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Spindle cell sarcomas consist of tumors with different biological features, of which distant metastasis is the most ominous sign for a poor prognosis. However, metastasis is difficult to predict on the basis of current histopathological analyses. We have identified actin filament-associated protein 1-like 1 (AFAP1L1) as a candidate for a metastasis-predicting marker from the gene expression profiles of 65 spindle cell sarcomas. A multivariate analysis determined that AFAP1L1 was an independent factor for predicting the occurrence of distant metastasis (P=0.0001), which was further confirmed in another set of 41 tumors by a quantitative mRNA expression analysis. Immunohistochemical staining using paraffin-embedded tumor tissues revealed that the metastasis-free rate was significantly better in tumors negative for AFAP1L1 (P=0.0093 by log-rank test). Knocking down the AFAP1L1 gene in sarcoma cells resulted in inhibition of the cell invasion, and forced expression of AFAP1L1 in immortalized human mesenchymal stem cells induced anchorage-independent growth and increased cell invasiveness with high activity levels of matrix metallopeptidase. Furthermore, tumor growth in vivo was accelerated in AFAP1L1-transduced sarcoma cell lines. These results suggest that AFAP1L1 has a role in the progression of spindle cell sarcomas and is a prognostic biomarker. [ABSTRACT FROM AUTHOR]

We previously reported that Frizzled homologue 10 (FZD10), a member of the Wnt signal receptor family, was highly and specifically upregulated in synovial sarcoma and played critical roles in its cell survival and growth. We here report a possible molecular mechanism of the FZD10 signaling in synovial sarcoma cells. We found a significant enhancement of phosphorylation of the Dishevelled (Dvl)2/Dvl3 complex as well as activation of the Rac1–JNK cascade in synovial sarcoma cells in which FZD10 was overexpressed. Activation of the FZD10–Dvls–Rac1 pathway induced lamellipodia formation and enhanced anchorage-independent cell growth cells. FZD10 overexpression also caused the destruction of the actin cytoskeleton structure, probably through the downregulation of the RhoA activity. Our results have strongly implied that FZD10 transactivation causes the activation of the non-canonical Dvl–Rac1–JNK pathway and plays critical roles in the development/progression of synovial sarcomas.Oncogene (2009) 28, 1110–1120; doi:10.1038/onc.2008.467; published online 12 January 2009 [ABSTRACT FROM AUTHOR]

To investigate the detailed molecular mechanism of mammary carcinogenesis and discover novel therapeutic targets, we previously analysed gene expression profiles of breast cancers. We here report characterization of a significant role of DTL/RAMP (denticleless/RA-regulated nuclear matrix associated protein) in mammary carcinogenesis. Semiquantitative RT–PCR and northern blot analyses confirmed upregulation of DTL/RAMP in the majority of breast cancer cases and all of breast cancer cell lines examined. Immunocytochemical and western blot analyses using anti-DTL/RAMP polyclonal antibody revealed cell-cycle-dependent localization of endogenous DTL/RAMP protein in breast cancer cells; nuclear localization was observed in cells at interphase and the protein was concentrated at the contractile ring in cytokinesis process. The expression level of DTL/RAMP protein became highest at G1/S phases, whereas its phosphorylation level was enhanced during mitotic phase. Treatment of breast cancer cells, T47D and HBC4, with small-interfering RNAs against DTL/RAMP effectively suppressed its expression and caused accumulation of G2/M cells, resulting in growth inhibition of cancer cells. We further demonstrate the in vitro phosphorylation of DTL/RAMP through an interaction with the mitotic kinase, Aurora kinase-B (AURKB). Interestingly, depletion of AURKB expression with siRNA in breast cancer cells reduced the phosphorylation of DTL/RAMP and decreased the stability of DTL/RAMP protein. These findings imply important roles of DTL/RAMP in growth of breast cancer cells and suggest that DTL/RAMP might be a promising molecular target for treatment of breast cancer.Oncogene (2008) 27, 5672–5683; doi:10.1038/onc.2008.186; published online 9 June 2008 [ABSTRACT FROM AUTHOR]

The p53 protein inhibits malignant transformation through direct and indirect regulation of transcription of many genes related to cell cycle, apoptosis and cellular senescence. A number of genes induced by p53 have been well characterized, but biological significance of genes whose expression was suppressed by p53 is still largely undisclosed. To clarify the roles of p53-suppressive genes in carcinogenesis, we analysed two data sets of whole-genome expression profiles, one for cells in which wild-type p53 was exogenously introduced and the other for a large number of clinical cancer tissues. Here, we identified CDC20 that was frequently upregulated in many types of malignancies and remarkably suppressed by ectopic introduction of p53. CDC20 expression was suppressed by genotoxic stresses in p53- and p21-dependent manners through CDE-CHR elements in the CDC20 promoter. Furthermore, small interference RNA (siRNA)-mediated silencing of p53 induced CDC20 expression in normal human dermal fibroblast cells. As we expected, treatment of cancer cells with siRNA against CDC20 induced G2/M arrest and suppressed cell growth. Our results indicate that p53 inhibits tumor cell growth through the indirect regulation of CDC20 and that CDC20 might be a good potential therapeutic target for a broad spectrum of human cancer.Oncogene (2008) 27, 1562–1571; doi:10.1038/sj.onc.1210799; published online 17 September 2007 [ABSTRACT FROM AUTHOR]

In an attempt to disclose mechanisms of bladder carcinogenesis and discover novel target molecules for development of treatment, we applied a cDNA microarray to screen genes that were significantly transactivated in bladder cancer cells. Among the upregulated genes, we here focused on a novel gene, (DEPDC1) DEP domain containing 1, whose overexpression was confirmed by northern blot and immunohistochemical analyses. Immunocytochemical staining analysis detected strong staining of endogenous DEPDC1 protein in the nucleus of bladder cancer cells. Since DEPDC1 expression was hardly detectable in any of 24 normal human tissues we examined except the testis, we considered this gene-product to be a novel cancer/testis antigen. Suppression of DEPDC1 expression with small-interfering RNA significantly inhibited growth of bladder cancer cells. Taken together, these findings suggest that DEPDC1 might play an essential role in the growth of bladder cancer cells, and would be a promising molecular-target for novel therapeutic drugs or cancer peptide-vaccine to bladder cancers.Oncogene (2007) 26, 6448–6455; doi:10.1038/sj.onc.1210466; published online 23 April 2007 [ABSTRACT FROM AUTHOR]