Esophageal squamous cell carcinoma (ESCC) has a multifactorial etiology involving environmental and/or genetic factors. End-binding protein 1 (EB1), which was cloned as an interacting partner of the adenomatous polyposis coli (APC) tumor suppressor protein, was previously found overexpressed in ESCC. However, the precise role of EB1 in the development of this malignancy has not yet been elucidated. In this study, we analysed freshly resected ESCC specimens and demonstrated that EB1 was overexpressed in approximately 63% of tumor samples compared to matched normal tissue. We report that overexpression of EB1 in the ESCC line EC9706 significantly promotes cell growth, whereas suppression of EB1 protein level by RNA interference significantly inhibited growth of esophageal tumor cells. In addition, EB1 overexpression induced nuclear accumulation of b-catenin and promoted the transcriptional activity of b-catenin/T-cell factor (TCF). These effects were partially or completely abolished by coexpression of APC or DN TCF4, respectively. Also, we found that EB1 affected the interaction between b-catenin and APC. Furthermore, EB1 overexpression was correlated with cytoplasmic/ nuclear accumulation of b-catenin in primary human ESCC. Taken together, these results support the novel hypothesis that EB1 overexpression may play a role in the development of ESCC by affecting APC function and activating the b-catenin/TCF pathway. Oncogene (2005) 24, 6637-6645.

Overexpression of human pituitary tumor transforming gene (PTTG) is wildly detected in many tumors, including esophageal cancer. Besides overexpression of PTTG in esophageal squamous cell carcinoma (ESCC) tissues and cells, we detected accumulation of cytoplasmic ␤-catenin in ESCC. In our study, a putative TCF4-binding element (TBE) was identified in PTTG promoter region. The activity of PTTG promoter containing the TBE was activated by S37A␤-catenin and inhibited by dominant-negative TCF. Furthermore, the activation by S37A␤-catenin was mostly abrogated among PTTG promoter region without the TBE or with a mutant one. By using biotin-streptavidin pull-down assay, we also found that the TBE among PTTG promoter bound to TCF-4 protein. Moreover, levels of PTTG mRNA and protein were increased by S37A␤-catenin. Finally, it is noticeable that we detected a correlation between ␤-catenin localization and PTTG expression in 69 primary ESCC (p<0.01). In brief, our study shows that overexpression of PTTG in ESCC is likely due to the activation of ␤-catenin/WNT signaling. The human pituitary tumor transforming gene (PTTG), also termed as human securin, was first obtained from fetal liver and identified as an oncogene. 1 The functional mechanism of PTTG in tumorigenesis is still barely understood, but accumulating evidence reveals that PTTG plays crucial roles in cell-cycle progression, appropriate cell division and chromosome stability, in addition to involvement in malignant transformation and tumorigenesis. 2-5 PTTG inhibits sister chromatid separation and is related to cell-cycle control. PTTG expression appears to be cell cycle dependent, reaches peak in mitosis and can be phosphorylated by Cdc2 kinase during mitosis. 6 PTTG, through direct interaction with MEK1, participates in the signaling cascade and can be phosphorylated by MAP kinase. 7 As a cotranscription factor, PTTG interacts with sequence-specific elements in the c-myc promoter and increases cell proliferation, suggesting that PTTG would mediate cellular transformation by activating this oncogene. 8 Moreover, PTTG's interacting with Ku 9 physically and binding to P53 10 suggest that PTTG may take part in DNA-damage-response pathway, DNA repair and apoptosis. 11,12 PTTG induces expression of b-FGF 1 and VEGF, 13 implying that it may play a role in tumor angiogenesis. The expression of PTTG in most normal tissues is very restricted, contrary to that in a number of human tumor tissues, such as pituitary adenomas, 1,14 lung and breast cancers, 14 colorectal tumor 15 and especially in esophageal cancer. 16 Human esophageal cancer is an aggressive tumor with a generally poor prognosis. Esophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer and has a higher incidence than esophageal adenocarcinomas (EADC) among Chinese population. Although it is widely believed that esophageal cancer arises from multistep genetic and cytogenetic alterations, 17 the mechanisms have yet to be convincingly identified. Molecular studies have revealed f...

Emerging evidence has shown the association of aberrantly expressed miR-106a with cancer development, however, little is known about its potential role in gastric carcinogenesis. In our present study, obviously overexpressed miR-106a was found in gastric cancer tissues compared with their nontumor counterparts. Suppression of miR-106a significantly inhibited gastric cancer cell proliferation and triggered apoptosis. Bioinformatic analysis combining with validation experiments identified FAS as a direct target of miR-106a. Rescue experiments and examination of caspase-8, PARP and caspase-3 further approved that miR-106a could inhibit gastric cancer cell apoptosis through interfering with FAS-mediated apoptotic pathway. Moreover, a significant inverse correlation was found between miR-106a and FAS expression not only in gastric cancer cell lines but also in gastric cancer specimens. Taken together, these findings suggest that ectopicly overexpressed miR-106a may play an oncogenic role in gastric carcinogenesis and impair extrinsic apoptotic pathway through targeting FAS.

Introduction Breast cancer is the leading cause of cancer death in women worldwide. Elevated expression of c-Myc is a frequent genetic abnormality seen in this malignancy. For a better understanding of its role in maintaining the malignant phenotype, we used RNA interference (RNAi) directed against c-Myc in our study. RNAi provides a new, reliable method to investigate gene function and has the potential for gene therapy. The aim of the study was to examine the anti-tumor effects elicited by a decrease in the protein level of c-Myc by RNAi and its possible mechanism of effects in MCF-7 cells.

Abstract. Many studies have demonstrated the overexpression and amplification of the miR-17-92 cluster in malignant human cancers, including B-cell lymphomas and lung cancers. The purpose of this study was to investigate for the first time, the expression of the miR-17-92 cluster in esophageal squamous cell carcinoma (ESCC). The miR-17-92 cluster was found to be overexpressed in 21 out of 28 (75%) esophageal cancer samples. It was also found that overexpression of the miR-17-92 cluster could promote cellular growth in vivo and in vitro. Furthermore, inhibition of miR-19a by antisense oligonucleotides (ONs) induced apoptosis, while antisense ONs against miR-17-5p, miR-18a, miR-20a and miR-92-1 did not exhibit such an effect. In addition, it was found that antagomir-19a treatment could impair tumor growth in vivo. Using Human Apoptosis RT 2 Profiler PCR Array 384HT, we found that tumor necrosis factor-α (TNF-α) was up-regulated 12-fold in cells transfected with miR-19a antisense ONs compared to the cells treated with the control scramble ONs. MiR-19a was predicted to target the 3' untranslated region of TNF-α mRNA, and this was confirmed by luciferase reporter assay. Taken together, we conclude that the miR-17-92 cluster is overexpressed in ESCC and that TNF-α is a novel target of miR-19a.