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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular markers (biomarkers) for hepatocellular carcinoma (HCC) metastasis and recurrence could provide additional information to that gained from traditional histopathological features. A large number of biomarkers have been shown to have potential predictive significance. One important aspect of this is to detect the transcripts of tumor-associated antigens (such as AFP, MAGEs, and CK19), which are proposed as predictive markers of HCC cells disseminated into the circulation and for metastatic recurrence. Another important aspect is to analyze the molecular markers for cellular malignancy phenotype, including DNA ploidy, cellular proliferation index, cell cycle regulators, oncogenes, and tumor suppressors (especially p53 gene), as well as telomerase activity. Molecular factors involved in the process of HCC invasion and metastasis, including adhesion molecules (E-cadherin, catenins, ICAM-1, laminin-5, CD44 variants, osteopontin), proteinases responsible for the degradation of extracellular matrix (MMPs, uPA system), as well as angiogenesis regulators (such as VEGF, intratumor MVD), have also been shown to be potential predictors for HCC metastatic recurrence and clinical outcomes. One important new trend is to widely delineate biomarkers with genomic and proteomic expression with reference to predicting metastatic recurrence, molecular diagnosis, and classification, which has been drawing more attention recently. Body fluid (particularly blood and urine) testing for biomarkers is easily accessible and more useful in clinical patients. The prognostic significance of circulating DNA in plasma or serum and its genetic alterations is another important direction. More attention should be paid to these areas in the future. As understanding of tumor biology deepens, more and more new biomarkers with high sensitivity and specificity for HCC metastatic recurrence could be found and routinely used in clinical assays. However, the combination of the pathological features and some of the biomarkers mentioned above seems to be more practical up to now.
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PMID:Recent progress in predictive biomarkers for metastatic recurrence of human hepatocellular carcinoma: a review of the literature. 1520 47

Osteoclast-like giant cell tumors (OLGT) are rare neoplasms of the pancreas and mostly associated with ductal adenocarcinomas. In this report, we present the rare case of OLGT associated with mucinous cystadenocarcinoma (MCC). We investigated the expression profile of both tumors by methods of molecular biology and immunohistochemistry. The panel of markers included osteopontin, her2/neu, mismatch repair genes, K-ras, p53, E-cadherin, VEGF-C, and podoplanin. Osteopontin was expressed by the osteoclast-like giant cells but not by the mononuclear tumor cells of the OLGT. We detected an amplification and overexpression of her2/neu in the MCC but not in the OLGT. Although we observed an immunohistochemical expression of hMSH2 and hMLH1 in the OLGT, we were not able to confirm this result by western blot analysis. We also did not find any microsatellite instability (D2S123, BAT26). While mutation of K-ras codon 12 was found in both tumor components, there was wild-type DNA of p53. E-cadherin was expressed in MCC but not in OLGT. VEGF-C was only positive in osteoclast-like giant cells and some of the mononuclear cells of OLGT. The vessel-rich stroma of OLGT did not present any podoplanin-positive lymphatic vessel. The observation of our case and others in the published literature may indicate separating OLGT with undifferentiated carcinoma from OLGT with MCC for the better clinical outcome of the latter.
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PMID:Osteoclast-like giant cell tumor in mucinous cystadenocarcinoma of the pancreas: an immunohistochemical and molecular analysis. 1573 12

Ovarian serous carcinoma (OSC) is the most common ovarian epithelial malignancy. Recently, a dualistic pathway of ovarian serous carcinogenesis has been proposed based on morphologic observations and molecular genetic analysis. In this scheme, low-grade OSC arises in a stepwise fashion from a benign serous cystadenoma through a usual serous borderline tumor through a micropapillary variant of serous borderline tumor. In contrast, the more common high-grade OSC arises de novo from the ovarian surface epithelium or the epithelium of cortical inclusion cysts with an as yet unrecognized precursor lesion. Although the division of OSC into low- and high-grade variants is gaining greater acceptance, and although there is accumulating molecular genetic evidence for this, there is little published information regarding a comparison of protein expression between these two types of OSC. In this study, we have investigated the immunohistochemical expression of a wide range of proteins in cases of low-grade (n = 22) and high-grade (n = 47) OSC. Antibodies used were p53, MIB1, BCL2, WT1, HER-2/neu, C-KIT, osteopontin, and survivin. For all antibodies, except MIB1, cases were scored as 0 (negative or occasional positive cells), 1+ (<10% cells positive), 2+ (10%-25% cells positive), 3+ (26%-50% cells positive), 4+ (51%-75% cells positive) or 5+ (>75% cells positive). For MIB1, the percentage of positive nuclei was calculated. There was a statistically significant higher expression of p53, MIB1, BCL2, HER-2/neu, and C-KIT in high-grade compared with low-grade OSC (P < 0.05). Thirty of 47 (64%) cases of high-grade OSC exhibited 5+ staining with p53 compared with 4 of 22 (18%) low-grade neoplasms. Twelve of 47 (26%) high-grade OSCs exhibited 5+ staining with BCL2 compared with 1 of 22 (5%) low-grade OSCs. The mean MIB1 proliferative index in high-grade OSCs was 55.4% compared with 23.0% in low-grade OSCs. Virtually all cases of both low-grade and high-grade OSCs exhibited diffuse nuclear positivity with WT1 and diffuse cytoplasmic positivity with survivin. Osteopontin expression was variable with no significant difference in expression between low-grade and high-grade OSC. Although expression of both HER-2/neu and C-KIT was significantly higher in high-grade compared with low-grade OSC, only rare cases exhibited strong positivity with these antibodies, which could be of therapeutic value in individual cases, although this would require additional molecular investigations. The significant differences in protein expression between low-grade and high-grade OSC provides further support for a different underlying pathogenesis. In particular, the differences in p53 immunoreactivity are in keeping with the observation that p53 gene mutation is more common in high-grade than low-grade OSC.
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PMID:An immunohistochemical comparison between low-grade and high-grade ovarian serous carcinomas: significantly higher expression of p53, MIB1, BCL2, HER-2/neu, and C-KIT in high-grade neoplasms. 1600 97

Stathmin, a major microtubule-depolymerizing protein, is involved in cell cycle progression and cell motility. This study aimed to elucidate its role in the progression, early tumour recurrence (ETR), and prognosis of hepatocellular carcinoma (HCC). Stathmin mRNA was overexpressed in 88/156 (56%) resected, unifocal, primary HCCs, while p53 mutation was present in 72 (46%) and osteopontin mRNA overexpression in 79 (51%). Stathmin mRNA expression exhibited high concordance (93%) with protein expression in 107 cases examined by immunohistochemistry. Stathmin overexpression correlated with high alpha-fetoprotein (>200 ng/ml, p = 0.02), larger tumour size (>5 cm, p = 0.012), high tumour grade (p < 0.0002), high tumour stage (stage IIIA-IV) with vascular invasion and various degrees of intrahepatic metastasis (p < 1 x 10(-8)), ETR (p = 0.003), and lower 5-year survival (p = 0.0007). Stathmin protein expression was often more intense in the peripheral regions of tumour trabeculae, tumour borders, and portal vein tumour thrombi. Stathmin overexpression correlated with p53 mutation (p = 0.017) and osteopontin overexpression (p = 1 x 10(-8)), both of which were associated with vascular invasion (both p < 0.0001) and poorer prognosis (p < 0.0004 and p = 0.0004, respectively). Regardless of the status of p53 mutation or osteopontin expression, stathmin overexpression was associated with higher vascular invasion (all p < 0.0001). Approximately 90% of HCCs harbouring stathmin overexpression with concomitant p53 mutation or osteopontin overexpression exhibited vascular invasion, and hence the lowest 5-year survival, p = 0.00018 and p = 0.0009, respectively. However, we did not find that stathmin overexpression exerted prognostic impact independent of tumour stage. In conclusion, stathmin expression correlates with metastatic potential, is an important prognostic factor for HCC, and may serve as a useful marker to predict ETR.
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PMID:Stathmin overexpression cooperates with p53 mutation and osteopontin overexpression, and is associated with tumour progression, early recurrence, and poor prognosis in hepatocellular carcinoma. 1673 96

Osteoporosis due to unloading-induced bone loss is a critical issue in the modern aging society. Although the mechanisms underlying this phenomenon are largely unknown, osteopontin (OPN) is one of the critical mediators required for unloading-induced bone loss [M. Ishijima, S.R. Rittling, T. Yamashita, K. Tsuji, H. Kurosawa, A. Nifuji, D.T. Denhardt, and M. Noda, Enhancement of osteoclastic bone resorption and suppression of osteoblastic bone formation in response to reduced mechanical stress do not occur in the absence of osteopontin, J Exp Med, 193 (2001) 399-404]. To clarify the molecular bases for OPN actions, we carried out microarray analyses on the genes expressed in the femoral bone marrow cells in wild type and OPN-/- mice. The removal of the mechanical load induced bone loss in wild type, but not in OPN-/- mice, as previously reported. Expression analysis of 9586 cDNAs on a microarray system revealed that OPN deficiency blocked tail-suspension-induced expression of ten genes (group A). This observation was confirmed based on semi-quantitative RT-PCR analyses. On the other hand, expression of four genes (group B) was not altered by tail suspension in wild type but was enhanced in OPN-deficient mice. NF-kappaB p105 subunit gene (Nfkb1) was found in group A and Bax in group B. p53 gene expression was upregulated by tail suspension in wild type mice, but it was no longer observed in OPN-/- mice. These data indicate that OPN acts to mediate mechanical stress signaling upstream to the genes encoding apoptosis-related molecules, and its action is associated with alteration of the genes.
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PMID:Osteopontin is associated with nuclear factor kappaB gene expression during tail-suspension-induced bone loss. 1688 70

Impairment of the complex regulatory network of cell death and survival is frequently the reason for therapy resistance of breast cancer cells and a major cause of tumor progression. We established two independent cell lines from a fast growing mouse breast tumor (WAP-SVT/t transgenic animal). Cells from one line (ME-A cells) are sensitive to apoptotic stimuli such as growth factor depletion or treatment with antitumor agents (e.g. doxorubicin). Cells from the second line (ME-C cells), which carry a missense mutation at the p53 codon 242, are very insensitive to apoptotic stimuli. Co-cultivation experiments revealed that the ME-C cells mediate cell death resistance to the ME-A cells. Microarray and Western blot analysis showed that osteopontin (OPN) is selectively overexpressed by the ME-C cells. This glycoprotein is the most abundant protein secreted by the ME-C cells and we obtained strong indications that OPN is the main antiapoptotic factor. However, the OPN containing ME-C cell medium does not alter the expression level of pro- or antiapoptotic genes or known inhibitors of apoptosis (IAPs). Its signaling involves mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)1/2 as the kinase inhibitor PD98059 restores apoptosis but not the Akt inhibitor. In the ME-A cells, mitochondrial cytochrome c release occurs with and without external apoptotic stimuli. OPN containing ME-C cell medium does not prevent the mitochondrial cytochrome c release and caspase-9 processing. In serum starved ME-A cells, the OPN containing ME-C cell medium prevents caspase-3 activation. However, in doxorubicin-treated cells, although apoptosis is blocked, it does not inhibit caspase-3. This indicates that the ME-A cells distinguish between the initial apoptotic stimuli and that the cells possess a further uncharacterized control element acting downstream from caspase-3.
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PMID:Chemotherapy resistance of mouse WAP-SVT/t breast cancer cells is mediated by osteopontin, inhibiting apoptosis downstream of caspase-3. 1716 24

Osteopontin (OPN) is a secreted, integrin-binding matrix phosphorylated glycoprotein that is overexpressed in many advanced cancers. However, the functional mechanisms by which OPN contributes to the development of ovarian cancer are poorly understood. Here, we reveal that acquired expression of OPN by HO-8910 ovarian cancer cells greatly promoted the progression of ovarian cancer. OPN expression dramatically increased the colony formation of ovarian cancer cells in vitro and tumor growth in vivo. Under the stress induced by serum depletion or curcumin treatment, OPN expression promoted the survival of ovarian cells through preventing stress-induced apoptosis. At the molecular level, both endogenous and exogenous OPN expression activated the PI3-K/Akt survival pathway and dramatically decreased p53 expression under serum depletion. In addition, HIF-1alpha was induced in OPN-producing cells under normoxia. Furthermore, we also found that inhibition of the PI3-K/Akt pathway attenuated OPN-mediated HIF-1alpha up-regulation in ovarian cancer cells. Taken together, these results indicate that OPN can increase the survival of ovarian cancer cells under stress conditions in vitro and promote the late progression of ovarian cancer in vivo, and the survival-promoting functions of OPN are mediated through Akt activation and the induction of HIF-1alpha expression.
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PMID:Osteopontin promotes ovarian cancer progression and cell survival and increases HIF-1alpha expression through the PI3-K/Akt pathway. 1901 48

For the application of microarray technology as an additional endpoint in toxicological studies, there is a need to understand associations between pathological processes and gene expression alterations. In the current study, we investigated gentamicin as a nephrotoxic model compound. Gene expression changes of the kidney in response to a dose of 80 mg/kg gentamicin were analyzed by using DNA microarray technology and alterations in gene expression were associated with results from conventional histopathological investigations and with the described pathomechanisms of gentamicin. Under the conditions of our experiment, the mRNA level of 211 genes were found to be deregulated by gentamicin. The gentamicin-induced affection of proximal convoluted tubules was associated with a strong up-regulation of mRNAs encoding for proteins which are used as nephrotoxicity markers in urine and plasma such as Kim-1, Osteopontin and TIMP1. Candidate marker genes for nephrotoxicity such as GATM were deregulated. Gentamicin-induced lysosomal phospholipidosis was indicated by deregulation of lysosomal located gene products such as ATP6V1D, a subunit of the lysosomal H+ transporting ATPase. Effects on glucose transport and metabolism were indicated by the down-regulation on SGLT-2 and glucose-6-phosphatase. Renal cell apoptosis was indicated by up-regulated genes as TP53 and BAX. The role of oxidative stress in gentamicin toxicity was reflected by deregulation of transferrin receptor and heme oxygenase. The results of the study show the potential of microarray technology to study a complex mechanism of toxicity in a single study.
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PMID:Identification of genes involved in gentamicin-induced nephrotoxicity in rats--a toxicogenomic investigation. 1966 12

Osteopontin (OPN) is highly expressed in cancer patients and plays important roles in many stages of tumor progression, such as anti-apoptosis, proliferation, and metastasis. From functional screening of human cDNA library, we isolated OPN as a caspase-8 substrate that regulates cell death during hypoxia/reoxygenation (Hyp/RO). In vitro cleavage assays demonstrate that OPN is cleaved at Asp-135 and Asp-157 by caspase-8. Cellular cleavage of OPN is observed in apoptotic cells exposed to Hyp/RO among various apoptotic stimuli and its cleavage is blocked by zVAD or IETD caspase inhibitor. Further, over-expression of OPN, the form with secretion signal, inhibits Hyp/RO-induced cell death. Caspase cleavage-defective OPN mutant (OPN D135A/D157A) is more efficient to suppress Hyp/RO-induced cell death than wild-type OPN. OPN D135A/D157A sustains AKT activity to increase cell viability through inhibition of caspase-9 during Hyp/RO. In addition, OPN is highly induced in some tumor cells during Hyp/RO, such as HeLa and Huh-7 cells, which is associated with their resistance to Hyp/RO by sustaining AKT activity. Notably, OPN C-terminal cleavage fragment produced by caspase-8 is detected in the nucleus. Plasmid-encoded expression of OPN C-terminal cleavage fragment increases p53 protein level and induces apoptosis of wild-type mouse embryonic fibroblast cells, but not p53(-/-) mouse embryonic fibroblast cells. These observations suggest that the protective function of OPN during Hyp/RO is inactivated via the proteolytic cleavage by caspase-8 and its cleavage product subsequently induces cell death via p53, postulating caspase-8 as a negative regulator of tumorigenic activity of OPN.
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PMID:Intracellular cleavage of osteopontin by caspase-8 modulates hypoxia/reoxygenation cell death through p53. 1970 14

Osteopontin (OPN) is a secreted glycoprotein implicated to function in cancer development and metastasis. Although elevated expression of OPN are observed in cancer cells of various types, in some cases, only the cells in the stromal region surrounding the tumor express OPN, suggesting distinct functional roles for this protein derived from host cells and from cancer cells. To provide a model for addressing the functions and mechanisms of host-derived OPN in cancer progression and metastasis, a cutaneous squamous cell carcinoma cell line (ONSC) that lacks the OPN gene, Spp1, was established. This line of cells was derived from a squamous cell carcinoma that developed in a female, OPN-null mouse subjected to two-stage skin carcinogenesis. Morphologically, ONSC cells resemble epithelial cells, and they express the epithelial markers, K1, K14, and p63, as confirmed by immunohistochemical analyses. Genomic analyses indicate the presence of mutated H-Ras and p53 genes. ONSC cells form colonies in soft agar and, subcutaneously injected into athymic nude mice, develop into squamous cell carcinomas that metastasize to the lungs. Lacking OPN expression, these squamous cell carcinoma cells provide a model to address the function of host OPN in the context of cancer progression and metastasis.
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PMID:Establishment and characterization of an osteopontin-null cutaneous squamous cell carcinoma cell line. 1991 34


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