Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since its first description 50 years ago, fibrolamellar carcinomas (FLCs) have been recognized as a unique type of primary liver cancer. FLCs occur principally in children and young adults and are not associated with chronic liver disease. Their etiology is unknown. The tumor is made up of large polygonal cells containing abundant eosinophilic cytoplasm, large vesiculated nuclei, and large nucleoli, with tumor cells that are embedded in lamellar bands of fibrosis. Although rare, the most common variant of FLC shows areas of glandular type differentiation with mucin production. The uniqueness of FLC extends to their molecular findings, as they show no evidence for involvement by many of the major pathways and genes that are dysregulated in typical hepatocellular carcinoma, including alpha-fetoprotein, TP53 mutations, and beta catenin mutations. FLCs are not indolent tumors, but have an overall better prognosis than hepatocellular carcinomas of the usual sort because of the younger age at presentation and lack of cirrhosis. The most important prognostic feature is resectability. Although their morphologic appearance on routine stains is well defined, their etiology is still unknown and much of their molecular biology remains poorly described and awaits future investigation.
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PMID:Review of the clinicopathologic features of fibrolamellar carcinoma. 1745 18

Hepatic adenomas are benign neoplasms of the liver that occur in several well-defined clinical settings, but principally that of excess hormone exposure. They have a small but poorly characterized risk of malignant degeneration. The clinical presentation and pathological findings were reviewed for all hepatic adenomas resected between January 1, 2003 and July 1, 2006. Immunohistochemistry for p53, beta-catenin and alpha-fetoprotein (AFP) were performed on those cases with malignant transformation and exon 3 of beta-catenin was amplified and sequenced. A total of 17 hepatic adenomas were resected and 3 showed malignant transformation. All three cases were in women with an age range of 23-33 years. The clinical presentations were vague abdominal pain. Histologically, the malignant transformation occurred within otherwise typical hepatic adenomas. Two of three cases showed patchy atypia throughout the hepatic adenoma. The hepatocellular carcinoma arose as distinct nodules directly within the adenomas, effectively ruling out synchronous lesions. The hepatocellular carcinomas were unifocal in two cases and multifocal in one case with the greatest dimensions of the hepatocellular carcinoma being 2.5, 2.2, and 1 cm. Immunostains for AFP and beta-catenin were negative in both the hepatic adenomas and areas of hepatocellular carcinoma. p53 immunostaining was positive within the areas of malignant transformation in one case. No mutations or deletions were seen in exon 3 of the beta-catenin gene for either the adenomas or the carcinoma. In conclusion, two of the cases that developed hepatocellular carcinomas showed cytological atypia in the background adenoma. The hepatocellular carcinomas arose as distinct nodules within the adenomas. No common molecular pathway of hepatocellular carcinogenesis was observed by examining AFP, beta-catenin, and p53 immunostains and no beta-catenin mutations or deletions were found.
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PMID:Malignant transformation of hepatic adenomas. 1824 41

Dendritic cell (DC)-based immunotherapy is rapidly emerging as a promising treatment in cancer therapy. We had previously shown that DC pulsed with either defined mRNA of tumor antigen (Ag) such as alpha-fetoprotein (AFP), or total RNA of hepatocellular carcinoma (HCC) could elicit Ag-specific cytotoxic T lymphocyte (CTL) response. Therefore, we suggested a novel DC-based therapeutic method, in which DCs derived from CD34(+) cells enriched peripheral blood mononuclear cells were pulsed with liposome-coated AFP and mutant P53 (mtP53) fused gene pEGFP-C3/AFP-mtP53 to induce bi-targeted specific CTL responses against HCC. Three different genotype HCC cell lines, HepG2 (human histocompatibility leukocyte antigens (HLA) A2 positive, AFP expressing positive, P53 expressing negative), SMMC7721 (HLA A2 positive, neither AFP nor P53 expressing positive), and HMCC97 (HLA A2 positive, both AFP and P53 expressing positive) were selected as targets for CTL responses. An important finding was that DCs pulsed with the liposome-coated fused gene could evoke more intensive bi-targeted Ag-specific CTL responses against HMCC97 than DCs pulsed with either AFP or P53 single gene (P < 0.05). This experimental therapeutic model provides a new promising cytotherapeutic approach, in that DCs pulsed with the fused gene of different Ags might induce more extensive multitargeted antitumor immunity.
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PMID:Dendritic cells pulsed with alpha-fetoprotein and mutant P53 fused gene induce bi-targeted cytotoxic T lymphocyte response against hepatic carcinoma. 1842 51

Despite years of study focused on the tumor suppressor p53, little is understood about its functions in normal, differentiated cells. We found that p53 directly interacts with lysine-specific demethylase 1 (LSD1) to alter chromatin structure and confer developmental repression of the tumor marker alpha-fetoprotein (AFP). Chromatin immunoprecipitation (ChIP) and sequential ChIP of developmentally staged liver showed that p53 and LSD1 cooccupy a p53 response element, concomitant with dimethylated histone H3 lysine 4 (H3K4me2) demethylation and postnatal repression of AFP transcription. In p53-null mice, LSD1 binding is depleted, H3K4me2 is increased, and H3K9me2 remains unchanged compared to those of the wild type, underscoring the specificity of p53-LSD1 complexes in demethylation of H3K4me2. We performed partial hepatectomy of wild-type mouse liver and induced a regenerative response, which led to a loss of p53, increased H3K4me2, and decreased LSD1 interaction at AFP chromatin, in parallel with reactivation of AFP expression. In contrast, nuclear translocation of p53 in mouse embryonic fibroblasts led to p53 interaction with p21/CIP1 chromatin, without recruitment of LSD1, and to activation of p21/CIP1. These findings reveal that LSD1 is targeted to chromatin by p53, likely in a gene-specific manner, and define a molecular mechanism by which p53 mediates transcription repression in vivo during differentiation.
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PMID:p53-targeted LSD1 functions in repression of chromatin structure and transcription in vivo. 1857 81

The expression of alpha-fetoprotein (AFP), a tumor-associated antigen, is silenced in normal adult hepatocyte but reactivated in human hepatocellular carcinoma (HCC). To investigate the roles of AFP in the regulation of cell growth, we silenced AFP expression in the HCC cell line Huh7 by transfection of specific Stealth RNAi. After the transfection for 48 h, the expression of AFP gene was almost abolished, the cell proliferation was inhibited by 46.15%, and the number of cells undergoing early apoptosis was significantly increased to 63.93%. Inhibition of AFP expression also resulted in an increased in Bax/Bcl-2 ratio, the release of cytochrome c from mitochondria and activation of caspase-3. The results suggest that AFP may positively regulate cell proliferation by enhancing the apoptosis resistance via dysfunction of the p53/Bax/cytochrome c/caspase-3 signaling pathway in AFP-producing HCC cell line. As such, the knockdown of AFP gene should be further investigated in vivo as a novel approach to HCC treatment.
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PMID:Silencing alpha-fetoprotein expression induces growth arrest and apoptosis in human hepatocellular cancer cell. 1865 99

Various molecular changes characterizing organ-specific carcinogenesis have been identified in human tumors; however, the molecular mechanisms of the genomic changes specific for each cancer are not well defined. A transgenic (Tg) mouse model with constitutive expression of the nucleotide-editing enzyme, activation-induced cytidine deaminase (AID), develops tumors in various organs as a result of the mutagenic activities of AID. This phenotypic character of AID Tg mice allowed us to analyze the organ-specific genetic changes in tumor-related genes commonly triggered by AID-mediated mutagenesis. Among the 80 AID Tg mice analyzed, 11 mice developed hepatocellular carcinomas, and 7 developed lung cancers. In addition, 1 developed the gastric cancer and 3 developed gastric adenomas. Organ-specific preferences for nucleotide changes were observed in some of the tumor-related genes in each epithelial tissue of the AID Tg mice. Of note, the c-myc and K-ras genes were the preferential targets of the mutagenic activity of AID in lung and stomach cancers, respectively, whereas mutations in the p53 and beta-catenin genes were commonly observed in all 3 organs. Quantitative RT-PCR analyses revealed that alpha-fetoprotein, insulin-like growth factor-2 and cyclin D1 genes were specifically upregulated in HCC, whereas upregulation of the matrix metalloproteinase-7 gene was more marked in lung cancer. Our findings suggest that AID, a DNA mutator that plays a critical role linking inflammation to human cancers, might be involved in the generation of organ-specific genetic diversity in oncogenic pathways during cancer development.
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PMID:Organ-specific profiles of genetic changes in cancers caused by activation-induced cytidine deaminase expression. 1878 63

The immunohistochemical investigation used 55 primary hepatic tumors (hepatocellular carcinoma (HCC)--32, cholangiocellular carcinoma (CCC)--23). Wide panels of such antibodies as hepatocytic marker (Hep Par--1) CK-8, CK-19, polyclonal CEA, CD10, alpha-fetoprotein, TTF-1 as well as proliferative features of HCC (Ki-67) including regulators of stage-to-stage transition through mitoses of tumor cells (cyclin-D1 and A, genes p53 and RB), unrestricted tumor cell mitosis (telomerases), and intercellular adhesion marker (beta-catenin) were employed for differential diagnosis of neoplasia. The most efficient marker HCC was Hep Par--l (sensitivity--100%, specificity--92%) while the sensitivity of CCC (CK-19) was 83% and specificity--78%. Of particular importance for differentiation between HCC and CCC were the nature of microcirculatory flow identifiable with the aid of CD31 and presence of pseudocapsule in HCC detected by means of calponin. CEA and CD10 played a part too while the remaining markers were either expressed very seldom (alpha-fetoprotein) or absent (TTF-1). Most nuclear antigens (Ki-67, cyclin-A, p53 and RB) were intensely expressed in poorly-differentiated HCC cells. Cyclin-D1 and mutated suppressor-gene p53 expression involved lowered overall and relapse-free survival.
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PMID:[The significance of immunohistochemistry in the investigation of liver neoplasms: differential diagnosis, prognostic markers]. 1894 95

The prognosis of hepatocellular carcinoma (HCC) is poor and current therapies are largely ineffective. Transcatheter arterial chemoembolization is a standard treatment option for patients with unresectable HCC, especially when combined with other therapies. We report a 62-year-old male with huge HCC. The patient was first treated with adenovirus-mediated wild-type p53 gene (Ad-p53, gendicine) combined with oxaliplatin (200 mg) and transcatheter arterial chemoembolization or transcatheter arterial chemotherapy for two cycles. Review showed tumor shrinkage and a decrease in alpha-fetoprotein. Oxaliplatin was stopped because of side effects. Then the patient was treated with a tumor feeding arterial injection of Ad-p53 (1 x 10 viral particles) twice and Ad-p53 (1 x 10 viral particles) followed by 5-fluorouracil (500-750 mg) six times through port-catheter system. We observed marked tumor shrinkage and sustained normal alpha-fetoprotein and liver function during a 614-day follow-up period.
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PMID:A patient with huge hepatocellular carcinoma who had a complete clinical response to p53 gene combined with chemotherapy and transcatheter arterial chemoembolization. 1931 14

Epigenetic control of genes that are silent in embryonic stem cells, but destined for expression during differentiation, includes distinctive hallmarks, such as simultaneous activating/repressing (bivalent) modifications of chromatin and DNA hypomethylation at enhancers of gene expression. Although alpha-fetoprotein (Afp) falls into this class of genes, as it is silent in pluripotent stem cells and activated during differentiation of endoderm, we find that Afp chromatin lacks bivalent histone modifications. However, critical regulatory sites for Afp activation, overlapping Foxa1/p53/Smad-binding elements, are located within a 300-bp region lacking DNA methylation, due to transposed elements underrepresented in CpG sequences: a short interspersed transposable element and a medium reiterated sequence 1 element. Forkhead family member Foxa1 is activated by retinoic acid treatment of embryonic stem cells, binds its DNA consensus site within the short interspersed transposable/medium reiterated sequence 1 elements, and displaces linker histone H1 from silent Afp chromatin. Small interfering RNA depletion of Foxa1 showed that Foxa1 is essential in providing chromatin access to transforming growth factor beta-activated Smad2 and Smad4 and their subsequent DNA binding. Together these transcription factors establish highly acetylated chromatin and promote expression of Afp. Foxa1 acts as a pioneer transcription factor in de novo activation of Afp, by exploiting a lack of methylation at juxtaposed transposed elements, to bind and poise chromatin for intersection with transforming growth factor beta signaling during differentiation of embryonic stem cells.
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PMID:Foxa1 functions as a pioneer transcription factor at transposable elements to activate Afp during differentiation of embryonic stem cells. 2034

We present the clinicopathological features of eight cases of large cell undifferentiated bladder carcinoma not otherwise specified (LCUBC). LCUBC was characterised by sheets of large polygonal or round cells with moderate to abundant cytoplasm and distinct cell borders. The LCUBC component varied from 90 to 100% of the tumour specimen with five cases showing pure LCUBC. The architectural pattern of the tumour varied from infiltrating tumour to solid expansile nests with focal (<5%) discohesive growth pattern in two cases. Immunohistochemical staining demonstrated that LCUBC cases were positive for cytokeratins AE1/AE3 and 7; CAM 5.2, CK20, thrombomodulin and uroplakin III were positive in six, three, three and two cases, respectively. Other immunohistochemical markers performed in the differential diagnosis context included alpha-fetoprotein, beta human chorionic gonadotrophin (betahCG), prostate specific antigen (PSA), vimentin, synaptophysin and chromogranin and all were negative. Ki-67 and p53 labelling indexes were 50-90% and 40-90%, respectively. All patients had advanced stage cancer (>or=pT3) and seven (87.5%) had lymph node metastases. Follow-up information was available in all cases, with a range of 6-26 months (mean 10.6 months). Six patients died of disease between 5 and 26 months and two patients were alive with metastases at 6 and 14 months. The prognosis of LCUBC was compared with conventional urothelial carcinoma of similar stages showing survival differences (p =0.0004). In summary, LCUBC is an aggressive variant of urothelial carcinoma that presents at an advanced stage.
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PMID:Large cell undifferentiated carcinoma of the urinary bladder. 2043 10


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