In the present study, we have investigated the effect of (i) ET-1 (endothelin-1) and its precursor, big ET-1, on MMP (matrix metalloproteinase)-2 and MMP-9 synthesis and activity in osteosarcoma tissue, and (ii) ET-1 receptor antagonists on cell invasion. Using Western blotting, zymography, RT-PCR (reverse transcription-PCR), immunohistochemistry, immunofluorescence and Northern blotting, we have shown that ET-1 and ET-1 receptors (ET(A) and ET(B)) were expressed in these cells. Additionally, we have demonstrated that ET-1 markedly induced the synthesis and activity of MMP-2, which was significantly increased when compared with MMP-9. Furthermore, inhibition of NF-kappaB (nuclear factor kappaB) activation blocked MMP-2 production and activity, indicating the involvement of NF-kappaB, a ubiquitous transcription factor playing a central role in the differentiation, proliferation and malignant transformation. Since ET-1 acts as an autocrine mediator through gelatinase induction and because inhibition of ET(A) receptor is beneficial for reducing both basal and ET-1-induced osteosarcoma cell invasion, targeting this receptor could be an attractive therapeutic alternative for the successful treatment of osteosarcoma.
Molecular profiling is a powerful approach to identify potential clinical markers for diagnosis and prognosis as well as providing a better understanding of the biology of epithelial ovarian cancer. On the basis of the analysis of HuFL expression data, we have previously identified genes that distinguish low malignant potential and invasive serous epithelial ovarian tumors. In this study, we used immunohistochemistry to monitor a subset of differently expressed candidates (Ahr, Paep, Madh3, Ran, Met, Mek1, Ccne1, Ccd20, Cks1 and Cas). A tissue array composed of 244 serous tumors of different grades (0–3) and stages (I–IV) was used in this analysis. All markers assayed presented differential protein expression between serous tumors of low and high grade. Significant differences in Ccne1 and Ran expression were observed in a comparison of low malignant potential and grade 1 tumor samples (p < 0.01). In addition, irrespective of the grade, Ccne1, Ran, Cdc20 and Cks1 showed significant differences of expression in association with the clinical stage of disease. While high level of Ccne1 have previously been associated with poor outcomes, here we found that high level of either Ran or Cdc20 appear to be more tightly associated with a poor prognosis (p < 0.001, 0.03, respectively). The application of these biomarkers in both the initial diagnosis and prognostic attributes of patients with epithelial ovarian tumors should prove to be useful in patient management. © 2006 Wiley‐Liss, Inc.
With low cure rates but increasing diverse treatment options that provide variable remission times, ovarian cancer is increasingly being recognized as a chronic disease. This reality indicates the need for a better understanding of factors influencing disease progression. In a previous global analysis of gene expression, we identified genes differentially expressed when comparing serous epithelial ovarian tumors of low and high malignant potential (grade 0 vs grade 3). In this analysis, 4 out of 5 members of the SET complex, SET, APE1, NM23 and HMGB2, were highly expressed in invasive grade 3 tumors. To further investigate the expression of these genes and the fifth member of the SET complex (pp32), we performed immunohistochemistry, on a tissue array composed of 235 serous tumors of different grades and disease stages. A significant correlation between expression of all SET complex proteins and the tumor differentiation was observed (p < 0.05). When combining all tumors, overexpression of Nm23 (p = 0.04), Set (p = 0.004) and Ape1 (p = 0.004) was associated with the clinical stage of the disease. No marker by itself was associated with prognosis. The combination of a high level of Nm23 in the context of a low level of Set compared to all other combinations of these markers did confer a better prognosis (p = 0.03). When combined, high expression of Hmgb2 and low expression of Ape1 was also associated with patient prognosis (p = 0.05). These findings suggest that a strategy that sums the activities of different partners within a pathway may be more appropriate in designing nomograms for patient stratification. © 2006 Wiley‐Liss, Inc.
Protein‐imprinted soft‐gel composite microspheres with magnetic susceptibility (MS‐PIGMs) were prepared by inverse suspension polymerization using Fe3O4 particles as magnetically susceptible component and bovine serum albumin and lysozyme (Lyz) as templates, respectively. The average content of magnetically susceptible component (Fe3O4) inside MS‐PIGMs was determined using thermogravimetric analyzer, and the magnetic characteristics of MS‐PIGMs were measured by vibrating sample magnetometer. The results showed that the resulting MS‐PIGMs had a certain magnetic response to external magnetic fields, and their average content of Fe3O4 was 2.08%. Their recognition specificity was investigated using BSA and Lyz as both templates and control molecules and characterized by high‐performance liquid chromatography, and the mechanism of imprinting and recognition was analyzed. It was shown that the resulting BSA imprinted soft‐gel composite microspheres with magnetic susceptibility (BSA‐PIGMs) and Lyz imprinted soft‐gel composite microspheres with magnetic susceptibility (Lyz‐PIGMs). All exhibited good recognition selectivity for their templates, and the relative separation factor (β) was 4.75 and 5.88, respectively. The recognition selectivity of MS‐PIGMs to their templates depended mainly on the synergic action of a large quantity of hydrogen binding being caused by complementation and very close contact of outer surface of proteins with inner surface of “imprinting cavities.” © 2005 Wiley Periodicals, Inc. J Appl Polym Sci, 2006
Vangl2 forms part of the planar cell polarity signalling pathway and is the gene defective in the Looptail (Lp) mouse mutant. Two previously described alleles, Lp and Lpm1Jus, segregate in a semi-dominant fashion, with heterozygotes displaying the looped-tail appearance, while homozygotes show the neural tube defect called craniorachischisis. Here, we report a novel experimentally-induced allele, Lpm2Jus, that carries a missense mutation, R259L, in Vangl2. This mutation was specific to the Lp phenotype and absent from both parental strains and 28 other inbred strains. Notably, this mutation segregates in a recessive manner with all heterozygotes appearing normal and 47% of homozygotes showing a looped-tail. Homozygous Lpm2Jus embryos showed spina bifida in 12%. Lpm2Jus genetically interacts with Lp with 77% of compound heterozygotes displaying craniorachischisis. Vangl2R259L behaved like the wild-type allele in overexpression and morpholino knockdown/rescue assays in zebrafish embryos. These data suggest that Lpm2Jus represents a new hypomorphic allele of Lp.
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