Expression of vascular endothelial growth factor in salivary gland carcinomas and its relation to p53, Ki-67 and prognosis.

BACKGROUND: Vascular endothelial growth factor (VEGF) has been demonstrated to play an important role in tumor angiogenesis and to influence prognosis in many cancers. But, its significance in salivary gland carcinomas has not been elucidated. The authors investigated the association between VEGF expression and clinicopathological factors, p53, and Ki-67 to verify its validity as a prognostic factor. METHODS: Surgical specimens from 45 patients with salivary gland carcinoma were examined for VEGF, p53, and Ki-67 expression by immunohistochemical staining. The results were compared with the clinicopathological factors and the relationships were correlated. RESULTS: VEGF expression was low in 14 cases, moderate in 15 cases, and high in 16 cases. It was significantly correlated with a variety of clinicopathological factors such as TNM stage, perineural and vascular invasion, and recurrence. VEGF showed significant association with the expression of p53 but not with that of Ki-67. Univariate analysis showed that age, gender, lymph node metastasis, vascular invasion, p53, Ki-67, and VEGF expression correlate with prognosis. Multivariate analysis demonstrated that VEGF is an independent prognostic factor for patients with salivary gland carcinomas. CONCLUSIONS: The results of this study suggest that VEGF expression is correlated with p53 expression and that it may have prognostic value in salivary gland carcinomas.

An in vitro bioassay for xenobiotics using the SXR-driven human CYP3A4/lacZ reporter gene.

The dose and time effect of nine xenobiotics, including 17beta-estradiol, corticosterone, dexamethasone, progesterone, nifedipine, bisphenol A, rifampicin, methamphetamine, and nicotine were investigated, in vitro, using human steroid and xenobiotics receptor (SXR)-binding sites on the human CYP3A4 promoter, which can enhance the linked lacZ reporter gene transcription. To test this, liver-specific SAP (human serum amyloid P component)-SXR (SAP/SXR) and human CYP3A4 promoter-regulated lacZ (hCYP3A4/lacZ) constructs were transiently transfected into HepG2 and NIH3T3 cells to compare the xenobiotic responsiveness between human and nonhuman cell lines. In the HepG2 cells, rifampicin, followed by corticosterone, nicotine, methamphetamine, and dexamethasone, exhibited enhanced levels of the lacZ transcript, whereas those of bisphenol A and nifedipine were found to be reduced. No significant responses were observed with 17beta-estradiol or progesterone. In addition, 17beta-estradiol and progesterone did not change the levels of the lacZ transcripts in the HepG2 cells, but did induce significant increases in the transcripts of the NIH3T3 cells. Treatment with corticosterone and dexamethasone, which were highly expressed in the HepG2 cells, did not affect the levels of the lacZ transcript in NIH3T3 cells. These results show that lacZ transcripts can be measured, rapidly and reproducibly, using reverse transcriptase-polymerase chain reaction (RT-PCR) based on the expression of the hCYP3A4/lacZ reporter gene, and was mediated by the SXR. Thus, this in vitro reporter gene bioassay is useful for measuring xenobiotic activities, and is a means to a better relevant bioassay, using human cells, human genes and human promoters, in order to get a closer look at actual human exposure.

Alterations in behavior, amyloid beta-42, caspase-3, and Cox-2 in mutant PS2 transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) occurs when neurons in the memory and cognition regions of the brain are accompanied by an accumulation of the long amyloid beta-proteins of the 39 to 43 amino acids derived from the amyloid precursor protein (APP) by cleavage with beta- and gamma-secretase. An increased production of Abeta-42 by mutation of PS2 genes promotes caspase expression and is associated with the Cox-2 found in the brain of AD patients. To address this question in vivo, we expressed the human mutant PS2 (hPS2m) (N141I) as well as wild PS2 (hPS2w) as a control in transgenic (Tg) mice under control of the neuron-specific enolase (NSE) promoter. Water maze tests were used to demonstrate the behavioral defect; dot blot, Western blot, and immunohistochemical analyses were performed on the brain with the hPS2, Abeta-42, caspase-3, and Cox-2 antibody. We concluded that 1) Tg mice showed a behavioral dysfunction in the water maze test, 2) levels of hPS2, Abeta-42, caspase-3, and Cox-2 expression were modulated in the brains of both Tg mice, 3) dense staining with antibody to hPS2, Abeta-42, caspase-3, and Cox-2 was visible in the brains of Tg mice compared with age-matched control mice, and 4) distinguishable AD phenotypes between hPS2w- and hPS2m-Tg mice did not appear. These results suggest that an elevation of Abeta-42 by overexpression of hPS2 and mutation of hPS2m might induce the behavioral deficit and caspase-3 and Cox-2 induction, which could be useful in the therapeutic testing of compounds to have considerable clinical effects.