Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The putative tumor metastasis suppressor protein Nm23-H1 is a nucleoside diphosphate kinase that exhibits a novel protein kinase activity when bound to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In this study we show that the glycolytic enzyme phosphoglycerate mutase B (PGM) becomes phosphorylated in the presence of the Nm23-H1.GAPDH complex in vitro. Mutation of His-10 in PGM abolishes the Nm23-H1.GAPDH complex-induced phosphorylation. Nm23-H1, GAPDH, and PGM are known to co-localize as shown by free flow isoelectric focusing. In association with Nm23-H1 and GAPDH, PGM could be activated by dCTP, which is a substrate of Nm23-H1, in addition to the well known PGM activator 2,3-bisphosphoglycerate. A synthetic cell-penetrating peptide (PGMtide) encompassing the phosphorylated histidine and several residues from PGM (LIRHGE) promoted growth arrest of several tumor cell lines, whereas proliferation of tested non-tumor cells was not influenced. Analysis of metabolic activity of one of the tumor cell lines, MCF-7, indicated that PGMtide inhibited glycolytic flux, consistent with in vivo inhibition of PGM. The specificity of the observed effect was further determined experimentally by testing the effect of PGMtide on cells growing in the presence of pyruvate, which helps to compensate PGM inhibition in the glycolytic pathway. Thus, growth of MCF-7 cells was not arrested by PGMtide in the presence of pyruvate. The data presented here provide evidence that inhibition of PGM activity can be achieved by exogenous addition of a polypeptide, resulting in inhibition of glycolysis and cell growth arrest in cell culture.
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PMID:Phosphoglycerate mutase-derived polypeptide inhibits glycolytic flux and induces cell growth arrest in tumor cell lines. 1518 Oct 8

Colorectal-carcinoma specimens are heterogeneous and include areas of nonmalignant mucosal and connective tissue. For those study designs in which laser microdissection and RNA preamplification are impracticable, the optimal yield of genuine cancer RNA is a key factor in gene-expression analysis. In this study we compared alternative methods of tissue purification. Three contiguous 0.5-cm(3) samples taken from an advanced primary adenocarcinoma of the sigmoid colon were processed immediately after surgery with the use of the following methods: (1) cryotomy after manual dissection (CMD), (2) microscopically assisted manual dissection (MAMD), and (3) tumor-cell isolation with the use of Ber-EP4 antibodies and Dynabeads (Dynal Biotech GmbH, Hamburg, Germany; technique abbreviated as DB). We generated gene-expression profiles with the use of GeneChip technology (Affymetrix, Santa Clara, Calif) and recorded preparation times, costs, and RNA quantity and quality. CMD took 60 minutes, MAMD 180 minutes, and DB 90 minutes to isolate 22, 8, and 23 microg of RNA, respectively. Expenses for materials amounted to 41, 23, and 91 US dollars for CMD, MAMD, and DB, respectively. The 3'/5' ratio, as determined with the GeneChips, for GAPDH/beta-actin was 1.01:1.03 for CMD, 1.13:1.28 for MAMD, 1.43:1.68 for DB, K-ras, APC, smad 2, transforming growth factor-beta, and p53 were marked as present in all cases, with the exception of APC, which was graded as marginal on DB. The correlation values of gene-expression profiles were 91% (CMD/DB), 93% (CMD/MAMD), and 97% (DB/MAMD). All 3 methods provided enough RNA, of sufficient quality, for gene-expression microarray analysis in colorectal carcinoma. Cross-methodologic analyses of array data should not be performed uncritically.
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PMID:Tissue preparation for gene expression profiling of colorectal carcinoma: three alternatives to laser microdissection with preamplification. 1519 50

Survivin has been identified as one of the top 4 transcripts among 3.5 million human transcriptomes uniformly up-regulated in cancer tissues but not in normal tissues. Therefore, we quantitatively determined the messenger RNA (mRNA) expression profile for survivin by a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) technique in 113 patients with leukemias, such as adult T-cell leukemia (ATL), acute lymphoid leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia in crisis, and chronic lymphocytic leukemia (CLL), and in 25 cell lines, including 7 ATL cell lines and 15 solid-tumor cell lines. Furthermore, we examined whether the plasma level of survivin protein as measured by enzyme-linked immunosorbent assay (ELISA) substituted for mRNA expression by PCR quantification. Gene expression was quantitatively confirmed to be up-regulated in approximately 90% of ATL and acute leukemia cases and in all of the cell lines tested, whereas it was down-regulated in almost all cases of CLL. Furthermore, with respect to the interpretation of the gene expression findings, attention was paid to standardization with a housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in the real-time PCR quantification, because the variability in GAPDH expression among the different cell types was significant. GAPDH expression was relatively low in ATL cells and high in ALL and AML cells. The rates of increase in the levels of survivin protein in the plasma of ATL patients and in the supernatants from in vitro cultures of solid-tumor cell lines were low compared with rates of increase of the mRNA and protein level in the cells, suggesting that the protein levels in plasma do not always reflect survivin expression in tumor cells. Our findings indicate the potential clinical relevance of survivin quantified by real-time PCR but not for the protein level in plasma as determined by ELISA, especially in cases of ATL and acute leukemias.
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PMID:Clinical relevance of survivin as a biomarker in neoplasms, especially in adult T-cell leukemias and acute leukemias. 1529 68

The importance of epigenetic modifications in carcinogenesis has been a source of controversy for some time. There is little doubt that changes in genomic hypermethylation contribute to the silencing of tumor suppressor genes. Furthermore, recent studies have also identified the significance of genomic hypomethylation associated with chromosomal instability and tumorigenesis. One of the most perplexing questions regarding epigenetic modifications and leukemogenesis is the relationship with DNA methyltransferases (DNMT's). The primary function of the DNMT enzymes is to methylate genomic DNA, whereas the methyl-CpG binding domain proteins (MBD) interpret this methylation signal and regulate gene expression and chromatin behavior. In this study we analyse these gene families by quantitative real-time PCR to investigate whether expression levels and the B-cell chronic lymphocytic leukemia (B-CLL) phenotype are associated. Furthermore, given the epigenetic crosstalk between genome stability and the histone chromatin code we have analysed eukaryotic histone methyltransferase (Eu-HMTaseI). Surprisingly, we did not observe significant changes in DNMT1 expression in B-CLL cases when compared to normal lymphocytes, regardless of whether we normalise against GAPDH or PCNA as reference standards. Indeed, expression of the maintenance and de novo methylases were independently regulated. Of particular note was the significant down regulation of DNMT3b. Furthermore, we observed a positive correlation between HMTaseI expression levels and stage of leukemia suggesting that changes in the methylation patterns in B-CLL may represent deregulation of the epigenetic repertoire that also include the methylation dependent binding proteins, MBD2 and MeCP2. We envisage changes in the epigenetic program are multifactorial in nature and postulate that the prevalent genomic methylases just one component of a larger epigenetic repertoire.
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PMID:Expression analysis of the epigenetic methyltransferases and methyl-CpG binding protein families in the normal B-cell and B-cell chronic lymphocytic leukemia (CLL). 1546 27

For interpretation of quantitative gene expression measurements in clinical tumor samples, a normalizer is necessary to correct expression data for differences in cellular input, RNA quality, and RT efficiency between samples. In many studies, a single housekeeping gene is used for normalization. However, no unequivocal single reference gene (with proven invariable expression between cells) has been identified yet. As the best alternative, the mean expression of multiple housekeeping genes can be used for normalization. In this study, no attempt was made to determine the gold-standard gene for normalization, but to identify the best single housekeeping gene that could accurately replace the measurement of multiple genes. Expression patterns of 13 frequently used housekeeping genes were determined in 80 normal and tumor samples from colorectal, breast, prostate, skin, and bladder tissues with real-time quantitative RT-PCR. These genes included, large ribosomal protein, beta-actin, cyclophilin A, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerokinase 1, beta-2-microglobin, beta-glucuronidase, hypoxanthine ribosyltransferase (HPRT), TATA-box-binding protein, transferrin receptor, porphobilinogen deaminase, ATP synthase 6, and 18S ribosomal RNA. Principal component analysis was used to analyze these expression patterns, independent of the level of expression. Our approach identified HPRT as the single best reference gene that could be used as an accurate and economic alternative for the measurement of multiple housekeeping genes. We recommend this gene for future studies to standardize gene expression measurements in cancer research and tumor diagnostics until a definite gold standard has been determined.
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PMID:Normalization of gene expression measurements in tumor tissues: comparison of 13 endogenous control genes. 1554 3

The authors recently reported that adoptive immunotherapy with autologous tumor-reactive tumor infiltrating lymphocytes (TILs) immediately following a conditioning nonmyeloablative chemotherapy regimen resulted in an enhanced clinical response rate in patients with metastatic melanoma. These observations led to the current studies, which are focused on a detailed analysis of the T-cell antigen reactivity as well as the in vivo persistence of T cells in melanoma patient 2098, who experienced a complete regression of all metastatic lesions in lungs and soft tissues following therapy. Screening of an autologous tumor cell cDNA library using transferred TILs resulted in the identification of novel mutated growth arrest-specific gene 7 (GAS7) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene transcripts. Direct sequence analysis of the expressed T-cell receptor beta chain variable regions showed that the transferred TILs contained multiple T-cell clonotypes, at least six of which persisted in peripheral blood for a month or more following transfer. The persistent T cells recognized both the mutated GAS7 and GAPDH. These persistent tumor-reactive T-cell clones were detected in tumor cell samples obtained from the patient following adoptive cell transfer and appeared to be represented at higher levels in the tumor sample obtained 1 month following transfer than in the peripheral blood obtained at the same time. Overall, these results indicate that multiple tumor-reactive T cells can persist in the peripheral blood and at the tumor site for prolonged times following adoptive transfer and thus may be responsible for the complete tumor regression in this patient.
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PMID:Persistence of multiple tumor-specific T-cell clones is associated with complete tumor regression in a melanoma patient receiving adoptive cell transfer therapy. 1561 45

A primary objective of many protein expression studies is to define expression patterns that can distinguish between normal and diseased states, enabling a better understanding of molecular events associated with disease development and progression and ultimately potentially finding novel markers or therapeutic targets. Exploration and confirmation of many proteins is often done using Western blotting with normalization against "housekeeping proteins", such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH), beta-actin, or beta-tubulin, to correct for protein loading and factors, such as transfer efficiency. Increasingly, in studies examining gene transcript levels, it has been shown that some of the commonly used housekeeping genes may be unsuitable due to the influence of various physiological and pathological factors on their expression. This has not been examined to any great extent for proteins, however. This study examines the degree of variability of three commonly used "housekeeping" proteins (GAPDH, beta-actin, and beta-tubulin) together with class I beta-tubulin, with comparisons being made between a number of different established renal cancer cell lines, matched pairs of renal tumor and normal kidney lysates as well as nine different human tissues and highlights some of the problems encountered.
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PMID:Housekeeping proteins: a preliminary study illustrating some limitations as useful references in protein expression studies. 1562 64

Human telomerase reverse transcriptase (hTERT) mRNA expression has been considered a surrogate marker for telomerase activity based on its parallel detection in urological malignancies, including transitional cell carcinoma (TCC) of the bladder. The objective of this study was to prospectively evaluate the diagnostic performance of urine hTERT mRNA marker and urine cytology in the detection of bladder cancer. The multiplex hTERT/GAPDH (glyceraldehyde-3-phosphate dehydrogenase) reverse transcription polymerase chain reaction (RT-PCR) assay was employed to assess hTERT mRNA expression in urine sediments from 43 patients with clinically apparent TCC undergoing transurethral resection. Tumor grade and pathological stage were determined. The results of urine cytology were compared with urine hTERT mRNA expression. The control group consisted of 46 age-matched healthy volunteers without known urinary tract disease. The sensitivity of hTERT mRNA expression marker in the detection of bladder cancer was significantly better than urine cytology (95% versus 65%, p<0.001). The hTERT mRNA was detected with high sensitivity in both low and high grade tumors, and in superficial and invasive phenotypes. No correlation was seen between hTERT mRNA and the histopathological grade and stage. The specificity of urinary hTERT mRNA marker was 93.5%. The detection of hTERT mRNA expression in urine was a highly sensitive marker for the diagnosis of TCC of the bladder in this study. This urine-based marker shows promise as a non-invasive adjunct to cystoscopy in patients undergoing bladder tumor surveillance.
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PMID:A prospective evaluation of the diagnostic and potential prognostic utility of urinary human telomerase reverse transcriptase mRNA in patients with bladder cancer. 1563 67

The matrix metalloproteinase (MMP) family members catalyze extracellular proteolysis. Recent reports have suggested that expression of MMP-2 and -9 might play a critical role in neoplastic tissue invasion or metastasis. In this study, the relationship between the expression of MMP-2 and -9 and the histological features of tissues from 21 cases of human glioma were investigated. MMP-2 and -9 proteins were detected by immnohistochemical studies. Amplification of MMP-2 and -9 mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR) assay. MMP-2 and -9 mRNA was measured quantitatively by the real-time RT-PCR method. Immunohistochemically, 38% of the cases were positive for MMP-2. Amplification of MMP-2 mRNA by RT-PCR was detected in 62% of the cases. There was no significant relationship between the expression of MMP-2 protein or mRNA and the biological nature of the tumors, including aggressiveness and histologic classification. The quantity of MMP-2 mRNA was 0.035 +/- 0.113 (MMP-2/GAPDH %), which was significantly elevated in cases of neoplastic dissemination or recurrence (P < 0.05). Tumor cells were immunohistochemically positive for MMP-9 in 81% of the samples. A positive reaction was found not only in neoplastic cells but also in endothelial cells, suggesting that the expression of MMP-9 protein might be associated with tumoral angiogenesis. The expression of mRNA in MMP-9 was detected in 91% of the cases, suggesting a close relationship between expression of MMP-9 and malignancy. The quantity of MMP-9 was 0.097 +/- 0.113 (MMP-9/GAPDH %) in all samples, which was significantly elevated in cases of glioblastoma (P < 0.05). The average Ki-67 labeling index was 8.14 +/- 5.26 in samples from G2 glioma, 19.92 +/- 11.29 in samples from G3 glioma, and 23.52 +/- 10.14 in samples from glioblastoma. All of the cases with elevated indices had recurrence or dissemination. The results of our study suggest that quantity analyses of MMP-2 and -9 mRNA and Ki-67 labeling index should be useful for discerning tumoral behaviors such as invasion, dissemination, and recurrence.
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PMID:Expression and quantitative analysis of matrix metalloproteinase-2 and -9 in human gliomas. 1569 70

Neuroblastoma (NB) is the most common malignant solid tumor in childhood, and among all childhood malignancies is second in prevalence only to leukemia. In NB we need to both make an accurate diagnosis and rapidly analyze the expression of genetic prognostic factors such as MYCN, H-ras, and trkA. Moreover, it has recently become important to analyze the expression of survivin mRNA, a member of the inhibitor of apoptosis protein family. Expression of the survivin gene is related to tumorigenesis and inhibition of apoptosis in some malignant tumors. We investigated its expression by reverse transcription-polymerase chain reaction (RT-PCR) in NB cell lines (SK-N-SH, NB-39, and IMR-32), two normal blood cell samples, and 13 clinical NB tumor samples. All three NB cell lines had high levels of mRNA expression for this gene, but normal blood cells had no expression. We detected expression of survivin mRNA in 7 of the 13 NB tumor samples (54%). Two NB patients were in stage I disease, 6 in stage II, and 5 in stage IV(A). Quantitative analysis by RT-PCR revealed that the ratio between survivin mRNA and human glyceraldehyde-3-phosphate dehydrogenase (h-GAPDH) mRNA was very low in stages I and II (0-0.017). In contrast, in advanced NBs (stage IV(A)) the ratio was much higher (0-0.050). The prognoses of the three patients in the advanced stage who had high ratios of expression were poor. A high level of expression of survivin mRNA indicates a high grade of malignancy, high likelihood of recurrence, and poor prognosis.
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PMID:Significance of survivin mRNA expression in prognosis of neuroblastoma. 1580 87


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