Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1519670 (tumor angiogenesis)
 6,052 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study investigated the inhibitory effect of the extract of fungi of Huaier (EFH) on the growth of hepatocellular carcinoma (HCC) cells. Hep-G2 cells, a human HCC cell line, were cultured in DMEM containing 10% fetal bovine serum and treated with EFH of different concentrations (1, 2, 4, 8 mg/mL) for 24, 48 and 72 h respectively. The apoptosis rate of the cells was flow cytometrically measured. Thirty-six tumor-bearing New Zealand rabbits were randomly divided into 3 groups: group A (control group), in which the rabbits were infused with 0.2 mL/kg normal saline via the hepatic artery; group B (transhepatic artery chemoembolization [TACE] group), in which the rabbits were given lipiodol at 0.2 mL/kg plus MMC at 0.5 mg/kg via the hepatic artery; group C (TACE+EFH group), in which EFH (500 mg/kg) were orally administered after TACE. Two weeks after TACE, the rabbits were sacrificed and the implanted tumors were sampled. The tumor volume and the necrosis rate were determined. The tumor tissues were immunohistochemically detected for the expressions of factor VIII, VEGF, P53, Bax and Bcl-2. The microvessel density (MVD) was calculated by counting the factor VIII-positive endothelial cells. Our results showed that after treatment with EFH, the apoptosis rate of Hep-G2 cells was enhanced in a concentration- and time-dependent manner. Two weeks after the treatment, the average tumor volume, the necrosis rate and the growth rate of the implanted tumor in group C were significantly different from those in groups A and B (P<0.05). MVD and VEGF expressions were significantly decreased in the group C when compared with those in groups B (P<0.05 for all). The Bax expression was weakest in group A and strongest in group C. The expressions of P53 and Bcl-2 were minimal in group C and maximal in group A. There were significant differences in the expressions of P53, Bax and Bcl-2 among the 3 groups (P<0.05 for all) and there was significant difference between group B and group C (P<0.05). It was concluded that EFH could suppress not only the growth of HCC cells but also tumor angiogenesis and it can induce the apoptosis of HCC cells. EFH serves as an alternative for the treatment of HCC.
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PMID:Inhibitory effect of extract of fungi of Huaier on hepatocellular carcinoma cells. 1939 4

Pituitary tumor-transforming gene-1 (PTTG1) is a transforming gene first discovered in rat pituitary tumor cells. It possesses transcriptional activity and also has securin functions. Chromatin immunoprecipitation-on-chip study reveals that PTTG1 is a global transcription factor, which exerts its transcriptional activity either by directly binding to DNA or by interacting with proteins including PTTG1 binding factor, p53, Sp1, and upstream stimulatory factor 1. PTTG1 has several validated transcriptional targets that are involved in different cellular processes. PTTG1 activates c-Myc in NIH 3T3 cells, suggesting a role in cell transformation. PTTG1 induces fibroblast growth factor 2 expression and promotes tumor angiogenesis.It binds to and inhibits p53 transcriptional activity. PTTG1 activates cyclin D3 and represses p21 expression, indicating a role in cell cycle regulation and cell senescence. Here, we review PTTG1 transcriptional targets and their functions.
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PMID:Transcriptional targets for pituitary tumor-transforming gene-1. 1943 93

The interplay among hypoxia-inducible factor 1-alpha (HIF-1alpha), p53 and human orthologue of murine double minute 2 (Hdm2) has been introduced as a key event in tumor promotion and angiogenesis. Recently, nutlin-3, a small-molecule antagonist of Hdm2, was demonstrated to inhibit the HIF-1-mediated vascular endothelial growth factor production and tumor angiogenesis. Yet, the mechanism by which nutlin-3 inhibits HIF-1 is an open question. We here addressed the mode-of-action of nutlin-3 with respect to the HIF-1alpha-p53-Hdm2 interplay. The effect of nutlin-3 on HIF-1alpha function was examined by reporter analyses, immunoprecipitation and immunoblotting. Nutlin-3 downregulated HIF-1alpha, which occurred p53-dependently but von Hippel-Lindau-independently. On the contrary, nutlin-3 blunted the hypoxic induction of vascular endothelial growth factor by inactivating HIF-1 even in p53-null cells. The C-terminal transactivation domain (CAD) of HIF-1alpha was inactivated by nutlin-3, and furthermore, the factor-inhibiting hypoxia-inducible factor (FIH) hydroxylation of Asn803 was required for the nutlin-3 action. In terms of protein interactions, Hdm2 competed with FIH in CAD binding and inhibited the Asn803 hydroxylation both in vivo and in vitro, which facilitated p300 recruitment. Moreover, nutlin-3 reinforced the FIH binding and Ans803 hydroxylation by inhibiting Hdm2. In conclusion, Hdm2 functionally activates HIF-1 by inhibiting the FIH interaction with CAD, and the Hdm2 inhibition by nutlin-3 results in HIF-1 inactivation and vascular endothelial growth factor suppression. The interplays among HIF-1alpha, Hdm2, FIH and p300 could be potential targets for treating tumors overexpressing HIF-1alpha.
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PMID:Nutlin-3, an Hdm2 antagonist, inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated inactivation of HIF-1alpha. 1969 66

CHM-1 (2'-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone) has been identified as a potent antitumor agent in human hepatocellular carcinoma; however, its role in tumor angiogenesis is unclear. This study investigated the effects of CHM-1 and the mechanisms by which it exerts its antiangiogenic and vascular disrupting properties. Using a xenograft model antitumor assay, we found that CHM-1 significantly inhibits tumor growth and microvessel formation. Flow cytometry, immunofluorescence microscopy, and cell death enzyme-linked immunosorbent assay kit revealed that CHM-1 inhibits growth of human umbilical vein endothelial cells (HUVEC) by induction of apoptotic cell death in a concentration-dependent manner. CHM-1 also suppresses HUVEC migration and capillary-like tube formation. We were able to correlate CHM-1-induced apoptosis in HUVEC with the cleavage of procaspase-3, -7, and -8, as well as with the cleavage of poly(ADP-ribose) polymerase by Western blotting assay. Such sensitization was achieved through up-regulation of death receptor 5 (DR5) but not DR4 or Fas. CHM-1 was also capable of increasing the expression level of p53, and most importantly, the induction of DR5 by CHM-1 was abolished by p53 small interfering RNA. Taken together, the results of this study indicate that CHM-1 exhibits vascular targeting activity associated with the induction of DR5-mediated endothelial cell apoptosis through p53 up-regulation, which suggests its potential as an antivascular and antitumor therapeutic agent.
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PMID:CHM-1, a new vascular targeting agent, induces apoptosis of human umbilical vein endothelial cells via p53-mediated death receptor 5 up-regulation. 2000 68

To investigate the role of tumor suppressors BRCA1 and p53 proteins in human breast tumorigenesis, we transformed immortalized human mammary epithelial cells, MCF10A, with or without BRCA1/p53 gene-specific knockdowns. Stable knockdown of BRCA1 alone in MCF10A cells led to centrosome amplification, impaired p53 protein stability, increased sensitivity towards DNA-damaging agents, defective chromosomal condensation at mitosis and elevated protein levels of cyclin D1 and c-myc. While over-expression of mutant H-Ras transformed MCF10A cells, depletion of BRCA1 dramatically enhanced the in vivo tumorigenesis that was associated with higher levels of VEGF, enhanced vascularization and less apoptosis in the BRCA1-deficient Ras-transformed tumors. The Ras-transformed BRCA1-deficient tumors exhibited features of the epithelial-to-mesenchymal transition, appeared to secrete matrix metalloproteases as visualized by in vivo bio-imaging of tumors using fluorescent probe MMP680, and were locally metastatic to lymph nodes. Our results suggest that loss of BRCA1 function may contribute to the aggressiveness of Ras-MAPK driven human breast cancer with associated increase in levels of cyclin D1 and c-myc, enhanced MAPK activity, angiogenic potential & invasiveness. This mammary xenograft tumor model may be useful as a tool to understand human breast tumor angiogenesis and metastasis, as well as to test candidate therapeutics.
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PMID:Reduced cell death, invasive and angiogenic features conferred by BRCA1-deficiency in mammary epithelial cells transformed with H-Ras. 2003 17

The pathway involving the tumor suppressor gene TP53 can regulate tumor angiogenesis by unclear mechanisms. Here we show that p53 regulates hypoxic signaling through the transcriptional regulation of microRNA-107 (miR-107). We found that miR-107 is a microRNA expressed by human colon cancer specimens and regulated by p53. miR-107 decreases hypoxia signaling by suppressing expression of hypoxia inducible factor-1beta (HIF-1beta). Knockdown of endogenous miR-107 enhances HIF-1beta expression and hypoxic signaling in human colon cancer cells. Conversely, overexpression of miR-107 inhibits HIF-1beta expression and hypoxic signaling. Furthermore, overexpression of miR-107 in tumor cells suppresses tumor angiogenesis, tumor growth, and tumor VEGF expression in mice. Finally, in human colon cancer specimens, expression of miR-107 is inversely associated with expression of HIF-1beta. Taken together these data suggest that miR-107 can mediate p53 regulation of hypoxic signaling and tumor angiogenesis.
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PMID:P53-induced microRNA-107 inhibits HIF-1 and tumor angiogenesis. 2030 59

Tissue hypoxia commonly occurs in tumors. Hypoxia- inducible factor (HIF)-1 and HIF-2, which are essential mediators of cellular response to hypoxia, regulate gene expression for tumor angiogenesis, glucose metabolism, and resistance to oxidative stress. Their key regulatory subunits, HIF1A (HIF-1alpha) and endothelial PAS domain protein 1 (EPAS1; HIF-2alpha), are overexpressed and associated with patient prognosis in a variety of cancers. However, prognostic or molecular features of colon cancer with HIF expression remain uncertain. Among 731 colorectal cancers in two prospective cohort studies, 142 (19%) tumors showed HIF1A overexpression, and 322 (46%) showed EPAS1 overexpression by immunohistochemistry. HIF1A overexpression was significantly associated with higher colorectal cancer-specific mortality in Kaplan-Meier analysis (log-rank test, P < 0.0001), univariate Cox regression (hazard ratio = 1.84; 95% confidence interval, 1.37 to 2.47; P < 0.0001) and multivariate analysis (adjusted hazard ratio = 1.72; 95% confidence interval, 1.26 to 2.36; P = 0.0007) that adjusted for clinical and tumoral features, including microsatellite instability, TP53 (p53), PTGS2 (cyclooxygenase-2), CpG island methylator phenotype, and KRAS, BRAF, PIK3CA, and LINE-1 methylation. In contrast, EPAS1 expression was not significantly associated with patient survival. In addition, HIF1A expression was independently associated with PTGS2 expression (P = 0.0035), CpG island methylator phenotype-high (P = 0.013), and LINE-1 hypomethylation (P = 0.017). EPAS1 expression was inversely associated with high tumor grade (P = 0.0017) and obesity (body mass index > or = 30 kg/m2) (P = 0.039). In conclusion, HIF1A expression is independently associated with poor prognosis in colorectal cancer, suggesting HIF1A as a biomarker with potentially important therapeutic implications.
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PMID:HIF1A overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers. 2036 10

Vascular endothelial growth factor A (VEGFA) is a specific mitogen for vascular endothelial cells that plays a critical role in cancer neoangiogenesis. Here, we report that the nucleolar tumor suppressor p19(ARF) suppresses VEGFA expression, acting at the level of mRNA translation without affecting the transcription of the VEGFA gene. Translational repression of VEGFA mRNA by p19(ARF) does not require p53, a major target of the ARF tumor suppressor pathway, but instead correlates with binding to nucleophosmin/B23. Maintaining VEGFA expression relies on nucleophosmin/B23, and downregulating this protein by RNAi or p19(ARF) leads to translational repression of VEGFA. p19(ARF) inhibits VEGFA-dependent tumor angiogenesis in nude mice. Additionally, p14(ARF) expression and microvessel density are inversely correlated in human colon carcinomas. Taken together, our results define a mechanism by which the ARF tumor suppressor targets the translational repression of specific oncogenes during neoplastic transformation.
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PMID:ARF suppresses tumor angiogenesis through translational control of VEGFA mRNA. 2050 56

The inhibitor of growth (ING) family proteins have been defined as candidate tumor suppressors. ING4 as a novel member of ING family has potential suppressive effect on different tumors via multiple pathways. However, the role of adenovirus-mediated ING4 (Ad-ING4) gene therapy for human breast carcinoma remains unknown. This study investigates the therapeutic effect of Ad-ING4 on human breast cancers in vitro and in vivo in an athymic nude mouse model, using two human breast carcinoma cell lines MDA-MB-231 (mutant p53) and MCF-7 (wild-type p53) and elucidated its underlying mechanism. It was found that Ad-ING4 treatment could induce in vitro significant growth suppression in both mutant p53 MDA-MB-231 and wild-type p53 MCF-7 breast carcinoma cells despite p53 status. This study further demonstrates that Ad-ING4 gene transfer resulted in G2/M phase arrest and apoptosis, upregulated P21, P27, and Bax, downregulated Bcl-2, IL-8, and Ang-1, promoted cytochrome c release from mitochondria into cytosol, and activated caspase-9, caspase-3, and PARP in mutant p53 MDA-MB-231 breast carcinoma cells. Moreover, intratumoral injections of Ad-ING4 in nude mice bearing mutant p53 MDA-MB-231 breast tumors remarkably inhibited the human breast xenografted tumor growth and reduced CD34 expression of tumor vessels and microvessel density. This retarded MDA-MB-231 breast carcinoma growth in vitro and in vivo elicited by Ad-ING4 closely correlated with the upregulation of cell cycle-related molecules P21 and P27, decrease in the ratio of anti- to proapoptotic molecules Bcl-2/Bax, release of cytochrome c from mitochondria into cytosol followed by caspase-9 and -3 activation leading to apoptosis via intrinsic apoptotic pathway, and the reduced expression of proangiogenic factors IL-8 and Ang-1 involved in the inhibition of tumor angiogenesis. Thus, the results indicate that Ad-ING4 is a potential candidate for breast cancer gene therapy.
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PMID:Tumor-suppressive effect of adenovirus-mediated inhibitor of growth 4 gene transfer in breast carcinoma cells in vitro and in vivo. 2070 19

Micro RNAs (miRNAs) are small non-coding RNAs which regulate fundamental cellular and developmental processes at the transcriptional and translational level. In breast cancer, expression of miRNAs is frequently dysregulated. Both tumor suppressor activity and oncogenic properties have been assigned to specific miRNAs, which modulate virtually all relevant stages of breast cancer progression, including tumor cell proliferation, apoptosis resistance, cancer cell migration, invasiveness and metastasis, tumor angiogenesis and cancer stem cell self-renewal. miRNA expression has been studied by microarray profiling, bead-based technologies and quantitative real-time PCR in archived formalin-fixed paraffin-embedded tumor specimens as well as blood and serum samples, allowing to identify specific miRNAs as novel diagnostic, prognostic and predictive markers. Moreover, the investigation of single nucleotide polymorphisms both in putative miRNA binding sites in the 3'UTRs of target genes, as well as in miRNA-endocing genes have revealed their diagnostic potential. In vitro experiments employing established breast cancer cell lines and in vivo xenograft studies have demonstrated the efficacy of oligonucleotide-based overexpression and inhibitor approaches of miRNA-targeted experimental therapies. Numerous studies have identified specific targets of miRNA action in breast cancer, including the established markers Her2/neu and ERalpha, TP53, and markers of angiogenesis. The future application of locked-nucleic acid miRNA inhibitors, and synergistic approaches involving conventional breast cancer therapeutics opens up promising new perspectives in breast cancer therapy.
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PMID:MicroRNAs in breast cancer pathogenesis. 2107 77


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