http://www.carcinogenesis.com/currentissue.asp Table of Contents:J Carcinog 2009 - 8(1) Journal of Carcinogenesis Medknow Publications1477-3163 Bernice Robinson-Bennett Editorial Journal of Carcinogenesis 2009 8(1):1-1doi:10.4103/1477-3163.45315 Journal of Carcinogenesis 10.4103/1477-3163.45315 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=1;epage=1;aulast=Robinson-Bennett http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=1;epage=1;aulast=Robinson-Bennett81 1 1 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=1;epage=1;aulast=Robinson-Bennett Bernice Robinson-Bennett

Journal of Carcinogenesis 2009 8(1):1-1

]]> http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=1;epage=1;aulast=Robinson-Bennett John L Barkinge Radhika Gudi Hawkins Sarah Fei Chu Alip Borthakur Bellur S Prabhakar Kanteti V.S Prasad Original Article Journal of Carcinogenesis 2009 8(1):2-2doi:10.4103/1477-3163.45389 Journal of Carcinogenesis 10.4103/1477-3163.45389 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=2;epage=2;aulast=Barkinge http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=2;epage=2;aulast=Barkinge81 2 2 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=2;epage=2;aulast=Barkinge John L Barkinge, Radhika Gudi, Hawkins Sarah, Fei Chu, Alip Borthakur, Bellur S Prabhakar, Kanteti V.S Prasad

Journal of Carcinogenesis 2009 8(1):2-2

Background: The pro-apoptotic protein Siva-1 functions in both extrinsic and intrinsic cell death signaling; however, the exact contribution of the endogenous Siva-1 to DNA damage-induced apoptosis is unclear. Using cisplatin, a chemotherapeutic drug, to induce DNA damage and cell death, we determined the role of Siva-1. Methods: Cisplatin treated HCT116 colorectal carcinoma cells (p53+/+ and -/-) were used in the study. With the help of recombinant lentivirus that can express siSiva (siRNA that specifically targets Siva-1), we also generated Siva-1 knockdown HCT116 cells. Apoptosis was determined by tetramethyl rhodamine methyl ester (TMRM) staining and propidium iodide (PI) staining. Results: Treatment with cisplatin induced Siva-1 expression in a p53 dependent manner. In Siva-1 knockdown p53+/+ HCT116 colorectal carcinoma cells, loss of Siva-1 expression conferred significant resistance to cisplatin-induced apoptosis. Although Siva-1 levels were positively regulated by p53, Siva-1-induced apoptosis did not require p53. Despite the fact that Siva-1 lacks even a minimal BH3 domain, similar to other proapoptotic Bcl2 family members induced by p53, we showed that Siva-1 mediated apoptosis is characterized by Bax oligomerization and cytochrome c leakage from mitochondria. The putative amphipathic helical region in Siva-1 (SAH) appeared to function analogously to a BH3 domain. Conclusion: The p53 induced Siva-1 is one of the effector molecules, which plays a significant role in DNA damage-induced cell death.]]> http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=2;epage=2;aulast=Barkinge Jose Pontes-Junior Sabrina Thalita Reis Marcos Dall'Oglio Luis Carlos Neves de Oliveira Jose Cury Paulo Afonso Carvalho Leopoldo Alves Ribeiro-Filho Katia Ramos Moreira Leite Miguel Srougi Original Article Journal of Carcinogenesis 2009 8(1):3-3doi:10.4103/1477-3163.48453 Journal of Carcinogenesis 10.4103/1477-3163.48453 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=3;epage=3;aulast=Pontes-Junior http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=3;epage=3;aulast=Pontes-Junior81 3 3 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=3;epage=3;aulast=Pontes-Junior Jose Pontes-Junior, Sabrina Thalita Reis, Marcos Dall'Oglio, Luis Carlos Neves de Oliveira, Jose Cury, Paulo Afonso Carvalho, Leopoldo Alves Ribeiro-Filho, Katia Ramos Moreira Leite, Miguel Srougi

Journal of Carcinogenesis 2009 8(1):3-3

Background: Integrins and adhesion molecules are responsible for the maintenance of the epithelial phenotype. Cell culture studies have reported the correlation between adhesion molecule expression and prostate carcinoma, but their role in the metastatic process is not yet known. Our aim is to study the expression profiles of these molecules and evaluate their association with the metastatic behavior of prostate adenocarcinoma. Materials and Methods: A Tissue Microarray containing two samples from 19 primary tumors and one from their corresponding lymph node metastases was constructed and subjected to immunohistochemical analysis of the expression of integrins, E-cadherin and β and γ-catenins. Within each case, paired analyses were also performed to evaluate gains or losses in metastasis compared to its primary tumor. Results: The expression of av, αvβ 3, α2β 1 and γ-catenin were abnormal in almost every case. Marked loss of E-cadherin and β 4 integrin was found in primary and metastatic lesions. β -catenin was normal in all primary cases and in 94% of metastases. a6 was normal in all primary tumors and metastases. α3 and α3β 1 were normal in 32% of primary cases and in 53% and 6% of metastases, respectively. In paired analyses, loss of E-cadherin, β 4, αv, α3β 1 and αvβ 3 was found in 65%, 71%, 59%, 53% and 47% of patients, respectively. Catenins and α2β 1 showed maintenance of expression in most of the cases. Conclusions: In this preliminary study we have shown that the loss of cell adhesion molecules can be considered a characteristic of the metastatic phenotype in prostate cancer. Larger series should be evaluated in order to confirm our findings.]]> http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=3;epage=3;aulast=Pontes-Junior Gopala Kovvali Editorial Journal of Carcinogenesis 2009 8(1):4-4doi:10.4103/1477-3163.48607 Journal of Carcinogenesis 10.4103/1477-3163.48607 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=4;epage=4;aulast=Kovvali http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=4;epage=4;aulast=Kovvali81 4 4 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=4;epage=4;aulast=Kovvali Gopala Kovvali

Journal of Carcinogenesis 2009 8(1):4-4

]]> http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=4;epage=4;aulast=Kovvali Takuji Tanaka Review Article Journal of Carcinogenesis 2009 8(1):5-5doi:10.4103/1477-3163.49014 Journal of Carcinogenesis 10.4103/1477-3163.49014 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=5;epage=5;aulast=Tanaka http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=5;epage=5;aulast=Tanaka81 5 5 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=5;epage=5;aulast=Tanaka Takuji Tanaka

Journal of Carcinogenesis 2009 8(1):5-5

This review gives a comprehensive overview of cancer development and links it to the current understanding of tumorigenesis and malignant progression in colorectal cancer. The focus is on human and murine colorectal carcinogenesis and the histogenesis of this malignant disorder. A summary of a model of colitis-associated colon tumorigenesis (an AOM/DSS model) will also be presented. The earliest phases of colorectal oncogenesis occur in the normal mucosa, with a disorder of cell replication. The large majority of colorectal malignancies develop from an adenomatous polyp (adenoma). These can be defined as well-demarcated masses of epithelial dysplasia, with uncontrolled crypt cell proliferation. When neoplastic cells pass through the muscularis mucosa and infiltrate the submucosa, they are malignant. Carcinomas usually originate from pre-existing adenomas, but this does not imply that all polyps undergo malignant changes and does not exclude de novo oncogenesis. Besides adenomas, there are other types of pre-neoplasia, which include hyperplastic polyps, serrated adenomas, flat adenomas and dysplasia that occurs in the inflamed colon in associated with inflammatory bowel disease. Colorectal neoplasms cover a wide range of pre-malignant and malignant lesions, many of which can easily be removed during endoscopy if they are small. Colorectal neoplasms and/or pre-neoplasms can be prevented by interfering with the various steps of oncogenesis, which begins with uncontrolled epithelial cell replication, continues with the formation of adenomas and eventually evolves into malignancy. The knowledge described herein will help to reduce and prevent this malignancy, which is one of the most frequent neoplasms in some Western and developed countries.]]> http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=5;epage=5;aulast=Tanaka Hui-Yun Wang Danielle Greenawalt Xiangfeng Cui Irina V Tereshchenko Minjie Luo Qifeng Yang Marco A Azaro Guohong Hu Yi Chu James Y Li Li Shen Yong Lin Lianjun Zhang Honghua Li Original Article Journal of Carcinogenesis 2009 8(1):6-6doi:10.4103/1477-3163.50886 Journal of Carcinogenesis 10.4103/1477-3163.50886 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=6;epage=6;aulast=Wang http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=6;epage=6;aulast=Wang81 6 6 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=6;epage=6;aulast=Wang Hui-Yun Wang, Danielle Greenawalt, Xiangfeng Cui, Irina V Tereshchenko, Minjie Luo, Qifeng Yang, Marco A Azaro, Guohong Hu, Yi Chu, James Y Li, Li Shen, Yong Lin, Lianjun Zhang, Honghua Li

Journal of Carcinogenesis 2009 8(1):6-6

Context: Cancer cell lines are used extensively in various research. Knowledge of genetic alterations in these lines is important for understanding mechanisms underlying their biology. However, since paired normal tissues are usually unavailable for comparison, precisely determining genetic alterations in cancer cell lines is difficult. To address this issue, a highly efficient and reliable method is developed. Aims: Establishing a highly efficient and reliable experimental system for genetic profiling of cell lines. Materials and Methods: A widely used breast cancer cell line, MCF-7, was genetically profiled with 4,396 single nucleotide polymorphisms (SNPs) spanning 11 whole chromosomes and two other small regions using a newly developed high-throughput multiplex genotyping approach. Results: The fractions of homozygous SNPs in MCF-7 (13.3%) were significantly lower than those in the control cell line and in 24 normal human individuals (25.1% and 27.4%, respectively). Homozygous SNPs in MCF-7 were found in clusters. The sizes of these clusters were significantly larger than the expected based on random allelic combination. Fourteen such regions were found on chromosomes 1p, 1q, 2q, 6q, 13, 15q, 16q, 17q and 18p in MCF-7 and two in the small regions. Conclusions: These results are generally concordant with those obtained using different approaches but are better in defining their chromosomal positions. The used approach provides a reliable way to detecting possible genetic alterations in cancer cell lines without paired normal tissues.]]> http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=6;epage=6;aulast=Wang Jared L Snider James A Cardelli Original Article Journal of Carcinogenesis 2009 8(1):7-7doi:10.4103/1477-3163.50892 Journal of Carcinogenesis 10.4103/1477-3163.50892 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=7;epage=7;aulast=Snider http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=7;epage=7;aulast=Snider81 7 7 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=7;epage=7;aulast=Snider Jared L Snider, James A Cardelli

Journal of Carcinogenesis 2009 8(1):7-7

Background: The hepatocyte growth factor (HGF) receptor, c-Met, is strongly implicated in late-stage cancer progression and poor patient prognosis. The stomach pathogen, Helicobacter pylori ( H. pylori ), was recently proposed to stimulate c-Met phosphorylation dependent upon interaction of c-Met with the bacterial CagA protein required for H. pylori -induced cancer cell motility and invasion. Materials and Methods: In this report, we employed short hairpin RNA (shRNA), western blot analysis using antibodies recognizing phosphorylation at discrete c-Met residues, and immunofluorescence microscopy to investigate the CagA-c-Met interaction. Results: The data showed that shRNA-mediated c-Met knockdown did not reduce H. pylori -induced cell motility, suggesting that c-Met was not required for motility. Surprisingly, c-Met knockdown did not reduce the level of an H. pylori -induced protein recognized by a phospho-c-Met antibody. This 125 kD protein was 10 kD smaller than c-Met, suggesting that H. pylori did not phosphorylate c-Met but cross-reacted with another protein. This hypothesis was confirmed when c-Met phosphorylation inhibitors did not lower the levels of the bacteria-induced 125 kD protein, and c-Met immunoprecipitation (IP) did not detect this 125 kD protein from H. pylori -treated lysates. This protein was identified as a product of antibody cross reactivity with phosphorylated CagA. We also confirmed that CagA interacts with c-Met, but this interaction may have caused previous authors to misinterpret phosphorylated CagA as c-Met phosphorylation. Finally, pretreatment with the proteasomal inhibitor, lactacystin, caused prolonged HGF-induced c-Met phosphorylation and facilitated a CagA-negative H. pylori to stimulate AGS cell motility, suggesting that sustained c-Met phosphorylation compensates for the loss of CagA-dependent signaling. Conclusions: These data demonstrate that H. pylori stimulates cancer cell motility independent of the c-Met receptor. We further hypothesize that although H. pylori does not target c-Met, the bacteria may still utilize c-Met effector signaling to stimulate CagA-independent cancer cell motility, which may provide a further mechanism of H. pylori -dependent gastric cancer progression.]]> http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=7;epage=7;aulast=Snider Mariola Kulawiec Vanniarajan Ayyasamy Keshav K Singh Original Article Journal of Carcinogenesis 2009 8(1):8-8doi:10.4103/1477-3163.50893 Journal of Carcinogenesis 10.4103/1477-3163.50893 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=8;epage=8;aulast=Kulawiec http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=8;epage=8;aulast=Kulawiec81 8 8 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=8;epage=8;aulast=Kulawiec Mariola Kulawiec, Vanniarajan Ayyasamy, Keshav K Singh

Journal of Carcinogenesis 2009 8(1):8-8

Background: We previously hypothesized a role for mitochondria damage checkpoint (mito-checkpoint) in maintaining the mitochondrial integrity of cells. Consistent with this hypothesis, defects in mitochondria have been demonstrated to cause genetic and epigenetic changes in the nuclear DNA, resistance to cell-death and tumorigenesis. In this paper, we describe that defects in mitochondria arising from the inhibition of mitochondrial oxidative phosphorylation (mtOXPHOS) induce cell cycle arrest, a response similar to the DNA damage checkpoint response. Materials and Methods: Primary mouse embryonic fibroblasts obtained from p53 wild-type and p53-deficient mouse embryos (p53 -/-) were treated with inhibitors of electron transport chain and cell cycle analysis, ROS production, mitochondrial content analysis and immunoblotting was performed. The expression of p53R2 was also measured by real time quantitative PCR. Results: We determined that, while p53 +/+ cells arrest in the cell cycle, p53 -/- cells continued to divide after exposure to mitochondrial inhibitors, showing that p53 plays an important role in the S-phase delay in the cell cycle. p53 is translocated to mitochondria after mtOXPHOS inhibition. Our study also revealed that p53-dependent induction of reactive oxygen species acts as a major signal triggering a mito-checkpoint response. Furthermore our study revealed that loss of p53 results in down regulation of p53R2 that contributes to depletion of mtDNA in primary MEF cells. Conclusions: Our study suggests that p53 1) functions as mito-checkpoint protein and 2) regulates mtDNA copy number and mitochondrial biogenesis. We describe a conceptual organization of the mito-checkpoint pathway in which identified roles of p53 in mitochondria are incorporated.]]> http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=8;epage=8;aulast=Kulawiec Thangaiyan Rabi Anupam Bishayee Original Article Journal of Carcinogenesis 2009 8(1):9-9doi:10.4103/1477-3163.51368 Journal of Carcinogenesis 10.4103/1477-3163.51368 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=9;epage=9;aulast=Rabi http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=9;epage=9;aulast=Rabi81 9 9 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=9;epage=9;aulast=Rabi Thangaiyan Rabi, Anupam Bishayee

Journal of Carcinogenesis 2009 8(1):9-9

Background: Clinical trials have shown that docetaxel combined with other novel agents can improve the survival of androgen-independent prostate cancer patients. d -Limonene, a non-nutrient dietary component, has been found to inhibit various cancer cell growths without toxicity. We sought to characterize whether a non-toxic dose of d -limonene may enhance tumor response to docetaxel in an in vitro model of metastatic prostate cancer. Materials and Methods: Human prostate carcinoma DU-145 and normal prostate epithelial PZ-HPV-7 cells were treated with various concentrations of d -limonene, docetaxel or a combination of both, and cell viability was determined by MTT assay. Intracellular reactive oxygen species (ROS), reduced glutathione (GSH) and caspase activity were measured. Apoptosis and apoptosis-related proteins were studied by enzyme-linked immunosorbent assay and Western blotting, respectively. Results: d -Limonene and docetaxel in combination significantly enhanced the cytotoxicity to DU-145 cells than PZ-HPV-7 cells. Exposure of DU-145 cells to a combined d -limonene and docetaxel resulted in higher ROS generation, depletion of GSH, accompanied by increased caspase activity than docetaxel alone. It also triggered a series of effects involving cytochrome c , cleavages of caspase-9, 3 and poly (ADP-ribose) polymerase, and a shift in Bad:Bcl-xL ratio in favor of apoptosis. Apoptotic effect was significantly blocked on pretreatment with N -acetylcystein, indicating that antitumor effect is initiated by ROS generation, and caspase cascades contribute to the cell death. Conclusion: Our results show, for the first time, that d -limonene enhanced the antitumor effect of docetaxel against prostate cancer cells without being toxic to normal prostate epithelial cells. The combined beneficial effect could be through the modulation of proteins involved in mitochondrial pathway of apoptosis. d -Limonene could be used as a potent non-toxic agent to improve the treatment outcome of hormone-refractory prostate cancer with docetaxel.]]> http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=9;epage=9;aulast=Rabi Yumiko Yasui Takuji Tanaka Original Article Journal of Carcinogenesis 2009 8(1):10-10doi:10.4103/1477-3163.51851 Journal of Carcinogenesis 10.4103/1477-3163.51851 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=10;epage=10;aulast=Yasui http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=10;epage=10;aulast=Yasui81 10 10 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=10;epage=10;aulast=Yasui Yumiko Yasui, Takuji Tanaka

Journal of Carcinogenesis 2009 8(1):10-10

Background: Chronic inflammation is a risk factor for colorectal cancer (CRC) development. The aim of this study was to determine the differences in protein expression between CRC and the surrounding nontumorous colonic tissues in the mice that received azoxymethane (AOM) and dextran sodium sulfate (DSS) using a proteomic analysis. Materials and Methods: Male ICR mice were given a single intraperitoneal injection of AOM (10 mg/kg body weight), followed by 2% (w/v) DSS in their drinking water for seven days, starting one week after the AOM injection. Colonic adenocarcinoma developed after 20 weeks and a proteomics analysis based on two-dimensional gel electrophoresis and ultraflex TOF/TOF mass spectrometry was conducted in the cancerous and nontumorous tissue specimens. Results: The proteomic analysis revealed 21 differentially expressed proteins in the cancerous tissues in comparison to the nontumorous tissues. There were five markedly increased proteins (beta-tropomyosin, tropomyosin 1 alpha isoform b, S100 calcium binding protein A9, and an unknown protein) and 16 markedly decreased proteins (Car1 proteins, selenium-binding protein 1, HMG-CoA synthase, thioredoxin 1, 1 Cys peroxiredoxin protein 2, Fcgbp protein, Cytochrome c oxidase, subunit Va, ETHE1 protein, and 7 unknown proteins). Conclusions: There were 21 differentially expressed proteins in the cancerous tissues of the mice that received AOM and DSS. Their functions include metabolism, the antioxidant system, oxidative stress, mucin production, and inflammation. These findings may provide new insights into the mechanisms of inflammation-related colon carcinogenesis and the establishment of novel therapies and preventative strategies to treat carcinogenesis in the inflamed colon.]]> http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=10;epage=10;aulast=Yasui Ana Isabel Flores Fernando Bedoya Montserrat Grau Rafael Enriquez de Salamanca Irene Vegh Original Article Journal of Carcinogenesis 2009 8(1):11-11doi:10.4103/1477-3163.51852 Journal of Carcinogenesis 10.4103/1477-3163.51852 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=11;epage=11;aulast=Flores http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=11;epage=11;aulast=Flores81 11 11 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=11;epage=11;aulast=Flores Ana Isabel Flores, Fernando Bedoya, Montserrat Grau, Rafael Enriquez de Salamanca, Irene Vegh

Journal of Carcinogenesis 2009 8(1):11-11

Background: The hypothalamic luteinizing hormone-releasing hormone (LHRH) is well known for its role in the control of pituitary gonadotropin secretion and it has demonstrated a direct antiproliferative effect on some cancer cell lines of LHRH and its synthetic analogs. The study was designed to assess whether administration of the LHRH analog (goserelin) has any effect on the expression of the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR) in rats with N-nitroso-N-methylurea (NMU)-induced-mammary tumors " in vivo". Materials and Methods: The animals with tumors were assessed after acute or chronic treatment with goserelin, and in all the animals VEGF and EGFR expression was examined both in plasma and tumor homogenates by enzyme immunoassay. Results: The basal plasma values of VEGF were lower in the healthy control group than in rats with NMU-induced tumors ( P = 0.025). Following acute treatment with goserelin, VEGF expression in plasma increased above basal levels after 60 min ( P = 0.05) and dropped during chronic treatment. Likewise, in the tumor homogenate the mean VEGF expression was higher at 60 min post-goserelin administration than the basal levels, although VEGF expression then diminished at 90 min. Plasma EGFR expression was higher in rats with NMU-induced tumors than in healthy controls ( P < 0.01). Conclusions: The results allow us to conclude that goserelin may exert a short-term stimulatory effect on the release of VEGF, as well as a long-term inhibitory effect on VEGF but not EGFR expression.]]> http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=11;epage=11;aulast=Flores Regina Monaco Ramon Rosal Michael A Dolan Matthew R Pincus Greg Freyer Paul W Brandt-Rauf Original Article Journal of Carcinogenesis 2009 8(1):12-12doi:10.4103/1477-3163.54918 Journal of Carcinogenesis 10.4103/1477-3163.54918 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=12;epage=12;aulast=Monaco http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=12;epage=12;aulast=Monaco81 12 12 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=12;epage=12;aulast=Monaco Regina Monaco, Ramon Rosal, Michael A Dolan, Matthew R Pincus, Greg Freyer, Paul W Brandt-Rauf

Journal of Carcinogenesis 2009 8(1):12-12

Aim: The xeroderma pigmentosum D (XPD) protein is a DNA helicase involved in the repair of DNA damage, including nucleotide excision repair (NER) and transcription-coupled repair (TCR). The C-terminal domain of XPD has been implicated in interactions with other components of the TFIIH complex, and it is also the site of a common genetic polymorphism in XPD at amino acid residue 751 (Lys->Gln). Some evidence suggests that this polymorphism may alter DNA repair capacity and increase cancer risk. The aim of this study was to investigate whether these effects could be attributable to conformational changes in XPD induced by the polymorphism. Materials and Methods: Molecular dynamics techniques were used to predict the structure of the wild-type and polymorphic forms of the C-terminal domain of XPD and differences in structure produced by the polymorphic substitution were determined. Results: The results indicate that, although the general configuration of both proteins is similar, the substitution produces a significant conformational change immediately N-terminal to the site of the polymorphism. Conclusion: These results provide support for the hypothesis that this polymorphism in XPD could affect DNA repair capability, and hence cancer risk, by altering the structure of the C-terminal domain.]]> http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=12;epage=12;aulast=Monaco Xuan-Fu Xu Chuan-Yong Guo Jun Liu Wen-Juan Yang Yu-Jing Xia Ling Xu Yong-Chun Yu Xing-Peng Wang Original Article Journal of Carcinogenesis 2009 8(1):13-13doi:10.4103/1477-3163.55429 Journal of Carcinogenesis 10.4103/1477-3163.55429 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=13;epage=13;aulast=Xu http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=13;epage=13;aulast=Xu81 13 13 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=13;epage=13;aulast=Xu Xuan-Fu Xu, Chuan-Yong Guo, Jun Liu, Wen-Juan Yang, Yu-Jing Xia, Ling Xu, Yong-Chun Yu, Xing-Peng Wang

Journal of Carcinogenesis 2009 8(1):13-13

Background: Aberrant activation of Hedgehog (Hh) signaling pathway has been reported to be related to malignant biological behavior of pancreatic cancer but its mechanism is unclear yet. Since IGF pathway and Bcl-2 family are involved in proliferation and apoptosis of pancreatic cancer cells, we hypothesize that they are possibly associated with Hh pathway. Materials and Methods: We studied the relationship of Shh-Gli1 signaling pathway with proliferation and apoptosis of pancreatic cancer cells and the regulation of transcription factor Gli1 to insulin-like growth factor binding protein 6 (IGFBP6) and Bcl-2 genes at the level of transcription. Results: Sonic hedgehog (Shh), Smoothened (Smo), patched and Gli1 were expressed in pancreatic cancer cells. Cyclopamine inhibited cell proliferation at low concentration and induced apoptosis at high concentration. Effect of RNA interference (RNAi) for Gli1 to cell survival is mainly due to proliferation inhibition though involved in apoptosis. The transcription factor Gli1 bound to promoter regions of Bcl-2 and IGFBP6 genes and the levels of IGFBP6, proliferating cell nuclear antigen (PCNA) and Bcl-2 messenger RNA (mRNA) were decreased as well as Gli1 mRNA significantly by cyclopamine or RNAi in cultured pancreatic cancer cells (p < 0.01). Finally PCNA, IGFBP6 and Bcl-2 mRNA were upregulated as well as Shh or Gli1 in pancreatic cancer tissues (p < 0.01). Conclusions: Our study reveals that Gli1 maintained cell survival by binding the promoter regions and facilitating transcription of IGFBP6 and Bcl-2 genes in a parallel manner in pancreatic cancer cells and suggests it may be one of the mechanisms of Shh-Gli1 signaling pathway in pancreatic cancer.]]> http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=13;epage=13;aulast=Xu Yongliang Li Changmin Long George Lin Marie-Jeanne Marion Greg Freyer Regina M Santella Paul W Brandt-Rauf Original Article Journal of Carcinogenesis 2009 8(1):14-14doi:10.4103/1477-3163.56290 Journal of Carcinogenesis 10.4103/1477-3163.56290 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=14;epage=14;aulast=Li http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=14;epage=14;aulast=Li81 14 14 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=14;epage=14;aulast=Li Yongliang Li, Changmin Long, George Lin, Marie-Jeanne Marion, Greg Freyer, Regina M Santella, Paul W Brandt-Rauf

Journal of Carcinogenesis 2009 8(1):14-14

Background: Recent epidemiologic evidence suggests that the common polymorphism at amino acid residue 399 of the x-ray cross complementing-1 (XRCC1) protein, a key component of the base excision repair (BER) pathway for DNA damage, plays a significant role in the genetic variability of individuals in terms of the mutagenic damage they experience following exposure to the carcinogen vinyl chloride (VC). The aim of this study was to provide support for the biological plausibility of these epidemiologic observations with experimental data derived from cell lines in culture from individuals who were either homozygous wild-type or homozygous variant for this XRCC1 polymorphism following exposure to chloroethylene oxide (CEO), the active metabolite of VC, with measurement of the induced etheno-DNA adducts before and after repair. Materials and Methods: Immortalized lymphoblast cell lines from seven VC workers (four homozygous wild-type and three homozygous variant for the 399 XRCC1 polymorphism) were exposed to CEO, and etheno-adenosine (&#949;A) adduct levels were determined by enzyme-linked immunosorbent assay (ELISA) pre-exposure and at 0, 4, 8 and 24 h following exposure. Results: The average &#949;A adduct levels were statistically significantly higher in the variant cells compared to the wild-type cells at 8 and 24 h following exposure (P<0.05) with an overall average repair efficiency of 32% in the variant cells compared to 82% in the wild-type cells. Conclusion: These results are consistent with the epidemiologic findings of the types of VC-induced biomarkers observed in exposed individuals and the mutational spectra found in the resultant tumors as well as the key role that BER, especially XRCC1, plays in this carcinogenic pathway.]]> http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=14;epage=14;aulast=Li Leonardo Faoro Gustavo M Cervantes Benjamin D Ferguson Tanguy Y Seiwert Soheil Yala Wicki T Vigneswaran Maria Westerhoff Maria S Tretiakova Mark K Ferguson Glaci L Moura Aliya N Husain Everett E Vokes Ravi Salgia Original Article Journal of Carcinogenesis 2009 8(1):15-15doi:10.4103/1477-3163.57857 Journal of Carcinogenesis 10.4103/1477-3163.57857 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=15;epage=15;aulast=Faoro http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=15;epage=15;aulast=Faoro81 15 15 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=15;epage=15;aulast=Faoro Leonardo Faoro, Gustavo M Cervantes, Benjamin D Ferguson, Tanguy Y Seiwert, Soheil Yala, Wicki T Vigneswaran, Maria Westerhoff, Maria S Tretiakova, Mark K Ferguson, Glaci L Moura, Aliya N Husain, Everett E Vokes, Ravi Salgia

Journal of Carcinogenesis 2009 8(1):15-15

Background: Treatment of non-small cell lung cancer (NSCLC) remains a difficult task in oncology. Targeted inhibition of oncogenic proteins is promising. In this study, we evaluate the expression of MET and PKC&#223; and in vitro effects of their inhibition using SU11274 and enzastaurin (LY317615.HCl) respectively. Materials and Methods: Patient samples were analyzed by immunohistochemistry for expression of PKC&#223; and MET, utilizing tissue microarrays under an IRB-approved protocol. Expression of PKC&#223; and MET was evaluated in cell lines by immunoblotting. Treatment with SU1174 against MET and enzastaurin against PKC&#223; was performed in H1993 and H358 cell lines, and cell proliferation and downstream signaling (phosphorylation of MET, AKT, FAK, and GSK3&#223;) were evaluated by immunoblotting. Statistical analysis was performed using SPSS 16.0. Results: Expression of MET positively correlated with lymph node metastases (p=.0004), whereas PKC&#223; showed no correlation (p=0.204). MET and PKC&#223; expression were also strongly correlated (p<0.001). Expression of MET was observed in 5/8 cell lines (H358, H1703, A549, H1993, H2170; absent from H522, H661, or SW1573), whereas PKC&#223; expression was observed in 8/8 cell lines. Cell proliferation was significantly impaired by treatment with SU11274 and enzastaurin, and their effects were synergistic in combination (CI=0.32 and 0.09). Phosphorylation of MET, FAK, AKT, and GSK3&#223; were strongly inhibited with both agents in combination. Conclusions: Concomitant inhibition of MET and PKC&#223; significantly increased cytotoxicity in vitro against NSCLC, disrupting important downstream signaling pathways. Further evaluation in animal models is warranted.]]> http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=15;epage=15;aulast=Faoro Idit Sagiv Pavel Idelevich Ilia Rivkin Rimona Margalit Adi Elkeles Alexander Levitzki Original Article Journal of Carcinogenesis 2009 8(1):16-16doi:10.4103/1477-3163.58372 Journal of Carcinogenesis 10.4103/1477-3163.58372 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=16;epage=16;aulast=Sagiv http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=16;epage=16;aulast=Sagiv81 16 16 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=16;epage=16;aulast=Sagiv Idit Sagiv, Pavel Idelevich, Ilia Rivkin, Rimona Margalit, Adi Elkeles, Alexander Levitzki

Journal of Carcinogenesis 2009 8(1):16-16

Background: Advanced diagnostic tools stand today at the heart of successful cancer treatment. CellDetect&#174; is a new histochemical staining technology that enables color discrimination between normal cells and a wide variety of neoplastic tissues. Using this technology, normal cells are colored blue/green, while neoplastic cells color red. This tinctorial difference coincides with clear morphological visualization properties, mainly in tissue samples. Here we show that the CellDetect&#174; technology can be deployed to distinguish normal cells from transformed cells and most significantly detect cells in their early pre-cancerous transformed state. Materials and Methods: In tissue culture, we studied the ability of the CellDetect&#174; technology to color discriminate foci in a number of two stage transformation systems as well as in a well defined cellular model for cervical cancer development, using HPV16 transformed keratinocytes. Results: In all these cellular systems, the CellDetect&#174; technology was able to sensitively show that all transformed cells, including pre-cancerous HPV 16 transformed cells, are colored red, whereas normal cells are colored blue/green. The staining technology was able to pick up: (i) early transformation events in the form of small type 1 foci (non-invasive, not piled up small, with parallel alignment of cells), and (ii) early HPV16 transformed cells, even prior to their ability to form colonies in soft agar. The study shows the utility of the CellDetect&#174; technology in early detection of transformation events.]]> http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=16;epage=16;aulast=Sagiv Faizeh Alquobaili Stacy-Ann Miller Seid Muhie Agnes Day Marti Jett Rasha Hammamieh Original Article Journal of Carcinogenesis 2009 8(1):17-17doi:10.4103/1477-3163.59539 Journal of Carcinogenesis 10.4103/1477-3163.59539 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=17;epage=17;aulast=Alquobaili http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=17;epage=17;aulast=Alquobaili81 17 17 http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=17;epage=17;aulast=Alquobaili Faizeh Alquobaili, Stacy-Ann Miller, Seid Muhie, Agnes Day, Marti Jett, Rasha Hammamieh

Journal of Carcinogenesis 2009 8(1):17-17

Context: The estrogen receptor (ER) status in breast cancer plays a major role in the progression and metastatic potential of breast cancer in women. Breast cancer cells lacking the ER are usually more advanced and more difficult to treat than ER+ breast cancer cells. ER- women have more advanced breast cancer at the time of diagnosis than ER+ women. ER- breast cancer cells in women, regardless of age, are more likely to have tumor Grade III or IV with fewer Grade I and II tumor stages combined for each individual stage group. Studies have suggested a strong correlation between fat intake and the elevated risk of ER+ breast cancer cells. Materials and Methods: We studied the role of ER status on the gene expression in breast cancer cells in response to omega-3 and omega-6 fatty acids using microarrays. We have studied gene expression patterns in 8 breast cancer cell lines (4 ER- and 4 ER+) in response to Eicosapentanoic (EPA) and Arachidonic (AA) acids. Statistical Analysis: Analysis of Variance (ANOVA) t-test analysis was carried out to identify genes differentially expressed between the two groups. Results: We identified genes which were significantly correlated with the ER status when breast cancer cells were treated with these fatty acids. Conclusion: We have determined ER-related gene expression patterns in breast cancer cells in response to fatty acids. Additional studies of these biomarkers may enlighten the importance of the ER status on the mechanistic and therapeutic roles of fatty acids in breast cancer.]]> http://www.carcinogenesis.com/article.asp?issn=1477-3163;year=2009;volume=8;issue=1;spage=17;epage=17;aulast=Alquobaili