (i.e., the labile Bcl-2 homologue Mcl-1 but not other survival proteins). To reduce Mcl-1 levels, melanoma cells were pretreated with several different agents, including Mcl-1 small interfering RNA (siRNA), UV light, or the purine nucleoside analogue fludarabine. By simultaneously triggering production of NOXA (using bortezomib) as well as reducing Mcl-1 levels (using siRNA, UV light, or fludarabine), significantly enhanced killing of melanoma cells was achieved. These results show binding interactions between distinct Bcl-2 family members, such as NOXA and Mcl-1, in melanoma cells, paving the way for novel and rational therapeutic combination strategies, which target guardians of the proapoptotic Bak- and Bax-mediated pathways, against this highly aggressive and often fatal malignancy. (Cancer Res 2006; 66(19): 9636-45)
Deleted in Colorectal Cancer Is a Putative Conditional Tumor-Suppressor Gene Inactivated by Promoter Hypermethylation in Head and Neck Squamous Cell Carcinoma
Authors: Carvalho André Lopes , Chuang Alice , Jiang Wei-Wen , Lee Juna , Begum Shahnaz , Poeta Luana , Zhao Ming , Jerónimo Carmen , Henrique Rui , Nayak Chetan S. , Park Hannah L. , Brait Mariana R.O. , Liu Chunyan , Zhou Shaoyu , Koch Wayne , Fazio Vito Michele , Ratovitski Edward , Trink Barry , Westra William , Sidransky David , Moon Chul-so , Califano Joseph A. 
Published: October 2006

Abstract
Deleted in colorectal cancer (DCC) is a candidate tumor-suppressor gene located at chromosome 18q21. However, DCC gene was found to have few somatic mutations and the heterozygous mice (DCC+/−) showed a similar frequency of tumor formation compared with the wild-type mice (DCC+/+). Recently, DCC came back to the spotlight as a better understating of its function and relationship with its ligand (netrin-1) had shown that DCC may act as a conditional tumor-suppressor gene. We evaluated hypermethylation as a mechanism for DCC inactivation in head and neck squamous cell carcinoma (HNSCC). DCC promoter region hypermethylation was found in 75% of primary HNSCC. There was a significant correlation between DCC promoter region hypermethylation and DCC expression (assessed by immunohistochemistry; P = 0.021). DCC nonexpressing HNSCC cell lines JHU-O12 and JHU-O19 with baseline hypermethylation of the DCC promoter were treated with 5-aza-2′-deoxycytidine (a demethylating agent) and reexpression of DCC was noted. Transfection of DCC into DCC-negative HNSCC cell lines resulted in complete abrogation of growth in all cell lines, whereas additional cotransfection of netrin-1 resulted in rescue of DCC-mediated growth inhibition. These results suggest that DCC is a putative conditional tumor-suppressor gene that is epigenetically inactivated by promoter hypermethylation in a majority of HNSCC. (Cancer Res 2006; 66(19): 9401-07)
The Tumor Antigen Repertoire Identified in Tumor-Bearing Neu Transgenic Mice Predicts Human Tumor Antigens
Authors: Lu Hailing , Knutson Keith L. , Gad Ekram , Disis Mary L. 
Published: October 2006

Abstract
FVB/N mice transgenic for nontransforming rat neu develop spontaneous breast cancers that are neu positive and estrogen receptor negative, mimicking premenopausal human breast cancer. These animals have been widely used as a model for immunobased therapies targeting HER-2/neu. In this study, we used serological analysis of recombinant cDNA expression libraries to characterize the antigenic repertoire of neu transgenic (neu-tg) mice and questioned the ability of this murine model to predict potential human tumor antigens. After screening 3 × 106 clones from 3 different cDNA libraries, 15 tumor antigens were identified, including cytokeratin 2-8, glutamyl-prolyl-tRNA synthetase, complement C3, galectin 8, and serine/threonine-rich protein kinase 1. Multiple proteins involved in the Rho/Rho-associated, coiled coil–containing protein kinase (Rock) signal transduction pathway were found to be immunogenic, including Rock1, Rho/Rac guanine nucleotide exchange factor 2, and schistosoma mansoni adult worm antigen preparation 70. All of the identified antigens are self-proteins that are expressed in normal tissues in addition to breast tumors and the majority of the antigens are intracellular proteins. More than half of the mouse tumor antigens have human homologues that have been reported previously as tumor antigens. Finally, the tumor-specific antibody immunity and marked immune cell infiltration that was observed in mice with spontaneous tumors were not observed in mice with transplanted tumors. Our results indicate that neu-tg mice bearing spontaneous tumors develop humoral immunity to their tumors similar to cancer patients and that tumor antigens identified in transgenic mouse may predict immunogenic human homologues. (Cancer Res 2006; 66(19): 9754-61)
Genetic Interaction between Rb and N-ras: Differentiation Control and Metastasis
Authors: Takahashi Chiaki , Ewen Mark E. 
Published: October 2006

Abstract
The retinoblastoma tumor suppressor gene, Rb, and the ras proto-oncogenes regulate various cellular processes, including differentiation and proliferation. Rb and ras genetically interact to positively influence differentiation in the mouse. This genetic interaction between Rb and ras also affects tumor development, either positively or negatively depending on cell type. Loss of one or two N-ras alleles allows medullary thyroid (C cell) adenomas occurring in Rb heterozygous mice to progress to metastatic carcinomas, an event associated with C cells displaying a less-differentiated phenotype. Here, we discuss the genetic interaction between Rb and ras and the development of a mouse model of medullary thyroid carcinoma. (Cancer Res 2006; 66(19): 9345-8)
Identification of a Chemical Inhibitor of the Oncogenic Transcription Factor Forkhead Box M1
Authors: Radhakrishnan Senthil K. , Bhat Uppoor G. , Hughes Douglas E. , Wang I-Ching , Costa Robert H. , Gartel Andrei L. 
Published: October 2006

AbstractThe oncogenic transcription factor forkhead box M1 (FoxM1) is overexpressed in a number of different carcinomas, whereas its expression is turned off in terminally differentiated cells. For this reason, FoxM1 is an attractive target for therapeutic intervention in cancer treatment. As a first step toward realizing this goal, in this study, using a high-throughput, cell-based assay system, we screened for and isolated the antibiotic thiazole compound Siomycin A as an inhibitor of FoxM1. Interestingly, we observed that Siomycin A was able to down-regulate the transcriptional activity as well as the protein and mRNA abundance of FoxM1. Consequently, we found that the downstream target genes of FoxM1, such as Cdc25B, Survivin, and CENPB, were repressed. Also, we observed that consistent with earlier reports of FoxM1 inhibition, Siomycin A was able to reduce anchorage-independent growth of cells in soft agar. Furthermore, we found that Siomycin A was able to induce apoptosis selectively in transformed but not normal cells of the same origin. Taken together, our data suggest that FoxM1 inhibitor Siomycin A could represent a useful starting point for the development of anticancer therapeutics. (Cancer Res 2006; 66(19): 9731-5)
Autophagy in Cancer: Good, Bad, or Both?
Authors: Hippert Melanie M. , O'Toole Patrick S. , Thorburn Andrew 
Published: October 2006

Abstract
Autophagy has been recognized as an important cellular process for at least 50 years; however, it is only with the recent identification of key regulators of autophagy (Atg genes) that we have begun a mechanistic exploration of its importance in cancer. Recent studies suggest that autophagy may be important in the regulation of cancer development and progression and in determining the response of tumor cells to anticancer therapy. However, the role of autophagy in these processes is complicated and may, depending on the circumstances, have diametrically opposite consequences for the tumor. In this article, we discuss recent discoveries regarding autophagy in cancer. (Cancer Res 2006; 66(19): 9349-51)
Antitumor Activity of an Oncolytic Adenovirus-Delivered Oncogene Small Interfering RNA
Authors: Zhang Yu-An , Nemunaitis John , Samuel Shirley K. , Chen Patrick , Shen Yuqiao , Tong Alex W. 
Published: October 2006

Abstract
Despite successes in animal models, cancer gene therapy with small interfering RNAs (siRNA) is hindered by the lack of an optimal delivery platform. We examined the applicability of the replication-competent, oncolytic adenovirus, ONYX-411, to deliver a mutant K-ras siRNA transgene to human cancer cells. Proof-of-principle studies showed an additive tumor growth–inhibitory response through siRNA-mediated K-ras knockdown and ONYX-411-mediated cancer cell lysis. A novel construct, termed Internavec (for interfering RNA vector), was generated by cloning a K-rasv12-specific siRNAras-4 hairpin construct under the control of the human H1 promoter into the deleted E3b region of ONYX-411. Internavec acquired an increase in potency of ∼10-fold in human cancer cells expressing the relevant K-rasv12 mutation (H79, H441, and SW480), as defined by a reduction in the effective dose needed to achieve 50% growth inhibition (ED50). Internavec remained attenuated in nonmalignant epithelial cells. Daily intratumoral injections of Internavec (five daily injections of 1 × 108 plaque-forming units) significantly reduced the growth of s.c. H79 pancreatic cancer xenografts in nu/nu mice by 85.5%, including complete growth suppression in three of five mice. Parental ONYX-411 or ONYX-411-siRNAGFP was markedly less effective (47.8% growth reduction, P = 0.03; and 44.1% growth reduction, P = 0.03, respectively). siRNAras transgene activity contributed to cell cycle blockage, increased apoptosis, and marked down-regulation of Ras signaling–related gene expression (AKT2, GSK3β, E2F2, and MAP4K5). These findings indicate that Internavec can generate a two-pronged attack on tumor cells through oncogene knockdown and viral oncolysis, resulting in a significantly enhanced antitumor outcome. (Cancer Res 2006; 66(19): 9736-43)
Tumor-Specific p73 Up-regulation Mediates p63 Dependence in Squamous Cell Carcinoma
Authors: DeYoung Maurice Phillip , Johannessen Cory M. , Leong Chee-Onn , Faquin William , Rocco James W. , Ellisen Leif W. 
Published: October 2006

Abstract
p63 is essential for normal epithelial development and is overexpressed in the vast majority of squamous cell carcinomas (SCC). Recent work had shown that ΔNp63α is essential for survival of SCC cells, raising the possibility that the p63 pathway may be an attractive therapeutic target in these tumors. Nevertheless, it is unknown whether a therapeutic window exists for inhibiting p63 in tumor cells versus normal epithelia. Here, we show that SCC cells are uniquely dependent on ΔNp63α for survival, unlike normal p63-expressing epithelial cells, and that dependence is mediated through tumor-specific up-regulation of the related protein p73. In normal primary human keratinocytes, we find that inhibition of endogenous p63 by RNA interference (RNAi) induces p21CIP1 expression, inhibits cell cycle progression, and ultimately promotes cellular senescence. In contrast, p63 inhibition in SCC cells induces proapoptotic bcl-2 family members and rapidly triggers apoptosis. Expression of p73 is low in uncultured basal keratinocytes but is markedly up-regulated in both SCC cell lines and primary tumors in vivo. Whereas p21CIP1 induction following loss of p63 in normal cells is independent of p53 and p73, both proapoptotic gene induction and cell death following p63 RNAi in tumor cells are p73 dependent. Finally, ectopic p73 expression in primary keratinocytes does not affect baseline cell proliferation but is sufficient to trigger cell death following loss of p63. Together, these findings define a specific molecular mechanism of p63 dependence through p73 up-regulation, and they provide a rationale for targeting the p63 pathway as a therapeutic strategy in SCCs. (Cancer Res 2006; 66(19): 9362-8)
Activation of Cancer Cell Migration and Invasion by Ectopic Synthesis of Coagulation Factor VII
Authors: Koizume Shiro , Jin Ming-Shou , Miyagi Etsuko , Hirahara Fumiki , Nakamura Yoshiyasu , Piao Jin-Hua , Asai Akio , Yoshida Akira , Tsuchiya Eiju , Ruf Wolfram , Miyagi Yohei 
Published: October 2006

Abstract
Blood coagulation factor VII (fVII) is physiologically synthesized in the liver and released into the blood. Binding of fVII to tissue factor (TF) at sites of vascular injury triggers coagulation and hemostasis. TF/fVIIa complex formation on the surface of cancer cells plays important roles in cancer biology. Although fVII is synthesized by hepatocellular carcinoma, it remained unclear how TF/fVIIa complex formation and promigratory signaling can occur for most other cancers in extravascular locations. Here, we show by reverse transcription-PCR analysis that nonhepatic cancer cell lines constitutively express fVII mRNA and that endogenously synthesized fVIIa triggers coagulation activation on these cells. fVIIa expression in cancer cells is inducible under hypoxic conditions and hypoxia-inducible factor-2α bound the promoter region of the FVII gene in chromatin immunoprecipitation analyses. Constitutive fVII expression in an ovarian cancer cell line enhanced both migration and invasion. Enhanced motility was blocked by anti-TF antibodies, factor Xa inhibition, and anti–protease-activated receptor-1 antibody treatment, confirming that TF/fVIIa stimulated migration by triggering cell signaling. This study shows that ectopic synthesis of fVII by cancer cells is sufficient to support proinvasive factor Xa–mediated protease-activated receptor-1 signaling and that this pathway is inducible under hypoxia. (Cancer Res 2006; 66(19): 9453-60)
The Differential Staurosporine-Mediated G1 Arrest in Normal versus Tumor Cells Is Dependent on the Retinoblastoma Protein
Authors: McGahren-Murray Mollianne , Terry Nicholas H.A. , Keyomarsi Khandan 
Published: October 2006

Abstract
Previously, we reported that breast cancer cells with retinoblastoma (pRb) pathway–defective checkpoints can be specifically targeted with chemotherapeutic agents, following staurosporine-mediated reversible growth inhibition in normal cells. Here we set out to determine if the kinetics of staurosporine-mediated growth inhibition is specifically targeted to the G1 phase of cells, and if such G1 arrest requires the activity of wild-type pRb. Normal human mammary epithelial and immortalized cells with intact pRb treated with low concentrations of staurosporine arrested in the G1 phase of the cell cycle, whereas pRb-defective cells showed no response. The duration of G1 and transition from G1 to S phase entry were modulated by staurosporine in Rb-intact cells. In pRb+ cells, but not in Rb− cells, low concentrations of staurosporine also resulted in a significant decrease in cyclin-dependent kinase 4 (CDK4) expression and activity. To directly assess the role of pRb in staurosporine-mediated G1 arrest, we subjected wild-type (Rb+/+) and pRb−/− mouse embryo fibroblasts (MEFs) to staurosporine treatments. Our results show that whereas Rb+/+ MEFs were particularly sensitive to G1 arrest mediated by staurosporine, pRb−/− cells were refractory to such treatment. Additionally, CDK4 expression was also inhibited in response to staurosporine only in Rb+/+ MEFs. These results were recapitulated in breast cancer cells treated with siRNA to pRb to down-regulate the pRb expression. Collectively, our data suggest that treatment of cells with nanomolar concentrations of staurosporine resulted in down-regulation of CDK4, which ultimately leads to G1 arrest in normal human mammary epithelial and immortalized cells with an intact pRb pathway, but not in pRb-null/defective cells. (Cancer Res 2006; 66(19): 9744-53)
In vivo and In vitro Evidence for Transforming Growth Factor-β1-Mediated Epithelial to Mesenchymal Transition in Esophageal Adenocarcinoma
Authors: Rees Jonathan R.E. , Onwuegbusi Benjamin A. , Save Vicki E. , Alderson Derek , Fitzgerald Rebecca C. 
Published: October 2006

Abstract
There is increasing evidence that epithelial to mesenchymal transition (EMT) is involved in cancer progression. Because local invasion and metastasis occurs early in the pathogenesis of esophageal adenocarcinoma, we hypothesized that EMT may be important in this disease. Using immunohistochemistry in a well-characterized set of adenocarcinoma tissues, we showed down-regulation of epithelial markers (E-cadherin and cytokeratin 18) and up-regulation of mesenchymal markers (vimentin and α-smooth muscle actin) with concomitant transforming growth factor-β1 (TGF-β1) expression at the invasive margin compared with the central tumor. A panel of esophageal cell lines was examined for the ability of TGF-β1 to induce EMT in vitro. TE7 cells were selected as a model because TGF-β1 (0-5 ng/mL) treatment induced morphologic and molecular expression changes suggestive of EMT. In TE7 cells, these TGF-β1-induced changes were reversed by 100 ng/mL of bone morphogenetic protein 7 (BMP7), another member of the TGF-β1 superfamily. EMT was mediated via canonical TGF-β1 signaling with concomitant up-regulation of SMAD-interacting protein 1. Alterations in functional variables (aggregation, wounding, motility, and invasion) following TGF-β1 treatment were consistent with a more invasive phenotype. These functional changes were reversed by BMP7 and SMAD4 RNA interference in vitro. These data suggest that TGF-β1-mediated EMT may be relevant in esophageal carcinogenesis. (Cancer Res 2006; 66(19): 9583-90)
Feedbacks of Vegetation on Summertime Climate Variability over the North American Grasslands. Part I: Statistical Analysis
Authors: Wang Weile , Anderson Bruce T. , Phillips Nathan , Kaufmann Robert K. , Potter Christopher , Myneni Ranga B. 
Published: October 2006

AbstractFeedbacks of vegetation on summertime climate variability over the North American Grasslands are analyzed using the statistical technique of Granger causality. Results indicate that normalized difference vegetation index (NDVI) anomalies early in the growing season have a statistically measurable effect on precipitation and surface temperature later in summer. In particular, higher means and/or decreasing trends of NDVI anomalies tend to be followed by lower rainfall but higher temperatures during July through September. These results suggest that initially enhanced vegetation may deplete soil moisture faster than normal and thereby induce drier and warmer climate anomalies via the strong soil moisture–precipitation coupling in these regions. Consistent with this soil moisture–precipitation feedback mechanism, interactions between temperature and precipitation anomalies in this region indicate that moister and cooler conditions are also related to increases in precipitation during the preceding months. Because vegetation responds to soil moisture variations, interactions between vegetation and precipitation generate oscillations in NDVI anomalies at growing season time scales, which are identified in the temporal and the spectral characteristics of the precipitation–NDVI system. Spectral analysis of the precipitation–NDVI system also indicates that 1) long-term interactions (i.e., interannual and longer time scales) between the two anomalies tend to enhance one another, 2) short-term interactions (less than 2 months) tend to damp one another, and 3) intermediary-period interactions (4–8 months) are oscillatory. Together, these results support the hypothesis that vegetation may influence summertime climate variability via the land–atmosphere hydrological cycles over these semiarid grasslands.