This study aims to isolate potential molecular targets for diagnosis, treatment, and/or prevention of lung and esophageal carcinomas.
We screened for genes that were frequently overexpressed in the ...tumors through gene expression profile analyses of 101 lung cancers and 19 esophageal squamous cell carcinomas (ESCC) by cDNA microarray consisting of 27,648 genes or expressed sequence tags. In this process, we identified epithelial cell transforming sequence 2 (ECT2) as a candidate. Tumor tissue microarray was applied to examine the expression of ECT2 protein in 242 archived non-small-cell lung cancers (NSCLC) and 240 ESCC specimens and to investigate its prognostic value. A role of ECT2 in lung and esophageal cancer cell growth and/or survival was examined by small interfering RNA experiments. Cellular invasive activity of ECT2 in mammalian cells was examined using Matrigel assays.
Northern blot and immunohistochemical analyses detected expression of ECT2 only in testis among 23 normal tissues. Immunohistochemical staining showed that a high level of ECT2 expression was associated with poor prognosis for patients with NSCLC (P = 0.0004) as well as ESCC (P = 0.0088). Multivariate analysis indicated it to be an independent prognostic factor for NSCLC (P = 0.0005). Knockdown of ECT2 expression by small interfering RNAs effectively suppressed lung and esophageal cancer cell growth. In addition, induction of exogenous expression of ECT2 in mammalian cells promoted cellular invasive activity.
ECT2 cancer-testis antigen is likely to be a prognostic biomarker in clinic and a potential therapeutic target for the development of anticancer drugs and cancer vaccines for lung and esophageal cancers.
Through genome-wide gene expression analysis of lung carcinomas, we detected in the great majority of lung cancer samples cotransactivation of cell division cycle associated 8 (CDCA8) and aurora ...kinase B (AURKB), which were considered to be components of the vertebrate chromosomal passenger complex. Immunohistochemical analysis of lung cancer tissue microarrays showed that overexpression of CDCA8 and AURKB was significantly associated with poor prognosis of lung cancer patients. AURKB directly phosphorylated CDCA8 at Ser(154), Ser(219), Ser(275), and Thr(278) and seemed to stabilize CDCA8 protein in cancer cells. Suppression of CDCA8 expression with small interfering RNA against CDCA8 significantly suppressed the growth of lung cancer cells. In addition, functional inhibition of interaction between CDCA8 and AURKB by a cell-permeable peptide corresponding to 20-amino acid sequence of a part of CDCA8 (11R-CDCA8(261-280)), which included two phosphorylation sites by AURKB, significantly reduced phosphorylation of CDCA8 and resulted in growth suppression of lung cancer cells. Our data imply that selective suppression of the CDCA8-AURKB pathway could be a promising therapeutic strategy for treatment of lung cancer patients.
Background & Aims The current treatment regimen for chronic hepatitis C virus (HCV) infection is peg-interferon plus ribavirin combination therapy. The majority of developing therapeutic strategies ...also contain peg-interferon with or without ribavirin. However, interferon is expensive and sometimes intolerable for some patients because of severe side effects. Methods Using human hepatocyte chimeric mice, we examined whether a short term combination therapy with the HCV NS3-4A protease inhibitor telaprevir and the RNA polymerase inhibitor MK-0608 with or without interferon eradicates the HCV from infected mice. The effect of telaprevir and MK-0608 combination therapy was examined using subgenomic HCV replicon cells. Results Combination therapy with the two drugs enhanced inhibition of HCV replication compared with either drug alone. In in vivo experiments, early emergence of drug resistance was seen in mice treated with either telaprevir or MK-0608 alone. However, emergence was prevented by the combination of these drugs. Mice treated with a triple combination therapy of telaprevir, MK-0608, and interferon became negative for HCV RNA soon after commencement of the therapy, and HCV RNA was not detected in serum of these mice 12 weeks after cessation of the therapy. Furthermore, all mice treated with a high dose telaprevir and MK-0608 combination therapy for 4 weeks became negative for HCV RNA 1 week after the beginning of the therapy and remained negative after 18 weeks. Conclusions Eradication of HCV from mice with only 4 weeks of therapy without interferon points the way to future combination therapies for chronic hepatitis C patients.
The patient was a 15-year-old woman who had a history of operation of cavernous hemangioma at her left knee at the age of 2. She had hemangiomas of the skin, ion-defficiency anemia, and also gastric ...and colonic hemangiomas detected by the examination of the alimen-tary tract, which leads to the diagnosis of blue rubber bleb nevus syndrome. Endoscopic mucosal resection, local injection of ethanol, etc. were carried out against the hemangiomas of stomach and colon. We have followed her up successfully through the endoscopic treatment of the newly developed hemangimas of stomach and colon without laparotomy during subsequent ten years. We proved in this case that the endoscopic treatment of the alimentary tract hemangiomas showing blue rubber bleb nevus syndrome was safe and useful.
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