Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have shown that resistance to apoptosis may contribute to chemoresistance. Alteration of caspases, such as caspase-3, results on decreased apoptosis. Genes of IAP (inhibitor of apoptosis proteins) family, such as survivin, were also implicated in tumor development where they are mutated or have deregulated expression. Initial studies revealed strong survivin expression in several fetal tissues and some proliferating adult tissues, whereas no survivin expression was detected in a range of adult tissues. Although the factors at the origins on survivin re-expression in tumors are still unknown, the anti-apoptotic function of survivin is mediated in part by inhibiting caspase-3 activity. Recently, functionally divergent splice variants resulting from alternative splicing, with apoptotic (for caspase-3) or anti-apoptotic (for survivin) opposite activities have been described. The alternative splice variant, caspase-3s results from exon 6 deletion and shows antagonist of apoptotic property of caspase-3. Three alternative splice variants of survivin (survivin-DeltaEx3, survivin-2B and survivin-3B) differing in their anti-apoptotic properties were reported. While the anti-apoptotic effect of survivin-DeltaEx3 is preserved, survivin-2B has lost its anti-apoptotic potential and may act as a naturally occurring antagonist of survivin and survivin-DeltaEx3. At present, little is known about properties of survivin-3B. Several evidences indicate that in several cancers, the ratio of splice variants is significantly altered, and modifications of splicing pathways have been developed for cancer treatment. Recent investigations have shown that expression of alternative splice variants of caspase-3 and of survivin were also altered in many human cancers, and that variations in their expression were associated with tumor progression and chemoresistance. In this article, we describe recent data concerning alternative splice variants of these two proteins.
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PMID:[Implication of alternative splice transcripts of caspase-3 and survivin in chemoresistance]. 1582 Sep 16

Gene signatures that predict aggressive tumor behavior at the earliest stages of disease, ideally before overt tissue abnormalities, are urgently needed. To search for such genes, we generated a transgenic model of survivin, an essential regulator of cell division and apoptosis overexpressed in cancer. Transgenic expression of survivin in the urinary bladder did not cause histologic abnormalities of the urothelium. However, microarray analysis revealed that survivin-expressing bladders exhibited profound changes in gene expression profile affecting extracellular matrix and inflammatory genes. Following exposure to a bladder carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (OH-BBN), survivin transgenic animals exhibited accelerated tumor progression, preferential incidence of tumors as compared with premalignant lesions, and dramatically abbreviated survival. Conversely, transgenic expression of a survivin Thr34-->Ala dominant-negative mutant did not cause changes in gene expression or accelerated tumor progression after OH-BBN treatment. Therefore, survivin expression induces global transcriptional changes in the tissue microenvironment that may promote tumorigenesis. Detection of survivin or its associated gene signature may provide an early biomarker of aggressive tumor behavior before the appearance of tissue abnormalities.
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PMID:A survivin gene signature predicts aggressive tumor behavior. 1586 43

Survivin, a recently characterized novel member of the inhibitor of apoptosis (IAP) family, is not detectable in most differentiated normal adult tissues but is expressed in a wide range of cancer tissues. Its expression in cancer has been correlated with poor prognosis, cancer progression and drug resistance. We immunohistochemically examined the expression of survivin in 62 cases of oral epithelial dysplasia (ED) and 96 cases of oral squamous cell carcinoma (SCC). Cytoplasmic survivin staining was detected in 60 of the 62 (97%) ED specimens and 94 of the 96 (98%) SCC specimens but not in adjacent normal oral mucosal tissues. The labeling index (LI) for survivin protein significantly increased from ED (32.3+/-16.3%) to SCC samples (49.4+/-28.5%) (p<0.001). In addition, the mean LI for ED cases with further malignant transformation into SCC (45.6+/-8.8%) was higher than those without malignant transformation (30.1+/-16.3%) (p=0.008). No significant correlation was found between the survivin expression and the patients' age, sex, oral habit, cancer location, or STNM status in SCC cases. Kaplan-Meier curves showed oral SCC patients with high survivin expression (LI>25%), advanced stage, larger tumor size, or positive lymph node metastasis had significantly shorter overall survival (p=0.014, 0.012, 0.005 and 0.011, respectively by log-rank test) than others. The associations remained significant after adjusting for age. These results indicate that survivin protein expression may be an important early event in oral carcinogenesis and predicts unfavorable prognosis for oral SCC. Furthermore, the unique expression of survivin in cancer cells but not in most normal adult tissues suggests that modulation of survivin protein expression may provide a novel strategy for the therapy of oral SCC.
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PMID:Survivin expression predicts poorer prognosis in patients with areca quid chewing-related oral squamous cell carcinoma in Taiwan. 1592 24

Rebamipide accelerates healing of gastric ulcers and gastritis but its actions on gastric cancer are not known. Survivin, an anti-apoptosis protein, is overexpressed in stem, progenitor, and cancer cells. In gastric cancer, increased and sustained survivin expression provides survival advantage and facilitates tumor progression and resistance to anti-cancer drugs. Aurora-B kinase is essential for chromosome alignment and mitosis progression but surprisingly its role in gastric cancer has not been explored. We examined in human gastric cancer AGS cells: (1) survivin expression, (2) localization of survivin and Aurora-B, (3) cell proliferation, and (4) effects of specific survivin siRNA and/or rebamipide (free radical scavenging drug) on survivin and Aurora-B expression and cell proliferation. Survivin and Aurora-B are strongly expressed in human AGS gastric cancer cells and co-localize during mitosis. Survivin siRNA significantly reduces AGS cell viability. Rebamipide significantly downregulates in AGS cell survivin expression, its association with Aurora-B and cell proliferation. Rebamipide-induced downregulation of survivin is at the transcription level and does not involve ubiquitin-proteasome pathway.
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PMID:Rebamipide inhibits gastric cancer growth by targeting survivin and Aurora-B. 1599 41

The expression of calcitonin (CT) and CT-receptor (CTR) mRNA in primary prostate tumors increase with tumor progression. Since advanced prostate tumors display chemoresistance, we tested a hypothesis that CT increases apoptosis resistance of prostate cells against cytotoxic drugs. We examined the effect of CT on etoposide-induced apoptosis in PC-3M, LNCaP and NRP-152 cell lines. The cytoprotective actions of CT were then tested on paclitaxel-, dexamethasone- and selenite-induced apoptosis. We also examined cytotoxic actions of these drugs in CTR-silenced PC-3M cells. Since the role of Akt and inhibitors of apoptosis proteins (IAPs) in chemoresistance of advanced prostate cancers has been established, we tested the effect of CT on phospho-Akt and survivin levels in PC-3M cells. Finally, the cytoprotective effect of CT on PC-3M cells was tested in the presence of PI3K inhibitors such as LY 294002 and wortmannin. Acutely added CT significantly attenuated apoptosis of PC cell lines in response to etoposide, dexamethasone and selenite treatment, but could not reduce paclitaxel-induced apoptosis. CT potently stimulated phospho-Akt and survivin synthesis in PC-3M cells in a sustained manner, and LY 294002 attenuated CT-induced survivin synthesis as well as apoptosis resistance. These results suggest that CT induces chemoresistance to etoposide, dexamethasone and selenite but not to paclitaxel in prostate cells. Cytoprotective action of CT is mediated by CTR-induced activation of Akt-survivin pathway. Since CT/CTR expression in prostate cancers increases with tumor progression, the suppression of "CT System" may enhance the effectiveness of chemotherapy.
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PMID:Calcitonin induces apoptosis resistance in prostate cancer cell lines against cytotoxic drugs via the Akt/survivin pathway. 1622 18

The question that transforming growth factor-beta (TGF-beta) provides a tumor-suppressive or a tumor promoting role is still unknown in hepatocellular carcinoma (HCC). In the present study, we quantitatively investigated the gene expression levels of TGF-beta in liver tissues from patients with HCC. We also evaluated the prognostic importance of TGF-beta gene in HCC patients. A total of 59 patients with primary HCC who underwent hepatectomy between 1993 and 2001 were enrolled. TGF-beta gene expression levels of tumors and of noncancerous livers were analyzed by real-time reverse transcriptase polymerase chain reaction (RT-PCR). The percentage of apoptotic cells in tumor cells (apoptotic index: AI) was evaluated with immunohistochemistry. Also the expression of survivin protein (apoptosis inhibitor) in tumors was detected by immunohistochemistry. TGF-beta gene expression levels of tumors were compared with clinicopathological findings of patients. The relative expression level of TGF-beta mRNA of 59 tumor tissues did not differ from those of 8 normal liver tissues or 59 noncancerous liver tissues. The mean AI of 29 tumors with normal expression levels of TGF-beta gene (4%) was significantly higher than that of 30 tumors with low expression levels of TGF-beta gene (2.5%, p = 0.03). Thirteen out of 30 tumors (43%) with low expression level of TGF-P gene showed survivin positive, while only 4 out of 29 tumors (14%) with preserved expression of TGF-beta gene showed survivin positive. This difference was significant (p = 0.012). The overall 5-year survival rate of 29 patients with tumors with preserved TGF-beta gene prolonged to 72% compared with that of 30 patients who had tumors with suppressed TGF-beta gene (58%, p = 0.156). In HCC, TGF-beta gene may play a defensive role against tumor progression by regulating survivin protein expression and by controlling occurrence of spontaneous apoptosis in tumors.
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PMID:The gene expression level of transforming growth factor-beta (TGF-beta) as a biological prognostic marker of hepatocellular carcinoma. 1627 May 28

Survivin is a protein with proposed roles in cell division and apoptosis. Transcripts encoding splice variants of human survivin have been described and their expression correlated with cancer progression. As survivin forms homodimers in vitro, it has been suggested that these isoforms could interfere with wild type function by forming heterodimers. Here we show that survivin-2beta and survivin-deltaEx3 can interact with wild type survivin but have reduced affinity for the partner protein of survivin, borealin, and thus do not localize with the chromosomal passenger complex in vivo. Furthermore, we demonstrate that overexpression of survivin-2beta-green fluorescent protein (GFP) or survivin-deltaEx3-GFP does not impede cell cycle progression. We also report that wild type survivin, but not survivin-2beta-GFP or survivin-deltaEx3-GFP, can rescue cell proliferation inhibited by small interfering RNA-mediated survivin depletion. These data suggest that, despite their ability to interact with wild type survivin, neither of these isoforms acts as its competitor during mitosis nor has an essential function.
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PMID:Molecular analysis of survivin isoforms: evidence that alternatively spliced variants do not play a role in mitosis. 1629 52

Mutations in Ki-ras occur in approximately 30-50% of patients with adenocarcinoma (AC) of the lung. We previously reported the development of a bitransgenic mouse model that expressed the human Ki-ras(G12C) allele in a lung-specific, tetracycline-inducible manner and gave rise to benign lung tumors. In the current study, these benign tumors, which represent relatively early lesions in neoplastic progression, were analyzed for molecular alterations secondary to mutant Ki-ras expression to determine the gene(s) that contribute to adenoma (AD) development. Tumors were removed following doxycycline (DOX) treatment for 9 and 12 mo and examined for alterations in cell-cycle regulatory genes. Quantification of mRNA expression for cyclin D1, retinoblastoma, p16(Ink4a), p19(Arf), and survivin was carried out by real-time PCR. All of the tumors examined exhibited a mean reduction of approximately fivefold for the retinoblastoma gene (P < 0.02). Increased expression of both p19(Arf) and survivin were detected in a majority of the tumors examined (P < 0.01 and 0.001, respectively), but no change in cyclin D1 RNA expression was observed. A subset of the lung tumors (8/28) displayed reduced levels of p16(Ink4a) expression (P = 0.02). Immunohistochemical analysis confirmed the upregulation of p19(Arf) and survivin in all 10 of the lung tumors examined. However, increased staining for cyclin D1 was observed in the tumor tissue. In addition, increased levels of activated p53 were found in lung tumor tissues stained with an anti-phospho-p53 antibody, while an absence of staining was observed with an anti-phospho-pRb antibody in both normal control and tumor tissue. Analysis of the methylation status of p16(Ink4a) by methylation-specific PCR (MSP) demonstrated that seven of eight tumors exhibiting decreased expression of p16(Ink4a) had at least partial methylation of the promoter region. Single stranded conformational polymorphism (SSCP) analysis demonstrated that neither exons 1 or 2 of p16(Ink4a) nor exons 5-8 of p53 exhibited mutations. These data thus identify alterations in specific genes and pathways that combine with the mutation in Ki-ras to promote the formation of benign lung tumors and suggest potential targets for the development of novel chemotherapeutic and chemopreventive agents during the early stages of lung tumor progression.
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PMID:Genetic and epigenetic alterations in lung tumors from bitransgenic Ki-rasG12C expressing mice. 1648 19

Tissue factor (TF) is a transmembrane glycoprotein that initiates blood coagulation when complexed with factor VIIa (FVIIa). TF is constitutively expressed in a variety of tumor cells and has been shown to play a role in cellular signaling and tumor progression. In this study, we investigated the effect of TF-FVIIa mediated signaling on apoptosis in human breast cancer cells. Apoptosis was induced by prolonged serum starvation and studied using the Adr-MCF-7 cell line, which has high endogenous TF expression. Treatment of the cells with the combination of FVIIa (10 nM) and FX (150 nM), reduced apoptosis by nearly 50% compared with untreated, control cells using an ELISA that detects histone-DNA fragments. In contrast, FVIIa (10 nM) alone did not significantly prevent apoptosis. Pretreatment of the Adr-MCF-7 cells with hirudin, a specific thrombin inhibitor, did not inhibit the anti-apoptotic effect of the combination of FVIIa and FX, whereas this effect could be abrogated by inhibition of phosphorylation of either p44/42 mitogen-activated protein kinase (MAPK) or protein kinase B (PKB/Akt). In addition, treatment of the Adr-MCF-7 cells with the combination of FVIIa and FX led to a 30-50% increase in the level of the anti-apoptotic protein, survivin, compared with untreated cells using Western blot analysis. These results indicate that formation of TF-FVIIa-FXa complex prevents apoptosis in breast cancer cells by a thrombin-independent pathway. Moreover, the anti-apoptotic effect of this signaling pathway involves phosphorylation of both p44/42 MAPK and PKB/Akt and might be mediated in part by an increase in cell survivin levels.
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PMID:Formation of tissue factor-factor VIIa-factor Xa complex prevents apoptosis in human breast cancer cells. 1689 64

Caspases and inhibitor of apoptosis proteins (IAPs) are antagonizing key apoptosis regulators. Limited studies of a few IAPs indicated their roles in astrocytomas. However, the overall expression status and significance of apoptosis regulators in astrocytomas is not clear. We examined the expression profile of the caspases (CASP3, 6, 7, 8, 9, 10, and 14), APAF1, SMAC, BCL2, the IAPs (BIRC5/survivin, CIAP1, CIAP2, XIAP, and LIVIN), and the proliferation markers Ki67 and PHH3 in 78 diffusely infiltrating astrocytomas and 24 normal brain samples by immunohistochemistry. Western blotting for major caspases and IAPs and reverse transcription-polymerase chain reaction analyses for IAPs were performed on a subset of 27 fresh samples. Our data showed BIRC5 nuclear labeling index (BIRC5-N) was the apoptosis marker most significantly different in World Health Organization grade II to IV astrocytomas and most strongly associated with proliferative activity. Expression level of other apoptosis-related proteins was modest or low in astrocytomas and did not correlate significantly with tumor grade or proliferation. Apoptosis regulators and proliferation markers were not detected in astrocytes of normal brain by immunostaining. This expression profile suggested involvement of apoptosis regulators in astrocytoma tumorigenesis, but tumor progression was more closely associated with proliferative advantages of which BIRC5 nuclear expression appeared to be a manifestation.
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PMID:Apoptosis and proliferation markers in diffusely infiltrating astrocytomas: profiling of 17 molecules. 1695 84


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