Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Fas (Apo-1/CD95)/Fas ligand (L) system is involved in cell death signaling, and has been suggested to be important for the regulation of germ cell apoptosis in the testis. Mutations of the Fas gene may result in accumulation of germ cells and thus might contribute to testicular carcinogenesis. The open reading frame of Fas cDNA was examined in 24 cases of testicular germ cell tumors (TGCTs), comprised of 19 pure histological type (15 seminomas, 3 embryonal carcinomas, 1 immature teratoma) and 5 mixed-type tumors. Mutations of the Fas gene were found in nine (37.5%) of these cases. Each lesion with a homogeneous histological picture was selectively microdissected using a laser capture microdissection method: samples consisted of 18 lesions from seminomas, 7 embryonal carcinomas, 4 immature teratomas, 2 choriocarcinomas, and 1 from a yolk sac tumor. Microdissected genomic DNA was examined to determine which mutations were derived from which kind of histological lesion. Eleven mutations were detected in 10 TGCT lesions from nine cases, but none were found in benign lesions. All were point mutations, and eight missense mutations occurred in exon 9 encoding the core protein of the death domain essential for apoptotic signal transduction. Three were silent mutations. Mutations were found in the seminoma (27.8%) and embryonal carcinoma lesions (62.5%), but none were found in the one yolk sac tumor, two choriocarcinomas, or four immature teratoma lesions. Each seminoma and embryonal carcinoma lesion found in the same case had a different type of Fas mutation from the others. Mouse T-cell lymphoma cells transfected with missense mutated genes were resistant to apoptosis induced by anti-Fas antibody, indicating these to be loss-of-function mutations. These findings suggested a role of Fas gene mutations in the pathogenesis of TGCTs.
 ...
PMID:Frequent Fas gene mutations in testicular germ cell tumors. 1216 88

Both antigen-specific and non-specific mechanisms may be involved in the pathogenesis of oral lichen planus (OLP). Antigen-specific mechanisms in OLP include antigen presentation by basal keratinocytes and antigen-specific keratinocyte killing by CD8(+) cytotoxic T-cells. Non-specific mechanisms include mast cell degranulation and matrix metalloproteinase (MMP) activation in OLP lesions. These mechanisms may combine to cause T-cell accumulation in the superficial lamina propria, basement membrane disruption, intra-epithelial T-cell migration, and keratinocyte apoptosis in OLP. OLP chronicity may be due, in part, to deficient antigen-specific TGF-beta1-mediated immunosuppression. The normal oral mucosa may be an immune privileged site (similar to the eye, testis, and placenta), and breakdown of immune privilege could result in OLP and possibly other autoimmune oral mucosal diseases. Recent findings in mucocutaneous graft-versus-host disease, a clinical and histological correlate of lichen planus, suggest the involvement of TNF-alpha, CD40, Fas, MMPs, and mast cell degranulation in disease pathogenesis. Potential roles for oral Langerhans cells and the regional lymphatics in OLP lesion formation and chronicity are discussed. Carcinogenesis in OLP may be regulated by the integrated signal from various tumor inhibitors (TGF-beta 1, TNF-alpha, IFN-gamma, IL-12) and promoters (MIF, MMP-9). We present our recent data implicating antigen-specific and non-specific mechanisms in the pathogenesis of OLP and propose a unifying hypothesis suggesting that both may be involved in lesion development. The initial event in OLP lesion formation and the factors that determine OLP susceptibility are unknown.
 ...
PMID:The pathogenesis of oral lichen planus. 1219 61

Barrett's esophagus, or columnar-lined esophagus (CLE), is a premalignant disorder in which the stratified squamous epithelium is replaced by metaplastic epithelium. To gain more insight into the process of carcinogenesis in CLE, we studied several factors involved in the apoptotic pathway in biopsies with gastric metaplasia (GM), intestinal metaplasia (IM), dysplasia, and/or adenocarcinoma. Immunohistochemistry was performed for Fas, Bcl-2, Bax, Bcl-xl, inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2). Fas staining was positive in the epithelium of all biopsies from patients with CLE but negative in normal gastric mucosa. Fas staining was positive in all tumor cells of the 8 cases containing adenocarcinoma. Bcl-2 was positive in lamina propria immune cells of all specimens. Bax staining was positive in the epithelium of all biopsies, including tumor cells. Bcl-xl was positive in dysplasia and tumor cells, but negative in 8 of 17 biopsies containing IM. iNOS was positive in 20 of 21 biopsies with IM and in 4 of 8 dysplasia biopsies. COX-2 was positive in 7 of 8 adenocarcinomas. We conclude that the apoptotic balance in the transformation from IM to adenocarcinoma switches to an antiapoptotic phenotype because of increased Bcl-xl expression and decreased Bax expression. Fas can be used as a marker for the differentiation of gastric mucosa and metaplasia in the esophagus. iNOS is highly positive in CLE-associated intestinal metaplasia. COX-2 is negative in nonmalignant CLE. Therefore, pharmacologic inhibition of COX-2 activity is unlikely to be effective in the preventing CLE-associated adenocarcinoma. There was no clear correlation between iNOS expression and activation of proapoptotic and antiapoptotic genes.
 ...
PMID:Expression of apoptosis-related proteins in Barrett's metaplasia-dysplasia-carcinoma sequence: a switch to a more resistant phenotype. 1219 18

Various cytokines and chemokines play a role in carcinogenesis. However, no study has previously been undertaken to investigate comprehensively the expressions of cytokines and chemokines in hepatoma cells. In this study, we determined which cytokines and chemokines are expressed in hepatoma cells. Recently, it was reported that the expressions of several chemokines could be increased by Fas stimulus in many normal and cancer cells. Therefore, we also investigated whether chemokines expression is regulated by Fas ligation. To address this issue, we performed RNase protection assays upon 13 cytokines and 8 chemokines genes in 10 human hepatoma cell lines, comprising 8 hepatitis B virus (HBV)-associated hepatoma cell lines. Transforming growth factor-beta2 (TGF-beta2) was found to be expressed in 8 HBV-associated hepatoma cell lines, and to be potently expressed in 5 cell lines; however, the mRNA expressions of interleukin-10 (IL-10), IL-12, interferon-gamma(IFN-gamma) and tumor necrosis factor-alpha(TNF-alpha) were not detected in any cell lines examined. Among the chemokines investigated in this study, IL-8 was expressed by 8 HBV- associated hepatoma cell lines, and monocyte chemoattractant protein-1 (MCP-1) by 7 HBV-associated hepatoma cell lines. However, the mRNA expressions of macrophage inflammatory protein-1alpha(MIP-1alpha), MIP-1beta, interferon-inducible protein-10 (IP-10), RANTES, lymphotactin and I-309 were either very weak or undetectable. Fas ligation did not increase chemokines expression in hepatoma cells. Conclusively, TGF-beta2, IL-8 and MCP-1 were overexpressed in HBV-associated hepatoma cells, and the expressions of chemokines were not increased by Fas ligation in human hepatoma cells.
 ...
PMID:Expression patterns of cytokines and chemokines genes in human hepatoma cells. 1240 81

Bile acids have been implicated in biliary tract carcinogenesis, in part, by activating the epidermal growth factor receptor (EGFR). Overexpression of Mcl-1, a potent antiapoptotic protein of the Bcl-2 family, has also been reported in cholangiocarcinomas. Because receptor tyrosine kinases like EGFR may modulate antiapoptotic protein expression, we examined the hypothesis that bile acids modulate Mcl-1 expression levels via EGFR. Deoxycholate increased cellular Mcl-1 protein in a concentration-dependent manner. The deoxycholate-mediated increase of cellular Mcl-1 protein was blocked equally by EGFR tyrosine kinase inhibitors or an EGFR-neutralizing antibody. Although inhibition of mitogen-activated protein kinases did not attenuate the deoxycholate-associated increase in Mcl-1 protein, the Raf-1 inhibitor, BAY 37-9751, effectively blocked the cellular increase of this protein. Neither Mcl-1 transcriptional activity nor its mRNA stability was altered by deoxycholate treatment. However, Mcl-1 protein stability was increased by bile acid treatment, an effect duplicated by proteasome inhibition. Deoxycholate prolongation of Mcl-1 turnover was blocked by either EGFR inhibitors or the Raf-1 inhibitor. Whereas the deoxycholate-induced increase in Mcl-1 reduced Fas-mediated apoptosis, the Raf-1 inhibitor potentiated Fas apoptosis. Our results demonstrate that bile acids block Mcl-1 protein degradation via activation of an EGFR/Raf-1 cascade resulting in its cellular accumulation. Raf-1 inhibitors block this increase of Mcl-1 and render the cells more susceptible to apoptosis, a potential therapeutic strategy for cholangiocarcinomas.
 ...
PMID:Bile acids inhibit Mcl-1 protein turnover via an epidermal growth factor receptor/Raf-1-dependent mechanism. 1243 43

The causal role of human papillomavirus (HPV) in cervical carcinogenesis is beyond reasonable questioning. The progression from HPV infection, squamous intraepithelial lesions (SIL) to squamous cell carcinomata (SCC), however, is very uncommon and inefficient. Host genetic factors that may confer the susceptibility of disease progression are largely unknown. Apoptosis is an important fail-safe check for tumor development, in which Fas/FasL interaction contributes substantially. The purpose of our study is to test the hypothesis that an A/G polymorphism at -670 of Fas promoter with different transcriptional activity is associated with the risk for cervical neoplasia. A hospital-based case-control study was conducted, in which 104 patients of low grade SIL (LSIL), 131 high grade SIL (HSIL) and 176 SCC as well as age-matched, 1:1 controls were tested for Fas polymorphism by PCR-RFLP. HPV genotypes were determined in case groups by MY PCR-reverse line blot. The frequency of A allele was significantly (p = 0.006) higher in SCC than in control, conferring an odd ratio of 1.5 (95% CI = 1.1-2.0). The distribution of Fas (-670) genotypes also differed significantly between HSIL, SCC and each of their control (p = 0.017 and 0.03, respectively), with the A/A genotype conferring an OR of 1.3 (95% CI = 1.1-1.6) and 1.6 (95% CI = 1.0-2.5), respectively. Remarkably, the frequency of A allele and A/A genotype increased gradually in accordance with the multi-step carcinogenesis from LSIL, HSIL to SCC (p(test for trend) = 0.0066 and 0.0007, respectively). In addition, there was no difference of Fas genotypes between HPV (+) and HPV (-) cases. Fas genotypes, however, differed in LSIL infected with different HPV types (p = 0.033). The present study demonstrated an association between Fas polymorphism and cervical carcinogenesis. We deduced a possible effect of apoptosis of immune cells in this virus-induced cancer.
 ...
PMID:Single nucleotide polymorphism at Fas promoter is associated with cervical carcinogenesis. 1531 39

Boswellic acids are the effective components of gum resin of Boswellia serrata, which has anti-inflammatory properties. Recent studies on brain tumors and leukemic cells indicate that boswellic acids may have antiproliferative and apoptotic effects with the mechanisms being not studied in detail. We studied their antiproliferative and apoptotic effects on colon cancer cells and the pathway leading to apoptosis. HT-29 cells were treated with beta-boswellic acid (BA), keto-beta-boswellic acid (K-BA) and acetyl-keto-beta-boswellic acid (AK-BA), respectively. Apoptosis was determined by flow cytometry, by cytoplasmic DNA-histone complex and the activity of caspase-3. The cleavage of poly-(ADP-ribose)-polymerase (PARP) and expression of Fas were examined by western blot. Specific caspase inhibitors, polyclonal Fas antibody, and antagonistic Fas antibody ZB4 were employed to elucidate apoptotic pathways. DNA synthesis and cell viability were examined. Both K-BA and AK-BA increased cytoplasmic DNA-histone complex dose-dependently and increased pre-G(1) peak in flow cytometer analysis, with the effects of AK-BA being stronger than K-BA. BA only increased the formation of DNA-histone complex at a high concentration. K-BA and AK-BA increased caspase-8, caspase-9 and caspase-3 activities accompanied by cleavage of PARP. The effects of AK-BA on formation of cytoplasmic DNA histone and on caspase-3 activation were 3.7- and 3.4-fold, respectively, more effective than those induced by camptothecin. The apoptosis induced by AK-BA was inhibited completely by caspase-3 or caspase-8 inhibitor and partially by caspase-9 inhibitor. ZB4 blocked exogenous Fas ligand-induced apoptosis, but had no effect on AK-BA-induced apoptosis. AK-BA had no significant effect on expression of Fas. Apart from apoptotic effect, these acids also inhibited [(3)H]thymidine incorporation and cell viability to different extent. In conclusion, boswellic acids, particularly AK-BA and K-BA have antiproliferative and apoptotic effects in human HT-29 cells. The apoptotic effect is mediated via a pathway dependent on caspase-8 activation but independent of Fas/FasL interaction.
Carcinogenesis 2002 Dec
PMID:Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells. 1250 32

Epidemiological studies have associated infection with Schistosoma japonicum and S. mansoni with increased risk of cancers of the liver and colon, although the mechanism of carcinogenesis remains unestablished. The livers of mice experimentally infected with S. japonicum or S. mansoni were analysed for expression of Fas (CD95/APO-1) and Fas ligand immunohistochemically and for apoptotic cell death by the TUNEL method. Fas expression was significantly decreased in hepatocytes around the inflammatory area of egg granulomas; this decrease was most prominent during the chronic phase of infection. Fas ligand was expressed in hepatocytes inside and outside granulomas, especially from mice at the early stage of infection, but not in hepatocytes from uninfected mice. Abnormal proliferation and Fas ligand expression were also observed in capillary bile ducts inside egg granulomas. Apoptotic cell death of inflammatory cells and, less frequently, of hepatocytes was found both inside and around granulomas. The rate of apoptotic cell death was high during the early stage of infection with S. mansoni, but decreased during the chronic phase of infection. Our results suggest that schistosome infection causes alterations of the Fas-Fas ligand system, one of the major apoptotic pathways, in mouse liver.
 ...
PMID:Altered Expression of Fas (APO-1, CD95) and Fas Ligand in the Liver of Mice Infected with Schistosoma Japonicum and Schistosoma Mansoni: Implications for Liver Carcinogenesis. 1271 95

The pathologic grade and clinical stage have some restrictions for the evaluation of the prognosis of prostate carcinoma. Recently, the function of genes related to apoptosis and tumor suppressor genes on the development, progression,and prognostic value of prostate carcinoma was paid close attention due to further research on the molecular pathology of prostate cancer. Overexpression of Bcl-2 was found in high malignant patients of prostate carcinoma and related to androgen refraction and resistance against anticancer agents as well. The mutation of p53 was found in prostatic intraepithelial neoplasia(PIN) and prostate cancer. p53 can be used as an independent prognostic factor for prostate cancer. The deletion of PTEN and p27 is an important negative factor of prognosis. Overexpression of p21 and p16 which are inhibition protein of cell cycle have effects on the formation and differentiation of prostate cancer. Fas/FasL system plays an important role in apoptosis of prostatic epithelial cells and takes part in the carcinogenesis of prostate. BRCA1 and p73 also have effects on the genesis and development of prostate cancer.
 ...
PMID:[Recent advances on molecular pathology of prostate carcinoma]. 1275 24

Sphingolipids can modulate cell growth, differentiation and apoptosis. In the present investigation, selective death of hepatocytes localized in enzyme-altered foci (EAF hepatocytes) was shown to be induced by sphingolipids. Sphingosine (20 micro M) caused rapid cell death predominantly of EAF hepatocytes in vitro. During 4 h of such exposure, cytochrome c was released from the mitochondria into the cytoplasm and the number of cells demonstrating cleaved caspase-9 activity increased. The selective sensitivity of EAF cells to sphingolipid-induced death was attenuated by tumor necrosis factor-alpha. In previous studies we have demonstrated that EAF hepatocytes are resistant to Fas-mediated apoptosis, a resistance shown here to be reversed by low concentrations of sphingosine. Immunohistological staining revealed higher levels of glucosylated ceramide in EAF than in the surrounding tissue. Furthermore, an inhibitor of glucosylation enhanced the toxicity of ceramide towards EAF cells. TLC analysis suggested low levels of sphingosine in preneoplastic lesions. In in vivo experiments EAF-bearing rats were fed a diet supplemented with 0.1% sphingomyelin for 2 weeks. Sphingolipid feeding reduced the number of EAF and EAF area in the liver by 40-50% as compared with rats fed a control diet. These studies indicate that the turnover of sphingolipids in preneoplastic EAF hepatocytes is altered. This alteration may explain not only the increased sensitivity of EAF cells towards sphingolipid-induced cell death, but also the resistance of these hepatocytes to cell death involving sphingolipids as second messengers. Furthermore, sphingomyelin in the diet may prevent EAF development. It is suggested that the altered turnover of sphingolipids might be a target for chemoprevention of hepatocellular carcinoma.
Carcinogenesis 2003 Jun
PMID:Sphingolipids suppress preneoplastic rat hepatocytes in vitro and in vivo. 1280 52


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>