UNIPROT:P10415 - FACTA Search

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Query: UNIPROT:P10415 (Bcl-2)
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In the present study the prognostic impact of new histological and molecular parameters were tested retrospectively in a series of 149 patients with esophageal squamous cell carcinoma (SCC) who underwent potentially curative resection therapy. In addition, the prognostic value of various molecular markers was investigated in a group of 38 patients with locally advanced esophageal SCC treated using combined therapy modalities. In the surgically treated carcinomas, the following morphological parameters proved to be prognostically significant in univariate survival analysis and multivariate survival analysis: pattern of invasion, inflammatory response, and lymph vessel invasion. In contrast, tumor grading according to the criteria of the WHO and tumor cell proliferation did not show significant prognostic impact. Concerning the prognostic influence of molecular parameters, strong expression of the proliferation regulating molecule p21WAF1 and weak expression of the apoptosis regulating molecule Bcl-XL were predictors of poor survival in univariate and multivariate survival analysis. No prognostic impact was shown in relation to the expression of p53 and the apoptosis regulating molecules Bcl-2 and Bax. In the multimodally treated esophageal cancer patients, strong expression of p21WAF1 and accumulation of p53 were predictors of poor survival, whereas expression of Bcl-2, Bax, and Bcl-XL had no prognostic significance. In conclusion, morphological and molecular parameters may provide important prognostic information for esophageal cancer patients.
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PMID:Modern pathology: prognostic parameters in squamous cell carcinoma of the esophagus. 1069 35

Our recent studies suggest that human squamous cell carcinoma of the head and neck (SCCHN) is capable of activating an intrinsic mechanism of programmed-cell death in interacting lymphocytes in situ and in vitro. The current study used Jurkat T-cell line as a model to investigate intracellular apoptotic events in T cells interacting with SCCHN. Apoptosis induced in T lymphocytes by tumor cells was in part Fas-mediated, since it was partially, but significantly, inhibited in the presence of anti-Fas ligand Ab or in Fas-resistant Jurkat cells. The synthetic caspase inhibitors, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK) and N-benzyloxycarbonyl-Asp-glu-Val-Asp-fluoromethyl ketone (Z-DEVD-FMK), effectively blocked apoptosis of Jurkat cells co-incubated with SCCHN cell lines, suggesting the involvement of caspases in tumor-induced apoptosis of lymphocytes. Overexpression of CrmA, an inhibitor of caspase-1 and caspase-8, partially inhibited tumor-induced T-cell death. Caspase-8 and caspase-3 were identified as effector molecules in the execution of tumor-induced T-cell death, since the proform enzymes were processed into active subunits during co-incubation of T cells with tumor cells. Furthermore, co-incubation with tumor cells resulted in cleavage of poly(ADP-ribose) polymerase (PARP), a common caspase-3 substrate, and in cleavage of TcR-zeta chain, shown by us to be a T-cell specific caspase-3 substrate. Overexpression of Bcl-2 did not provide protection of T cells from SCCHN-induced DNA degradation. Instead, the Bcl-2 protein was cleaved in the target T cells during their co-incubation with tumor cells. These findings demonstrate that tumor cells can trigger in T lymphocytes caspase-dependent apoptotic cascades, which are not effectively protected by Bcl-2. (Blood. 2000;95:2015-2023)
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PMID:Tumor-induced apoptosis of T lymphocytes: elucidation of intracellular apoptotic events. 1070 69

The prognostic impact of new histological and molecular parameters was tested retrospectively in a series of 149 patients with esophageal squamous cell carcinoma (SCC) who underwent potentially curative resection therapy (no distant metastases, no residual tumor, no radio- or chemotherapy). This analysis was performed in order to identify patients with increased risk for tumor-related death in spite of being treated by standard therapy and thus being candidates that most likely profit from postoperative adjuvant therapy. Additionally, the prognostic value of various molecular markers was investigated in a group of 38 patients with locally advanced esophageal SCC that have been treated with combined therapy modalities (radiochemotherapy and optionally surgery). Among surgically treated carcinomas, the following morphological parameters proved to be prognostically significant in univariate survival analysis and multivariate survival analysis: pattern of invasion, inflammatory response and lymphatic-vessel invasion. In contrast, the tumor grading according to the criteria of WHO and tumor cell proliferation did not show significant prognostic impact. Concerning the prognostic influence of molecular parameters strong expression of the proliferation-regulating molecule p21WAF1 and weak expression of the apoptosis-regulating molecule Bcl-XL were predictors of poor survival in univariate and multivariate survival analysis. No prognostic impact could be shown in relation to the expression of the proliferation-regulating molecule p53 and the apoptosis regulating-molecules Bcl-2 and Bax. Among multimodally treated esophageal cancer patients, again strong expression of p21WAF1 as well as accumulation of p53 were predictors of poor survival, whereas expression of Bcl-2, Bax and Bcl-XL did not show any prognostic influence. In conclusion, morphological and molecular parameters may provide important prognostic information for esophageal cancer patients.
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PMID:[Histological and molecular prognostic factors in esophageal cancer]. 1071 93

Ubiquitin-mediated proteolysis controls intracellular levels of various cell cycle regulatory proteins, and its inhibition has been shown to induce apoptosis in proliferating cells. In the present study, we examined induction of apoptosis in oral squamous cell carcinoma (OSCC) cells by treatment with specific proteasome inhibitors, carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal and lactacystin. In all three OSCC cell lines examined, apoptotic changes such as apoptotic body formation and DNA fragmentation were observed at various degrees after 24 h of the carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal or lactacystin treatment. HSC2 cells showed the most prominent apoptotic changes among the cell lines examined and demonstrated the highest level of accumulation of p27Kip1 protein after the treatment with proteasome inhibitor. Reduced expressions of cyclin D1 and phospho pRb were also observed after the treatment with proteasome inhibitor. Moreover, 12 h of treatment with the proteasome inhibitor inhibited cdk2/cyclin E kinase activity and increased the ratio of the cell cycle population at the G1 phase. The proteasome inhibitor led to inhibition of cell cycle progression. In addition, activation of CPP32 and reduced expression of Bcl-2 were observed. Because apoptosis induced by the proteasome inhibitor was inhibited by treatment with antisense p27Kip1 oligonucleotide, accumulation of the p27Kip1 protein might play an important role in the apoptosis induced by proteasome inhibitor. The present results suggest that inhibition of proteasome function may be used as a possible target of novel therapy for OSCC.
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PMID:p27Kip1 accumulation by inhibition of proteasome function induces apoptosis in oral squamous cell carcinoma cells. 1074 16

Among patients with resected non-small cell lung carcinoma, about 50% will present a tumor recurrence. Thus, it would be of major importance to be able to predict and try to prevent these relapses by an active chemotherapy and/or radiotherapy. In an attempt to answer this question, the tumors of 227 patients with a surgically resected non-small cell lung carcinoma were evaluated as follows: tumors were classified as squamous cell carcinoma (n = 132) or adenocarcinoma (n = 95), and tumor differentiation was evaluated for each type. Then, all tumors were classified in respect to their pathological TNM staging (WHO) and screened by immunohistochemistry for the detection of the expression of the following antigens: Bcl-2, A+B+H blood group antigens, c-erb-b2, p53, and Pan-Ras antigens. Furthermore, adenocarcinomas were screened for the presence of point mutations in Ki-Ras codons 1-31. Finally, the patient blood group was defined, and patient survival was analyzed using nonparametric tests and proportional hazard Cox models. Using Kaplan-Meier survival curves, disease pathological TNM staging was shown to be a strong predictive factor of survival for both squamous cell carcinoma and adenocarcinoma. Patients with squamous cell carcinoma experienced fewer relapses than those with adenocarcinoma (42% versus 63%; P = 0.0002) and had a significantly better survival. All evaluated antigens were more often present in squamous cell carcinoma than in adenocarcinoma except for Pan-Ras (three times more frequent in adenocarcinoma). In patients with squamous cell carcinoma, only tumor staging had a significant prognosis value (P = 0.01). In patients with lung adenocarcinoma, a well-differentiated tumor (P = 0.009) as well as a positive Bcl-2 staining (P = 0.009) and an A+B+H antigen tumor staining (P = 0.024) were associated with a better survival. In contrast, patients with a stage I or II disease and a p53-positive tumor staining and patients with the O blood group (P = 0.01) had a shorter survival. Interestingly, no relation with patient survival was related to c-erb-b2 and Pan-Ras staining. Finally, 12 point mutations were found out of 81 tumors (15%) evaluated for Ki-Ras codons 1-31; they involved codon 12 but also 8, 14, and 15 without any relationship to survival. In respect to lung adenocarcinoma, using Cox proportional hazard models stratified on tumor staging, the following markers were shown to be related to survival: (a) Independent markers of longer survival (ie., high histological degree of tumor differentiation and positive Bcl-2 and A+B+H blood group antigen expression by tumor cells); and (b) Independent markers of shorter survival (i.e., O blood group for all patients and p53 tumor staining in patients with stage I and II diseases). This study suggests that, in patients who undergo surgery for lung adenocarcinoma, the presence or absence of these criteria could be used to define a subset of patients who may benefit from a more specific follow-up.
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PMID:Predictive survival markers in patients with surgically resected non-small cell lung carcinoma. 2667 25

We investigated the proportion of apoptotic cells and the expression of apoptosis-associated proteins after the delivery of the first week of irradiation for stage IIIb uterine cervical cancer. Thirty patients with stage IIIb squamous cell carcinoma of the uterine cervix who received only irradiation therapy were registered in this study. Specimens were obtained before irradiation therapy and at the end of the first week of irradiation. The apoptotic index (AI) of each tissue specimen was calculated by counting the apoptotic cells and expressed as a percentage. Immunohistochemical evaluation for apoptosis-related proteins, p53, Bcl-2, Bax, caspase-1 and caspase-3 was also performed. The AI was 0.8+/-0.9% (mean+/-SD) before irradiation and 1.7+/-1.3% at the end of the first week of irradiation. We observed that the patients who survived more than 5 years had AI levels of 2.1+/-1.3% at the end of their first week of therapy. This rate was significantly higher than the rate of 1.1+/-0.8% (P=0.02) of the patients who died within 5 years. When the cut-off value of the AI was set at 1.7%, the sensitivity, specificity, positive predictive value, and negative predictive value for the prediction of patients' prognosis after irradiation therapy were 73.4%, 72.4%, 82.4%, and 61.5%, respectively. In 17 of the AI-positive cases, expressions of Bax (P=0.006), caspase-1 (P=0.045), and caspase-3 (P=0.013) at the end of the first week were significantly higher than before irradiation. The proportion of apoptotic cells and the expression of apoptosis-associated proteins, Bax, caspase-1, and caspase-3, at the end of the first week of irradiation could be useful predictors of the prognosis in stage IIIb squamous cell carcinoma of the uterine cervix treated by irradiation therapy.
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PMID:Detection of apoptosis and expression of apoptosis-associated proteins as early predictors of prognosis after irradiation therapy in stage IIIb uterine cervical cancer. 1074 54

The application of the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) can initiate and promote the development of oral squamous cell carcinoma of the tongue and buccal mucosa. In this study the level of expression of various markers related to the development of programmed cell death (PCD) in the respective oral carcinomas was analyzed. Sixteen male and female Syrian hamsters (Mesocrietus auratus) were treated with 0.05% DMBA for 16 weeks. Immunohistochemistry was used to observe the expression of p53, proliferating cell nuclear antigen (PCNA), Bcl-2, and nucleosome formation. Single-strand conformational polymorphism (SSCP) for exons 2-9 and sequence analysis of exon 9 of the p53 gene from normal buccal or tongue mucosa as well as the squamous cell carcinomas from the buccal mucosa or the tongue were determined. p53 (wild type) expression was significantly reduced in the tongue dysplastic mucosa or squamous cell carcinoma. The SSCP disclosed banding shifts or new bands in exons 2/3, 4, 8, and 9 for the tongue or buccal oral carcinomas (five of each). In exon 9 the mutation in codon 307 (ala)GCC-GTC(val) was present in the tongue but not in the buccal carcinoma. Other markers included the level of PCNA. PCNA was initially lower in the premalignant tongue lesions but increased in oral squamous cell carcinoma at both sites. In contrast, the amount of nucleosome formation in the tongue carcinomas was less than the level noted for buccal cancers but premalignant dysplasias in the tongue mucosa exhibited higher levels. The inhibitor of PCD, Bcl-2 was lower for dysplasias and carcinomas of the tongue compared to similar lesions of the buccal mucosa. These results indicate that oral carcinomas of different anatomical sites can exhibit differences in growth, oncogene mutation expression, and the development of PCD. The differences in Bcl-2 and nucleosome formation may signify their influence on oncogene expression and growth potential for developing transformed clones and established oral carcinomas.
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PMID:Experimental oral carcinoma of the tongue and buccal mucosa: possible biologic markers linked to cancers at two anatomic sites. 1074 77

Tumour progression is characterised by an imbalance between cell proliferation and apoptosis. The aim of our study was to estimate the importance of proliferation and apoptosis associated parameters in primary squamous cell carcinomas (SCCs) of the oral cavity and oropharynx. For determination of apoptosis, the enzymatic labelling of DNA fragmentation with a terminal transferase reaction was used in 156 tissue samples of 107 patients, including corresponding lymph-node metastases in nine cases. P53, bcl-2, and Ki-67 were determined immunohistologically. P53 was detectable in 50.5% of the cases. Positive staining was associated significantly with decreased apoptosis (P<0.003). Bcl-2 was upregulated in 31.8% of the cases depending on the tumour grading (P<0.001) and correlated negatively with apoptosis (P<0.001). Proliferation (P<0.006) and apoptosis (P<0.03) were enhanced in larger tumours, though a direct correlation between these two parameters was not proven. Nevertheless, in contrast to the conventional tumour staging and grading, neither the expression of p53 or bcl-2 nor the apoptosis or Ki-67 measurements were able to predict survival or recurrence-free survival of the patients suffering from a SCC in the oral cavity or oropharynx. Our observations suggest that the function of wild-type p53 to induce apoptosis is lost in at least half of the SCCs under study and that the physiological function of bcl-2 as potent inhibitor of apoptosis is widely preserved in oral SCC.
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PMID:Prognostic significance of apoptosis and associated factors in oral squamous cell carcinoma. 1075 98

Although carboplatin (CBDCA) has been used for the treatment of several types of tumors, the complete response rate has been limited, probably because of inherent or CBDCA-induced resistance. As a first step to overcome these problems, we tried to elucidate the mechanisms of CBDCA-mediated cytotoxicity in the squamous cell carcinoma cell line MIT7. The treatment of cells with CBDCA resulted in apoptosis in a dose-dependent manner, as assessed by the propidium iodide staining method and DNA degradation in a nucleosomal pattern. The induction of apoptosis was accompanied by the decline of mitochondrial membrane potential (Deltapsi(m) ) at 12 h following CBDCA stimulation. Variant forms of p18 Bax-alpha and p16 Bcl-x(L) were generated with the down-regulation of both Bax-alpha (p21) and Bcl-x(L) (p31) at 36 and 48 h following CBDCA stimulation, suggesting that the modulation of Bcl-2 family proteins Bax-alpha and Bcl-x(L) play some role in CBDCA-mediated apoptosis. The activation of caspase-3 and -8 occurred at 12 and 24 h following the stimulation, respectively. The pretreatment of cells with pan-caspase inhibitor Z-VAD-fmk markedly prevented CBDCA-mediated cytotoxicity/apoptosis and the modulation of Bcl-2 family proteins (generation of p18 Bax-alpha and p16 Bcl-x(L) ) with only slight prevention of decline of Deltapsi(m). Taken together, these results may suggest that activation of several caspases, including caspase-3 and -8, plays some role in CBDCA-mediated apoptosis, probably through the modification of Bcl-2 family proteins, Bax-alpha and Bcl-x(L). Moreover, caspase activation may occur downstream of membrane depolarization.
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PMID:Cleavage of Bax-alpha and Bcl-x(L) during carboplatin-mediated apoptosis in squamous cell carcinoma cell line. 1079 31

The autopsy of a 76-year-old Japanese female patient, which revealed thymic carcinoma with various tumor markers such as NSE, CYFRA, and CA-125, is presented. The patient died from hepatic failure because the liver was overtaken by the tumors. At autopsy, the thymic carcinoma was found to have metastased only in the liver. From microscopical analyses and electron microscopical findings, we diagnosed poorly differenciated squamous cell carcinoma of thymic origin. In the histochemical analyses, the tumor cells were positively stained in CA 125, CA 19-9, EMA, NSE, AE 1, AE 3, CEA, S-100, glimerius and Bcl-2. These date suggest that the tumor cells produced various tumor markers. In 222 autopsy cases of thymic malignant tumor observed in Japan over a period of 4 years, the dominant pathohistological image was squamous cell carcinoma. It is interesting that the greatest number of combined malignant tumors with thymic malignancies were thyroid papillary carcinomas.
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PMID:[An autopsy case of thymic carcinoma producing various tumor markers and the examination of 222 autopsy cases of thymic malignant tumor in Japan]. 1084 55

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