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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is estimated that 15% of all cancers are etiologically linked to viral infection. Specific cancers including adult T-cell leukemia, hepatocellular carcinoma, and uterine cervical cancer are associated with infection by human T-cell leukemia virus type I, hepatitis B virus, and high-risk human papilloma virus, respectively. In these cancers, genomic instability, a hallmark of multistep cancers, has been explicitly linked to the expression of oncoproteins encoded by these viruses. This review discusses mechanisms utilized by these viral oncoproteins, Tax, HBx, and E6/E7, to mediate genomic instability and cellular transformation.
Environ Mol Mutagen
PMID:Impact of transforming viruses on cellular mutagenesis, genome stability, and cellular transformation. 1564 40

This study examined the relationship between oxidative stress and enzymic antioxidant status in the erythrocytes of thirty-two adult cervical cancer patients and an equal number of age-matched cervicitis patients and healthy subjects. Lipid peroxidation was significantly increased, while the activities of enzymic antioxidants (superoxide dismutase, catalase, glutathione peroxidase) and glucose-6-phosphate dehydrogenase were decreased in the erythrocytes of cervical cancer patients as compared to healthy subjects and cervicitis patients. Thus, this study has demonstrated elevated lipid peroxidation and impaired enzymic antioxidant activities in the erythrocytes of cervical cancer patients.
Cell Mol Biol Lett 2004
PMID:Enhanced lipid peroxidation and impaired enzymic antioxidant activities in the erythrocytes of patients with cervical carcinoma. 1564 92

Cellular senescence can be triggered by a variety of signals, including loss of telomeric integrity or intense oncogenic signaling, and is considered a potent, natural tumor suppressor mechanism. Previously, it was shown that the promyelocytic leukemia protein (PML) induces cellular senescence when overexpressed in primary human fibroblasts. The mechanism by which the PML IV isoform elicits this irreversible growth arrest is believed to involve activation of the tumor suppressor pathways p21/p53 and p16/Rb; however, a requirement for either pathway has not been demonstrated unequivocally. To investigate the individual contributions of p53 and Rb to PML-induced senescence, we used oncoproteins E6 and E7 from human papillomaviruses (HPVs), which predominantly target p53 and Rb. We show that E7, but not E6, circumvents PML-induced senescence. Using different E7 mutant proteins, dominant negative cyclin-dependent kinase 4, and p16 RNA interference, we demonstrate that Rb-related and Rb-independent mechanisms of E7 are necessary for subversion of PML-induced senescence and we identify PML as a novel target for E7. Interaction between E7 and a functional prosenescence complex composed of PML, p53, and CBP perturbs transcriptional activation of p53, thus highlighting a significant effect also on the p53 tumor suppressor pathway. Given the importance of HPV in the pathogenesis of cervical cancer, our results warrant a more detailed analyses of PML in HPV infections.
Mol Cell Biol 2005 Feb
PMID:Human papillomavirus oncoprotein E7 targets the promyelocytic leukemia protein and circumvents cellular senescence via the Rb and p53 tumor suppressor pathways. 3310 71

The isolation of fully human monoclonal antibodies (MAb) against tumor targets has to date relied largely on combinatorial library-based antibody display techniques, which generally require lengthy antigen selection procedures due to a low frequency of clones expressing compatible heavy (VH) and light chain (VL) variable genes. Here we describe a method to directly isolate immunoglobulin sequences in situ from antibody-producing cells infiltrating human tumor tissue. Single B cells and plasma cells infiltrating cervical cancer were microdissected from tissue sections using laser-assisted microscopy, and VH and VL expressed by each individual cell amplified using nested reverse transcriptase- polymerase chain reaction (RT-PCR), thus retaining the native VH and VL pairing. Sequencing analysis determined that the isolated cells expressed functional immunoglobulin variable genes, consistent with an antitumor antibody response. The immunoglobulin sequences can be reassembled as Fab or scFv fragments using conventional recombinant antibody expression plasmids. This method will allow a more direct assessment of the humoral immune response to cancer, and the potential identification of novel human therapeutic cancer antibodies.
Mol Biotechnol 2005 Feb
PMID:In situ isolation of immunoglobulin sequences expressed by single tumor-infiltrating B cells using laser-assisted microdissection. 1569 67

The aim of this study was to characterize the immune system profile in the uterine cervix of 17 human papillomavirus (HPV)-infected women, compared with 17 whom were coinfected with HIV-1. Five histologically normal cervices in immunocompetent women were used as controls. HPV infection was associated with a marked increase in cells expressing interleukin (IL)-6, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha). Coinfection by HPV and HIV-1 led to decreased expression of IL-6, TNF-alpha, and IFN-gamma. However, coinfection led to increased numbers of cells expressing IL-4, IL-10, and IL-8. Compared with the histologically normal cervices, increased numbers of macrophages (CD68, RFD7) and T lymphocytes (CD4, CD8) were seen in HPV-infected cervices; coinfection with HIV-1 was associated with a higher number of CD8 cells and lower number of CD68 cells. HPV DNA localized exclusively to the dysplastic squamous cells, whereas HIV-1 RNA was detected mainly in CD68-positive stromal cells. In conclusion, this study shows differential expression of various cytokines and classes of inflammatory cells, relative to HIV-1 infection and HPV coinfection, which may relate to the risk of transmission of HIV-1 and increased risk of cervical cancer in these women.
Diagn Mol Pathol 2005 Mar
PMID:Distribution of immune cell subsets and cytokine-producing cells in the uterine cervix of human papillomavirus (HPV)-infected women: influence of HIV-1 coinfection. 1571 63

Mucin1 (MUC1) promoter has been cloned from the 5' flanking region of the MUC1 gene in breast carcinoma, functionally characterized and applied in gene therapy of breast and esophageal carcinoma. In the present study, we amplified a 786 base pair (bp) MUC1 promoter by two-step nest PCR, and identified the activity and tumor-specificity using an enhanced green fluorescent protein (EGFP) gene as a reporter gene by fluorescence microscopy and flow cytometry analysis in Panc-1, primary normal pancreatic (PNPC), and cervical cancer HeLa cell lines. Subsequently, the human somatostatin receptor subtype 2 (hSSTR2) gene driven by MUC1 promoter was cloned into the pAdTrack to produce recombinant adenovirus AdMUC1-hSSTR2. The anticancer effect of AdMUC1-hSSTR2 was determined in Panc-1. The results demonstrated that there was no AdMUC1-hSSTR2-induced apoptosis, but a significant cell proliferation inhibition even without somatostatin (SST) analogue Octreotide, involved in the up-regulation of the cyclin-dependent kinase (CDK) inhibitors p21 and p27. Moreover, the anticancer effect could not be augmented by the addition of Octreotide, revealing a mechanism that was independent from induction of Octreotide. Therefore, this adenovirus system can be used as a novel, potent and specific tool for gene-targeting therapy in the MUC1 positive pancreatic carcinoma as shown in Panc-1.
Int J Mol Med 2005 Apr
PMID:Amplification and functional characterization of MUC1 promoter and gene-virotherapy via a targeting adenoviral vector expressing hSSTR2 gene in MUC1-positive Panc-1 pancreatic cancer cells in vitro. 1575 23

We purified phytoestrogens from Pueraria root (Pueraria mirifica from Thailand and Pueraria lobata from Korea), which is used as a rejuvenating folk medicine in Thailand and China. Dried, powdered plant material was extracted with 100% ethanol and further separated by concentration, filtration, and thin layer silica gel chromatography. Using the fractions obtained during separation, we first investigated their cytotoxicity in several cancer cell lines from various tissues. The ethanol-extracted components (PE1, PE4) had significant antiproliferative effects on breast cancer cell lines, including MCF-7, ZR-75-1, MDA-MB-231, SK-BR-3, and Hs578T. Second, we compared these results with the cytotoxic effects of known flavonoids, sterols, and coumarins from Pueraria root. The known compounds were not as effective, and occurred in a different polarity region on HPLC. Third, further separation resulted in the isolation of eight different components (Sub PE-A to -H). One of these, PE-D, affected the growth of some breast cancer cell lines (MCF-7, MDA- MB-231) in a dose- and time-dependent manner, as well as the growth of ovarian (2774) and cervical cancer cells (HeLa). Finally, a transfection assay showed that this component had an estrogenic effect similar to 17beta - estradiol, which activates both estrogen receptor alpha (ERalpha) and ERbeta. The NMR analysis determined that spinasterol (stigmasta-7, 22-dien-3beta-ol) is an active cytotoxic component of Pueraria root.
Exp Mol Med 2005 Apr 30
PMID:Antitumor activity of spinasterol isolated from Pueraria roots. 1588 24

Among tumor sites, cervical cancer offers an ideal model for investigating differences in gene expression associated with transitions from normal to precancer and invasion to cancer. To evaluate the validity of assessing gene expression in cervical tissues acquired in a clinical setting, we investigated whether standard procedures, namely the application of acetic acid and/or Lugol's iodine, employed for the visualization of colposcopically directed biopsies, altered patterns in oligonucleotide (oligo) arrays. We compared microarray profiles from six women, each with three adjacent tissue samples removed from benign hysterectomy specimens and treated as follows: immediately frozen, acetic acid application only, acetic acid, and Lugol's iodine. Of the 22,464 original spots on the microarray, 4,850 spots were expressed at detectable levels for further evaluation upon data normalization and filtration. For each spot, the difference between topical applications was computed, and P values were calculated using a bivariate T2 test. Upon adjustment for multiple comparisons using both the Holm's and Hochberg's procedures as well as the False Discovery Rate (Benjamini-Hochberg and Benjamini-Yeuketili [BY]), we failed to identify genes differentially expressed and conclude that standard precolposcopic procedures do not substantially affect the overall gene expression patterns in the normal cervix.
Diagn Mol Pathol 2005 Jun
PMID:Towards improved biomarker studies of cervical neoplasia: effects of precolposcopic procedures on gene expression patterns. 1590 87

Constant expression of E6 and E7 mRNA by high-risk human papillomaviruses (HPV) abrogates p53 and retinoblastoma protein function, respectively, and is essential for the development of cervical cancer. Despite E6, some chemotherapy drugs can stabilize p53 in cervical cancer cells. It is not known how chemotherapy-induced p53 activation and cytotoxicity are affected when the amount of E6 mRNA is decreased before the drug treatment. In this study, HPV18-positive HeLa cervical cancer cells were transfected with short interfering RNA (siRNA) molecules targeting HPV18 E6 mRNA before treatment with carboplatin, cisplatin, doxorubicin, etoposide, gemcitabine, mitomycin, mitoxantrone, oxaliplatin, paclitaxel, and topotecan. Transfection with siRNA was followed by nuclear accumulation of p53, but the effect was transient despite continuously suppressed HPV mRNA levels. When treatment with E6 siRNA was coupled with chemotherapy, the p53 activity after treatment with carboplatin and paclitaxel was additively increased, whereas the p53 activation induced by the rest of the drugs was synergistically increased. Treatment with E6 siRNA alone moderately inhibited HeLa cell proliferation but did not induce detectable apoptosis. The combined cytotoxic effect of E6 siRNA and chemotherapy ranged from subadditive to synergistic, depending on the drug. The decrease of E6 mRNA sensitized HeLa cells, for example, to doxorubicin and gemcitabine but counteracted the cytotoxicity of cisplatin and etoposide. In conclusion, activating p53 by degrading E6 mRNA may either increase or decrease the chemosensitivity of cervical cancer cells, depending on the chemotherapy compound.
Mol Pharmacol 2005 Aug
PMID:Chemotherapy compounds in cervical cancer cells primed by reconstitution of p53 function after short interfering RNA-mediated degradation of human papillomavirus 18 E6 mRNA: opposite effect of siRNA in combination with different drugs. 1590 16

Cisplatin, a chemotherapeutic agent, is known to induce apoptosis of cancer cells. We examined the role of NF-kappaB during cisplatin-induced apoptosis in two human cervical cancer cell lines, HeLa and SiHa, known to differ in their response to cisplatin treatment. We found that SiHa cells were relatively more resistant than HeLa cells to the cytotoxic effects induced by cisplatin as measured by MTT assays. HeLa cells were more sensitive to the apoptotic effects induced by cisplatin as shown by increases in annexin staining, DNA fragmentation, and loss of mitochondrial membrane potential. Similarly the activities of caspases 3, 8, and 9 and cleavage of PARP induced by cisplatin were more in HeLa than SiHa cells. Cisplatin induced NF-kappaB DNA binding activity in HeLa and SiHa cells but not in primary cervical cells and the active DNA binding complex in SiHa cells consists of p50 and RelA heterodimers. However, when NF-kappaB DNA binding activity was blocked by chemical (curcumin, PDTC, or salicylic acid) or biological inhibitors (NIK-KM or IKK-beta DN), the cell viability was less in SiHa cells with cisplatin treatment, but these effects were not observed in HeLa cells. Similarly upon treatment with cisplatin SiHa cells had more activation of caspases compared to that seen in HeLa cells under conditions of NF-kappaB inhibition by biological or chemical inhibitors. These results suggest that NF-kappaB may contribute to the resistance of human cervical cancer cells to cisplatin and highlight the potential use of combination therapy involving cisplatin and NF-kappaB inhibitors.
Mol Carcinog 2005 Sep
PMID:Biological and chemical inhibitors of NF-kappaB sensitize SiHa cells to cisplatin-induced apoptosis. 1604 19


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