Spotlight on Differentially Expressed Genes in Urinary Bladder Cancer

INTRODUCTION: We previously identified common differentially expressed (DE) genes in bladder cancer (BC). In the present study we analyzed in depth, the expression of several groups of these DE genes. MATERIALS AND METHODS: Samples from 30 human BCs and their adjacent normal tissues were analyzed by whole genome cDNA microarrays, qRT-PCR and Western blotting. Our attention was focused on cell-cycle control and DNA damage repair genes, genes related to apoptosis, signal transduction, angiogenesis, as well as cellular proliferation, invasion and metastasis. Four publicly available GEO Datasets were further analyzed, and the expression data of the genes of interest (GOIs) were compared to those of the present study. The relationship among the GOI was also investigated. GO and KEGG molecular pathway analysis was performed to identify possible enrichment of genes with specific biological themes. RESULTS: Unsupervised cluster analysis of DNA microarray data revealed a clear distinction in BC vs. control samples and low vs. high grade tumors. Genes with at least 2-fold differential expression in BC vs. controls, as well as in non-muscle invasive vs. muscle invasive tumors and in low vs. high grade tumors, were identified and ranked. Specific attention was paid to the changes in osteopontin (OPN, SPP1) expression, due to its multiple biological functions. Similarly, genes exhibiting equal or low expression in BC vs. the controls were scored. Significant pair-wise correlations in gene expression were scored. GO analysis revealed the multi-facet character of the GOIs, since they participate in a variety of mechanisms, including cell proliferation, cell death, metabolism, cell shape, and cytoskeletal re-organization. KEGG analysis revealed that the most significant pathway was that of Bladder Cancer (p = 1.5×10(-31)). CONCLUSIONS: The present work adds to the current knowledge on molecular signature identification of BC. Such works should progress in order to gain more insight into disease molecular mechanisms

The UL144 gene product of human cytomegalovirus activates NFκB via a TRAF6-dependent mechanism

Molecular mimicry of cytokines and cytokine receptors is a strategy used by poxviruses and herpesviruses to modulate host immunity. The human cytomegalovirus (HCMV) UL144 gene, situated in the UL/b′ region of the viral genome, has amino-acid sequence similarity to members of the tumour necrosis factor receptor superfamily. We report that UL144 is a potent activator of NFκB-induced transcription in a TRAF6-dependent manner. This NFκB activation enhances expression of the chemokine CCL22 through the NFκB responsive elements found in its promoter. In contrast to the clinical HCMV isolates, extensively passaged laboratory strains lack the UL/b′ region and hence do not encode UL144. Consistent with this, infection with viruses that carry UL/b′ causes NFκB activation and CCL22 expression, a phenotype that is not observed after infections with strains lacking the UL/b′ region. Moreover, knockdown of UL144, TRAF6 or NFκB by specific siRNA in infections with UL144-encoding HCMV prevents the activation of CCL22 expression normally observed after infection with UL/b′ positive HCMV. Upregulation of CCL22, which attracts Th2 and regulatory T cells, may help HCMV evade immune surveillance