Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evidence of the involvement of cyclin genes in genetic alterations in human cancer is growing. In the present study, we investigated the amplification, in human breast and ovarian cancer, of 5 cyclin genes; cyclin A, cyclin D1, cyclin D2, cyclin D3 and cyclin E. For this purpose, a series of 1,171 breast and 237 ovarian tumors tested for DNA amplification by Southern blotting and a subset of 132 breast and 22 ovarian cancers were analyzed for RNA expression levels by slot-blot and Northern blotting. In breast tumors, only cyclin D1 was found to be activated in a sizeable fraction of the tumors (amplification 12.6%, overexpression 19%). Cyclin A, D2, D3, and E genes never, or only on rare occasions, showed increased DNA copy numbers and were never found overexpressed at the RNA level. Amplification of cyclin D1 correlated with ER+ breast cancer and the presence of lymph-node metastasis. Interestingly, we were also able to determine an association with invasive lobular carcinoma. Our data suggest that cyclin D1 activation determines the evolution of a particular subset of estrogen-responsive tumors. Data obtained in ovarian tumors contrasted with observations in breast cancer. Cyclin D1 DNA amplification was much less frequent in ovarian than in breast tumors (3.3% vs. 12.6%), whereas cyclin E amplification and overexpression were observed in a significant number of cases (12.5% and 18.0% respectively). Cyclin A, cyclin D2 and D3 rarely showed anomalies at the DNA level and were never overexpressed. No clear correlation could be observed between amplification of the cyclin E gene and tumor type, stage or grade in ovarian cancer. Data presented here suggest distinct pathways of cyclin activation in human breast and ovarian cancer.
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PMID:Cyclin gene amplification and overexpression in breast and ovarian cancers: evidence for the selection of cyclin D1 in breast and cyclin E in ovarian tumors. 879 62

Cyclin A-associated kinases, such as cyclin-dependent kinase 2 (CDK2), participate in regulating cellular progression from G(1) to S to G(2), and CDK2 has also been implicated in the transition to mitosis. The antitumor properties of CDK inhibitors, alone or in combination with taxanes, are currently being examined in clinical trials. Here, we examined whether the activity of kinases associated with cyclin A (such as CDK2) is important in determining cellular sensitivity to paclitaxel, a taxane and mitotic inhibitor used in chemotherapy for breast and ovarian cancer. We used adenoviral suppression or overexpression to manipulate the expression of CDK2 and cyclin A in one breast cancer and three ovarian cancer cell lines with different sensitivities to paclitaxel and assessed protein expression, kinase activity, cell cycle distribution, and sensitivity to paclitaxel. Transfection of a dominant-negative (DN)-CDK2 evoked resistance to paclitaxel by preventing cellular progression to mitosis through loss of CDK1 activity. Reexpression of wild-type CDK2 in DN-CDK2-transfected cancer cells restored CDK2 activity but not paclitaxel sensitivity. However, expression of cyclin A in DN-CDK2-transfected cells restored their sensitivity to paclitaxel. Although CDK2 activity was not directly involved in paclitaxel sensitivity, cyclin A-associated kinases did up-regulate CDK1 via phosphorylation. We conclude that cyclin A-associated kinase activity is required for these cells to enter mitosis and undergo paclitaxel-induced cell death. Combining taxane chemotherapy with any drug targeting cyclin A-associated kinases (e.g., pure CDK2 inhibitors) should be done with caution, if at all, because of the potential for enhancing taxane resistance.
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PMID:Cyclin A-associated kinase activity is needed for paclitaxel sensitivity. 1602 Jun 61

Cyclin-dependent kinases (CDK) play a crucial role in the control of the cell cycle. Aberrations in the control of cell cycle progression occur in the majority of human malignancies; hence, CDKs are promising targets for anticancer therapy. Here, we define the cellular effects of the novel CDK inhibitor NU6140, alone or in association with paclitaxel, with respect to inhibition of cell proliferation and cell cycle progression and induction of apoptosis in HeLa cervical carcinoma cells and in comparison with purvalanol A. Both CDK inhibitors induced a concentration-dependent cell cycle arrest at the G(2)-M phase and an increase in the apoptotic rate, with a concomitant down-regulation of the antiapoptotic protein survivin, a member of the inhibitors of apoptosis protein family. Notably, the addition of NU6140 to paclitaxel-treated cells resulted in markedly increased cytotoxic effect and apoptotic response in comparison with the paclitaxel-purvalanol A combination (86 +/- 11% and 37 +/- 8%, respectively). Similarly, the extent of caspase-9 and caspase-3 activation in paclitaxel-NU6140-treated cells was approximately 4-fold higher than after the paclitaxel-purvalanol A combination. Moreover, an almost complete abrogation of the expression of the active, Thr(34)-phosphorylated form of survivin was observed in cells exposed to the paclitaxel-NU6140 combination. A synergistic effect of the paclitaxel-NU6140 combination, as a consequence of survivin inhibition and increased activation of caspase-9 and caspase-3, was also observed in OAW42/e ovarian cancer line but not in the derived OAW42/Surv subline ectopically expressing survivin. Results from this study indicate that NU6140 significantly potentiates the apoptotic effect of paclitaxel, with inhibition of survivin expression/phosphorylation as the potential mechanism.
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PMID:Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: a possible role for survivin down-regulation. 1617 24

Ascites macrophages in advanced epithelial ovarian cancer (AdEOC) are involved in cancer metastasis and progression by modifying the tumor microenvironment. However, the precise mechanisms of cell-to-cell interaction between macrophages and tumor cells are still unclear. This study focused on the activation of signal transducer and activator of transcription 3 (Stat3) which is a critical signal transduction molecule at a point of convergence for numerous oncogenic signaling pathways as well as controlling the M2-poralization of macrophages. AdEOC ascites, in which high concentration of interleukin (IL)-6, IL-10, growth-related oncogene-alpha and vascular endothelial growth factor were detected, stimulated the proliferation of SKOV3 cells, a human ovarian cancer cell line. The simultaneous blocking of IL-6 and IL-10 by neutralizing antibodies suppressed ascites-induced tumor cell proliferation. Stat3 activation in SKOV3 cells was induced by co-culture with macrophages especially with macrophage colony stimulating factor-primed M2 macrophages but lesser extent with granulocyte-macrophage colony stimulating factor-primed immature macrophages. Cyclin-D1 expression in SKOV3 cells was also significantly induced by co-culture with macrophages. Blocking of Stat3 in macrophages by small interfering RNA inhibited the production of IL-6 and IL-10 by macrophages, and suppressed Stat3 activation and cyclin-D1 induction in co-cultured SKOV3 cells. Stat3 activation in SKOV3 cells was abrogated by simultaneous neutralization of IL-6 and IL-10. These results indicate that Stat3 activation by IL-6 and IL-10 plays an important role in cell-to-cell interaction between tumor cells and macrophages in the ascites of AdEOC.
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PMID:Involvement of M2-polarized macrophages in the ascites from advanced epithelial ovarian carcinoma in tumor progression via Stat3 activation. 2086 Jun 2

The principal objective of this study was to comprehensively assess the clinicopathologic and prognostic impacts of the expression of various cell cycle regulatory proteins in patients with ovarian epithelial tumors. The tissue microarrays were constructed from formalin-fixed, paraffin-embedded tissues of 205 ovarian epithelial tumors. We investigated 55 benign (20 serous cystadenomas, 17 mucinous cystadenomas, and 18 endometriotic cysts), 72 borderline (26 serous borderline tumors and 46 mucinous borderline tumors), and 78 malignant tumors (45 serous carcinomas, 10 mucinous adenocarcinomas, 15 endometrioid adenocarcinomas, and 8 clear cell carcinomas). Immunohistochemical staining was performed using antibodies to p16(Ink4a), p53, p21(Waf1/Cip1), p27(Kip1), Cyclin D1, Cyclin E, Cyclin A, Cyclin B1, and Cyclin-dependent Kinase2. We noted significantly different levels of p53 and Cyclin B1 expressions between malignant and borderline tumors and between borderline and benign tumors excepting the mucinous type. The p21(Waf1/Cip1) and Cyclin A were significantly overexpressed in malignant tumors compared with borderline tumors. Cyclin A, Cyclin E, and p16(Ink4a) were more pronounced proteins, showing differential expression patterns among the histologic types of ovarian carcinomas. We determined that the overexpression of p16(Ink4a) (P=0.031), Cyclin E (P=0.009), and Cyclin-dependent Kinase2 (P=0.004) were significantly associated with higher tumor grades. Overexpression of p16(Ink4a) was correlated with both lymph node metastasis (P=0.030) and distant metastasis (P=0.034). Overexpression of Cyclin E was associated with advanced stage (P=0.004). Higher tumor grade (P=0.008), advanced stage (P=0.001), mucinous histologic type (P=0.012), low expression levels of p16(Ink4a) (P=0.032), and overexpression of p53 (P=0.032) were associated with poor overall survival on multivariate analysis in patients with ovarian cancer. In serous carcinomas, old age (P=0.005), distant metastasis (P=0.020), low expression of p16(Ink4a) (P=0.047), and overexpression of cytoplasmic p27(Kip1) (P=0.007) and Cyclin A (P=0.031) were all independent predictors of worse overall survival. Our data indicate that the overexpression of p16 and Cyclin E are valuable factors predicting disease progression and metastatic potential. Low p16(Ink4a) expression, overexpression of p53, cytoplasmic p27(Kip1), and Cyclin A are predictive markers for shorter overall survival in ovarian carcinomas.
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PMID:Significance of cell cycle regulatory proteins as malignant and prognostic biomarkers in ovarian epithelial tumors. 2146 33

Various cyclin-dependent kinase (Cdk) complexes have been implicated in the regulation of transcription. In this study, we identified a 70-kDa Cyclin K (CycK) that binds Cdk12 and Cdk13 to form two different complexes (CycK/Cdk12 or CycK/Cdk13) in human cells. The CycK/Cdk12 complex regulates phosphorylation of Ser2 in the C-terminal domain of RNA polymerase II and expression of a small subset of human genes, as revealed in expression microarrays. Depletion of CycK/Cdk12 results in decreased expression of predominantly long genes with high numbers of exons. The most prominent group of down-regulated genes are the DNA damage response genes, including the critical regulators of genomic stability: BRCA1 (breast and ovarian cancer type 1 susceptibility protein 1), ATR (ataxia telangiectasia and Rad3-related), FANCI, and FANCD2. We show that CycK/Cdk12, rather than CycK/Cdk13, is necessary for their expression. Nuclear run-on assays and chromatin immunoprecipitations with RNA polymerase II on the BRCA1 and FANCI genes suggest a transcriptional defect in the absence of CycK/Cdk12. Consistent with these findings, cells without CycK/Cdk12 induce spontaneous DNA damage and are sensitive to a variety of DNA damage agents. We conclude that through regulation of expression of DNA damage response genes, CycK/Cdk12 protects cells from genomic instability. The essential role of CycK for organisms in vivo is further supported by the result that genetic inactivation of CycK in mice causes early embryonic lethality.
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PMID:The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. 2239 Dec 10

PNAS-4, a novel pro-apoptotic gene, was activated during the early response to DNA damage. Previous studies have shown that hPNAS-4 can inhibit tumor growth when over-expressed in ovarian cancer cells. However, the underlying action mechanism remains elusive. In this work, we found that hPNAS-4 expression was significantly increased in SKOV3 cells when exposed to cisplatin, methyl methanesulfonate or mitomycin C, and that its overexpression could induce proliferation inhibition, S phase arrest and apoptosis in A2780s and SKOV3 ovarian cancer cells. The S phase arrest caused by hPNAS-4 was associated with up-regulation of p21. p21 is p53-dispensable and correlates with activation of ERK, and activation of the Cdc25A-Cdk2-Cyclin E/Cyclin A pathway, while the pro-apoptotic effects of hPNAS-4 were mediated by activation of caspase-9 and -3 other than caspase-8, and accompanied by release of AIF, Smac and cytochrome c into the cytosol. Taken together, these data suggest a new mechanism by which hPNAS-4 inhibits proliferation of ovarian cancer cells by inducing S phase arrest and apoptosis via activation of Cdc25A-Cdk2-Cyclin E/Cyclin A axis and mitochondrial dysfunction-mediated caspase-dependent and -independent apoptotic pathways. To our knowledge, we provide the first molecular evidence for the potential application of hPNAS-4 as a novel target in ovarian cancer gene therapy.
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PMID:hPNAS-4 inhibits proliferation through S phase arrest and apoptosis: underlying action mechanism in ovarian cancer cells. 2332 88

Transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are key oncogenes in mammalian cells. Activities of YAP and TAZ are largely restricted by the Hippo tumor suppressor pathway through phosphorylation-ubiquitination mechanisms. The involvement of microRNA in cancer progression has recently been reported, though whether they have a role in activating YAP and TAZ in human cancer cells remains unclear. Here, we report a microRNA, miR-129-5p, directly represses YAP and TAZ expression, leading to the inactivation of TEA domain (TEAD) transcription, and the downregulation of Hippo downstream genes, connective tissue growth factor (CTGF) and Cyclin A. Furthermore, we reveal miR-129-5p inhibits ovarian cancer cell proliferation, survival and tumorigenicity, and that downregulation of miR-129-5p in ovarian cancer cells highly correlates with malignant progression and poor survival. Hence, we demonstrate a novel mechanism for YAP and TAZ activation in cancers, indicating not only a potentially pivotal role for miR-129-5p in the progression of ovarian cancer, but also offering new therapeutic strategies to circumvent the disease.
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PMID:A novel role for microRNA-129-5p in inhibiting ovarian cancer cell proliferation and survival via direct suppression of transcriptional co-activators YAP and TAZ. 2589 25

Cyclin G1 plays an essential role in the development of human carcinoma. Here, we characterized the clinical significance of Cyclin G1 and investigated its role in cellular proliferation and apoptosis of epithelial ovarian cancer (EOC). Western blot was used to evaluate the expression of Cyclin G1 in nine fresh EOC tissues and three fresh normal ovarian tissues. Immunohistochemistry analysis was performed on formalin-fixed paraffin-embedded section of 119 cases of EOCs. Using cell counting kit (CCK)-8 and colony formation assays, we analyzed the effect of Cyclin G1 in cellular proliferation of EOC. Besides, the immunofluorescence and flow cytometry analysis was performed to study the role of Cyclin G1 in cellular apoptosis of EOC. We found Cyclin G1 was up-regulated in EOC tissues compared with the normal ovary tissues. Cyclin G1 expression in EOC was closely correlated with differentiation grade (P = 0.009) and malignant tumor cells in ascites (P = 0.009). The Kaplan-Meier curve showed that higher expression of Cyclin G1 was associated with significantly shorter survival in EOC patients. Multivariate analysis suggested Cyclin G1 expression was an independent prognostic factor for overall survival. CCK-8 and colony formation assays revealed that depletion of Cyclin G1 inhibited the proliferation and clone formation. Combined immunofluorescence and flow cytometry analysis showed that silencing of Cyclin G1 with shRNA could promote apoptosis of ovarian cancer cells. Additionally, the result of immunoprecipitation test showed Cyclin G1 interacted with CDK2 in EOC cells. In summary, our findings suggest that Cyclin G1 may be involved in the prognosis of EOC patients and be a useful therapeutic target for EOC.
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PMID:The role of Cyclin G1 in cellular proliferation and apoptosis of human epithelial ovarian cancer. 2598 80

CCNE1 gene amplification is present in 15-20% ovary tumor specimens. Here, we showed that Cyclin E1 (CCNE1) was overexpressed in 30% of established ovarian cancer cell lines. We also showed that CCNE1 was stained positive in over 40% of primary ovary tumor specimens regardless of their histological types while CCNE1 staining was either negative or low in normal ovary and benign ovary tumor tissues. However, the status of CCNE1 overexpression was not associated with the tumorigenic potential of ovarian cancer cell lines and also did not correlate with pathological grades of ovary tumor specimens. Subsequent experiments with CCNE1 siRNAs showed that knockdown of CCNE1 reduced cell growth only in cells with inherent CCNE1 overexpression, indicating that these cells may have developed an addiction to CCNE1 for growth/survival. As CCNE1 is a regulatory factor of cyclin-dependent kinase 2 (Cdk2), we investigated the effect of Cdk2 inhibitor on ovary tumorigenecity. Ovarian cancer cells with elevated CCNE1 expression were 40 times more sensitive to Cdk2 inhibitorSNS-032 than those without inherent CCNE1 overexpression. Moreover, SNS-032 greatly prolonged the survival of mice bearing ovary tumors with inherent CCNE1 overexpression. This study suggests that ovary tumors with elevated CCNE1 expression may be staged for Cdk2-targeted therapy.
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PMID:Cyclin-dependent kinase 2 is an ideal target for ovary tumors with elevated cyclin E1 expression. 2620 91


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