No abstract

In order to identify genes involved in head and neck carcinogenesis, we compared the gene expression pro®le in matched primary normal epithelial cells and primary head and neck cancer cells from the same patients. A cDNA microarray analysis consisting of 12 530 human genes revealed signi®cant changes in the expression of 213 genes, with 91 genes being up-regulated and 122 being down-regulated. This comprehensive list of genes includes those associated with signal transduction (growth factors), cell structure, cell cycle, transcription, apoptosis, and cell ± cell adhesion. Further analysis of nine genes involved in cell ± cell interaction, using Western blot and/or reverse transcription (RT) ± PCR of four paired cell lines supported the reliability of our microarray analysis. More speci®cally, our study provides the ®rst evidence that claudin-7 and connexin 31.1 are down-regulated in head and neck squamous cell carcinomas (HNSCC) compared to normal cells. These ®ndings provide a large body of information regarding gene expression pro®les associated with head and neck carcinogenesis, and also represent a source of potential targets for HNSCC prevention and/or therapeutics.

1 Adrenoreceptor agonists induce a hypertrophic phenotype in vitro and in vivo. To investigate the molecular remodeling in chronic cardiac hypertrophy we infused adult male mice with vehicle, isoproterenol, phenylephrine or both agonists for 3, 7 or 14 days. 2 All drugs increased cardiac mass. After minipump removal cardiac mass regressed to control levels within 7 days after PE and ISO treatment whereas ISO+PE treated hearts were incompletely regressed. 3 ANF and b-MHC, but not a-MHC, expression were increased by agonists at all time points. GATA-4, Nkx-2.5, Egr-1, c-jun and c-fos expression were increased after 3, 7 and 14 days of treatment. Expression was greatest after ISO+PE44ISO4PE4vehicle infusion suggesting a synergistic eect of adrenoreceptor stimulation and indicating a greater eect of b-than a-adrenergic action in vivo. 4 After PE or ISO drug withdrawal the HW/BW was normal and Egr-1, c-jun, c-fos and GATA-4, but not Nkx2.5, expression dropped to control levels. HW/BW regression was incomplete after ISO+PE and elevated levels of Egr-1, c-jun and Nkx2.5 expression remained. 5 A hydralazine-mediated reduction in blood pressure had no eect on the agonist-induced cardiac hypertrophy or gene expression. 6 In conclusion, we found that continued agonist stimulation, and not blood pressure, is responsible for the maintained increase in gene expression. Further, we found the decrease in gene expression in the regression after drug withdrawal was gene speci®c.

Head and neck squamous cell carcinomas (HNSCC) are characterized by a marked propensity for local invasion and spread to cervical lymph nodes, with distant metastases developing in 30-40% of cases. HPV-16 is an important risk factor for HNSCC. How HPV enhances susceptibility to HNSCC is not fully understood, but seems to involve cofactors. In this study, we examined the effect of the cooperation between HPV-16 and the tyrosine kinase receptor ErbB-2 on E-cadherin/catenin complex patterns and neoplastic transformation of human normal oral epithelial (NOE) cells. We report that overexpression of ErbB-2 or E6/E7 alone does not affect E-cadherin/catenin complex patterns nor does it induce cell transformation of NOE cells. In contrast, coexpression of E6/E7 and ErbB-2 downregulates E-cadherin and catenin expression. This is accompanied by cytoplasmic localization of E-cadherin, as well as nuclear translocation of a, b, and c-catenins. Furthermore, we demonstrate that E6/E7 cooperate with overexpressed ErbB-2 to induce tumor formation in nude mice and to upregulate cyclin D1 and c-myc expression. Our data suggest that E6/E7 cooperate with ErbB-2 in head and neck carcinogenesis, at least in part, via the conversion of b-catenin from a cell adhesion to a nuclear function, that is, to act as a potential transcriptional regulator. This conversion leads to the upregulation of cyclin D1, c-myc and other oncoproteins necessary for alteration of the E-cadherin/catenin complex and cell transformation of NOE cells.

Background: Germline mutations of the SDHD, SDHB and SDHC genes, encoding three of the four subunits of succinate dehydrogenase, are a major cause of hereditary paraganglioma and pheochromocytoma, and demonstrate that these genes are classic tumor suppressors. Succinate dehydrogenase is a heterotetrameric protein complex and a component of both the Krebs cycle and the mitochondrial respiratory chain (succinate:ubiquinone oxidoreductase or complex II).