Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in one copy of the hepatocyte nuclear factors (HNF) 1alpha and 1beta homeodomain containing transcription factors predispose the carrier to maturity-onset diabetes of the young (MODY) types 3 and 5, respectively. Moreover, previous identification of biallelic inactivation of HNF1alpha in hepatocellular adenoma identified its tumor suppressor function in hepatocarcinogenesis. The seminal observation of an ovarian carcinoma in a MODY5 patient who subsequently developed a chromophobe renal cell carcinoma, prompted us to screen for HNF1beta and HNF1alpha inactivation in a series of 20 ovarian and 35 renal neoplasms. Biallelic HNF1beta inactivation was found in two of 12 chromophobe renal carcinomas by association of a germline mutation and a somatic gene deletion. In these cases, the expression of PKHD1 (polycystic kidney and hepatic disease 1) and UMOD (Uromodulin), two genes regulated by HNF1beta, was turned off. Interestingly, in two of 13 clear cell renal carcinomas, we found a monoallelic germline mutation of HNF1alpha with no associated suppression of target mRNA expression. In normal and tumor renal tissues, we showed the existence of a network of transcription factors differentially regulated in tumor subtypes. We identified two related clusters of co-regulated genes associating HNF1beta, PKHD1 and UMOD in the first group and HNF1alpha, HNF4alpha, FABP1 and UGT2B7 in the second group. Finally, these results suggest that germline mutations of HNF1beta and HNF1alpha may predispose to renal tumors. Furthermore, we suggest that HNF1beta functions as a tumor suppressor gene in chromophobe renal cell carcinogenesis through a PKHD1 expression control.
Hum Mol Genet 2005 Mar 01
PMID:Germline hepatocyte nuclear factor 1alpha and 1beta mutations in renal cell carcinomas. 1564 45

Cancer can be defined as a deregulation or hyperactivity in the ongoing network of intracellular and extracellular signaling events. Reverse phase protein microarray technology may offer a new opportunity to measure and profile these signaling pathways, providing data on post-translational phosphorylation events not obtainable by gene microarray analysis. Treatment of ovarian epithelial carcinoma almost always takes place in a metastatic setting since unfortunately the disease is often not detected until later stages. Thus, in addition to elucidation of the molecular network within a tumor specimen, critical questions are to what extent do signaling changes occur upon metastasis and are there common pathway elements that arise in the metastatic microenvironment. For individualized combinatorial therapy, ideal therapeutic selection based on proteomic mapping of phosphorylation end points may require evaluation of the patient's metastatic tissue. Extending these findings to the bedside will require the development of optimized protocols and reference standards. We have developed a reference standard based on a mixture of phosphorylated peptides to begin to address this challenge.
Mol Cell Proteomics 2005 Apr
PMID:Use of reverse phase protein microarrays and reference standard development for molecular network analysis of metastatic ovarian carcinoma. 1567 Oct 44

The aim of the study was to investigate the relationships between the expression of alphav, beta1, beta3, beta5, and beta6, integrin subunits and clinical parameters in ovarian cancers. Ovarian surface epithelium (OSE) from five donors and tumour samples from 39 patients with an epithelial ovarian cancer (39 primary tumours and 21 associated peritoneal metastases) were analysed using immunohistochemistry on paraffin-embedded or frozen tissue sections. The alphav and beta5 integrin subunits were always present in normal OSE and in tumours. beta1 and beta3 subunit expression was significantly less frequent in grade 3 than in grade 1-2 tumours. The proportion of stage IV tumours expressing beta3 was significantly lower as compared to other stages. The beta6 subunit was undetectable in OSE but was expressed in about 40% of primary tumours. For all integrin, there was a strong relationship between the expression in primary tumours and in associated peritoneal metastases. Survival analyses restricted to patients receiving platinum-based chemotherapy did not reveal any relationship between integrin subunit expression and 3-year survival rate, in this limited series of patients. In conclusion, the expression of the various beta integrin subunits was differentially altered in ovarian carcinoma, evocative of complementary roles of alphav integrins during tumour development.
J Mol Histol 2005 Feb
PMID:Expression of alpha V-associated integrin beta subunits in epithelial ovarian cancer and its relation to prognosis in patients treated with platinum-based regimens. 1570 6

Our study focused on aromatase cytochrome P450 (CYP19) expression in ovarian epithelial normal and cancer cells and tissues. Aromatase mRNA expression was analyzed by real-time PCR in ovarian epithelial cancer cell lines, in human ovarian surface epithelial (HOSE) cell primary cultures, and in ovarian tissue specimens (n=94), including normal ovaries, ovarian cysts and cancers. Aromatase mRNA was found to be expressed in HOSE cells, in BG1, PEO4 and PEO14, but not in SKOV3 and NIH:OVCAR-3 ovarian cancer cell lines. Correlation analysis of aromatase expression was performed according to clinical, histological and biological parameters. Aromatase expression in ovarian tissue specimens was higher in normal ovaries and cysts than in cancers (P<0.0001). Using laser capture microdissection in normal postmenopausal ovaries, aromatase was found to be predominantly expressed in epithelial cells as compared to stromal component. Using immunohistochemistry (IHC), aromatase was also detected in the epithelium component. There was an inverse correlation between aromatase and ERalpha expression in ovarian tissues (P<0.001, r=-0.34). In the cancer group, no significant differences in aromatase expression were observed according to tumor histotype, grade, stage and survival. Aromatase activity was evaluated in ovarian epithelial cancer (OEC) cell lines by the tritiated water assay and the effects of third-generation aromatase inhibitors (AIs) on aromatase activity and growth were studied. Letrozole and exemestane were able to completely inhibit aromatase activity in BG1 and PEO14 cell lines. Interestingly, both AI showed an antiproliferative effect on the estrogen responsive BG1 cell line co-expressing aromatase and ERalpha. Aromatase expression was found in ovarian epithelial normal tissues and in some ovarian epithelial cancer cells and tissues. This finding raises the possibility that some tumors may respond to estrogen and provides a basis for ascertaining an antimitogenic effect of AI in a subgroup of ovarian epithelial cancers.
J Steroid Biochem Mol Biol 2005 Jan
PMID:Aromatase expression in ovarian epithelial cancers. 1574 28

Replicative bypass of many DNA adducts is dependent on the interaction of hREV1 with DNA polymerase zeta and potentially with members of the Y family of DNA polymerases. To examine the role of hREV1 in the development of cisplatin (DDP) resistance, a subline (2008-shREV1-3.3) of the ovarian carcinoma cell line 2008 was isolated in which stable expression of a short hairpin RNA suppressed hREV1 expression to 20% and reduced hREV1 protein level to 43% of that found in the parental cells. The 2008-shREV1-3.3 cells were 1.5-fold more sensitive to the cytotoxic effect of DDP but less sensitive to the mutagenic effect of DDP as evidenced by a 2.6- or 2.7-fold reduction in the ability to induce clones highly resistant to 6-thioguanine or DDP itself, respectively, in the surviving population. Reduction of hREV1 did not alter the initial rate of DDP adduct removal from DNA but did impair both spontaneous and DDP-induced extra-chromosomal homologous recombination, as measured by the recombination-sensitive reporter vector pBHRF. DDP induced an increase in hREV1 protein level. DDP resistance at the population level evolved 2.8-fold more slowly in the 2008-shREV1-3.3 cells than in the parental cells during repeated cycles of drug exposure. The results indicate that hREV1 functions to enhance both cell survival and the generation of drug-resistant variants in the surviving population. DDP up-regulates hREV1, suggesting that it may enhance its own mutagenicity. Most importantly, hREV1 controls the rate of emergence of resistance to DDP at the population level. Thus, hREV1 is an important contributor to DDP-induced genomic instability and the subsequent emergence of resistance.
Mol Pharmacol 2005 Jun
PMID:Suppression of hREV1 expression reduces the rate at which human ovarian carcinoma cells acquire resistance to cisplatin. 1575 47

A "multitarget multiribozyme" (MTMR) was constructed. It consists of three trans-acting hammerhead ribozymes directed against the transcripts of the ABC transporters MDR1/P-gp, BCRP, and MRP2; three cis-acting MDR1/P-gp-specific ribozymes; and three MDR1/P-gp-homologous spacer sequences. The trans-acting hammerhead ribozymes are liberated from the MTMR through autocatalytic self-cleavage by the cis-acting ribozymes. The MTMR was characterized with regard to its kinetic parameters. Comparison of the MTMR-specific kinetic values with those of the corresponding monoribozymes demonstrated that MTMR fragments could cleave their specific substrates without loss of efficiency. The MTMR was applied to three cell models, each overexpressing another ABC transporter, i.e., the gastric carcinoma cell line EPG85-257RDB expresses MDR1/P-gp, the cell variant EPG85-257RNOV synthesizes BCRP, and the ovarian carcinoma line A2780RCIS produces MRP2. In all cellular systems, the MTMR could specifically decrease the expression of the respective ABC transporter at the mRNA level (97% decrease in the MDR1/P-gp mRNA, 80% decrease in the BCRP mRNA, 96% decrease in the MRP2 mRNA) and the protein level. Resistance against the selection drug was reversed completely (100% in EPG85-257RDB) or by 94 (EPG85-257RNOV) or 63% (A2780RCIS). Thus, the MTMR technology provides a novel tool for gene therapeutic applications to reverse different ABC-transporter-dependent drug-resistant phenotypes.
Mol Ther 2005 Apr
PMID:Reversal of different drug-resistant phenotypes by an autocatalytic multitarget multiribozyme directed against the transcripts of the ABC transporters MDR1/P-gp, MRP2, and BCRP. 1577 54

The effects of the separate and combined application of hypoxia and antisense oligonucleotides (ASO) against hypoxia inducible factor 1alpha (HIF1A) on cancer cells were examined. Experiments were carried out on human ovarian carcinoma cells in four series: (1) control [Normoxia (5% CO2 in air), no treatment], (2) hypoxia (1% O2, 5% CO2, and 94% N2 for 48 h), (3) treatment with ASO targeted to HIF1A (48 h), and (4) combined action of hypoxia and ASO. After treatment, the following processes and factors were monitored: apoptosis, cellular metabolism and viability, expression of genes encoding HIF1A, von Hippel-Lindau tumor suppressor protein (VHL), and genes responsible for cell death induction and antiapoptotic defense (P53, BCL2, BAX, and caspases 9 and 3). Expression of caspase 9 and HIF1A protein was confirmed by Western blotting. Liposomes were used as a delivery system of HIF1A ASO. It was found that hypoxia alone significantly disturbed cellular metabolism, reducing the level of respiration by 50% when compared with control. Hypoxia induced apoptosis by upregulating the P53-, BAX-, and caspase-dependent cell death pathways, while activating cellular antiapoptotic defense by the overexpression of BCL2 protein. Both opposing effects were dependent on the overexpression of hypoxia inducible factor. We conclude that hypoxia induces a bimodal effect, simultaneously promoting cell death and activating cellular resistance. The downregulation of HIF1A promoted cell death induction and prevented activation of cellular defense by hypoxia. This suggests that HIF1A is a potential candidate for anticancer therapeutic targeting.
Mol Pharm
PMID:Bimodal effect of hypoxia in cancer: role of hypoxia inducible factor in apoptosis. 1583 12

Elemene is a natural antitumor plant drug. However, the effect of elemene on cell growth in ovarian cancer is unknown. In this study, we show that beta-elemene inhibited the proliferation of cisplatin-resistant human ovarian cancer cells and their parental cells, but had only a marginal effect in human ovary cells, indicating differential inhibitory effects on cell growth between ovarian cancer cells and normal ovary cells. We also demonstrated for the first time that beta-elemene markedly enhanced cisplatin-induced growth inhibition in resistant cells compared to sensitive cells. In addition, cell cycle analysis revealed a synergistic effect of beta-elemene and cisplatin on the induction of cell cycle G2-M arrest in our resistant ovarian carcinoma cells. Furthermore, we showed that treatment of these cells with both drugs downregulated cyclin B1 and Cdc2 expression, but elevated the levels of p53, p21waf1/cip1, p27kip1 and Gadd45. Finally, the combination of beta-elemene and cisplatin was found to increase the phosphorylation of Cdc2 and Cdc25C, which leads to a reduction in Cdc2-cyclin B1 activity. These novel findings suggest that beta-elemene sensitizes chemoresistant ovarian carcinoma cells to cisplatin-induced growth suppression partly through modulating the cell cycle G2 checkpoint and inducing cell cycle G2-M arrest, which lead to blockade of cell cycle progression.
Cell Mol Life Sci 2005 Apr
PMID:Antiproliferative effect of beta-elemene in chemoresistant ovarian carcinoma cells is mediated through arrest of the cell cycle at the G2-M phase. 1586 12

Vascular endothelial growth factor (VEGF) performs as an angiogenic and permeability factor in ovarian cancer, and its overexpression has been associated with poor prognosis. However, models to study its role as a marker of tumor progression are lacking. We generated xenograft variants derived from the A2780 human ovarian carcinoma (1A9), stably transfected with VEGF(121) in sense (1A9-VS-1) and antisense orientation (1A9-VAS-3). 1A9, 1A9-VS-1, and 1A9-VAS-3 disseminated in the peritoneal cavity of nude mice, but only 1A9-VS-1, the VEGF(121)-overexpressing tumor variant, produced ascites. Tumor biopsies from 1A9-VS-1 showed alterations in the vascular pattern and caused an angiogenic response in the chorioallantoic membrane assay. A significant level of soluble VEGF was detectable in the plasma of mice bearing 1A9-VS-1 even at an early stage of tumor growth. Plasma VEGF correlated positively with tumor burden in the peritoneal cavity and ascites accumulation. Cisplatin reduced the tumor burden and ascites in mice bearing 1A9-VS-1; the response was associated with a significant decrease of VEGF in plasma. This 1A9-VS-1 xenograft model reproduces the behavior of human ovarian cancer by growing in the peritoneal cavity, being highly malignant, and producing ascites. Plasma VEGF as a marker of tumor progression offers a valuable means of detecting early tumor response and following up treatments in an animal model.
Mol Cancer Ther 2005 May
PMID:Circulating plasma vascular endothelial growth factor in mice bearing human ovarian carcinoma xenograft correlates with tumor progression and response to therapy. 1589 35

During the last two decades, novel nonclonogenic methods for pretherapeutic chemosensitivity testing have been developed that are likely to overcome major technical limitations of older assays such as low evaluability rates, low degree of standardization and reproducibility, lack of technical robustness, and poor methodological efficacy. Among these, the microplate adenosine triphosphate (ATP)-based tumor chemosensitivity assay (ATP-TCA) has gained particular merits for ex vivo chemosensitivity testing of native nonhematological tumors including cancers of the breast, ovary, gastrointestinal tract, cervix and corpus uteri, and lung; malignant melanomas; gliomas; sarcomas; and mesotheliomas. For this indication, the ATP-TCA can now be considered the best documented and validated technology. This assay, which is now commercially available, provides a highly reproducible, easy-to-handle kit technique; low technical failure rates; and a high methodological efficacy requiring only 1 x 106 tumor cells to test four to six different drugs or combinations. In ovarian and breast carcinomas, the predictive accuracy is > 90%, with a positive predictive value of 85-90% and a negative predictive value near 100%, respectively. In primary ovarian cancers, the ATP-TCA has been found to accurately predict both clinical response and survival. In two prospective clinical trials in patients with heavily pretreated ovarian cancer, chemotherapy individually selected by the ATP-TCA has been found to triple the response rates and nearly double the survival compared to empirically chosen regimens. Consequently, this assay, which is now under phase III evaluation, has successfully been used in new agent development to screen for novel chemotherapy regimens for the treatment of patients with breast and ovarian carcinoma and melanoma, respectively. This chapter highlights the recent preclinical and clinical experience with this promising technology and gives a detailed description of all the technical aspects of the ATP-TCA.
Methods Mol Med 2005
PMID:Chemosensitivity testing using microplate adenosine triphosphate-based luminescence measurements. 1590 31


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