Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Receptors for gut hormones, which are often overexpressed in cancer, are clinically relevant for receptor-targeted tumor imaging and therapy. Because the receptors for the gut hormone secretin are poorly characterized, we assessed secretin receptor expression in the main secretin target, the human pancreas. We investigated 58 non-neoplastic pancreases and 55 pancreatic tumors for receptor localization and density by in vitro receptor autoradiography using [(125)I]Tyr(10) rat secretin and for secretin receptor mRNA by reverse transcriptase-polymerase chain reaction. Secretin receptors were highly expressed in non-neoplastic ducts and lobuli and also in lower amounts in ductal neoplasias, including ductal adenocarcinoma, intraductal papillary mucinous tumors, and pancreatic intraepithelial neoplasia. Reverse transcriptase-polymerase chain reaction revealed wild-type receptor mRNA in the non-neoplastic pancreas and both wild-type and spliced variant receptor transcripts in ductal adenocarcinomas. Serous cystic tumors were highly positive for secretin receptors, whereas mucinous cystic tumors were negative. This study is the first to describe the precise secretin receptor distribution in human non-neoplastic pancreas and various pancreatic tumors. High secretin receptor expression in the non-neoplastic ducts reflects the major role of secretin in bicarbonate secretion. Reduced secretin binding in pancreatic ductal tumors may relate to (alternatively spliced) secretin receptor isoforms. Thus, secretin receptors in pancreatic tumors may represent potential clinical targets.
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PMID:Secretin receptors in normal and diseased human pancreas: marked reduction of receptor binding in ductal neoplasia. 1619 32

Human telomerase is a ribonucleoprotein complex composed of at least the reverse catalytic transcriptase hTERT and RNA component hTR. The enzyme stabilizes telomere length and thereby contributes to unlimited cell proliferation, i.e. immortality. Reactivation of telomerase activity during carcinogenesis is a common hallmark in most human tumor types. Consequently, telomerase is an attractive molecular target toward which to direct cancer therapeutic agents. RNA interference (RNAi) has been shown to be an effective method for inhibiting the expression of a given gene in human cells by targeting with short duplex RNA (short-interfering RNA or siRNA). Thus, we evaluated the ability of siRNAs to inhibit telomerase activity in the HT29 immortal human colorectal adenocarcinoma cell line as a model for colorectal carcinogenesis. By transient expression of a specific siRNA directed against hTERT, we reduced telomerase activity in the transfected cells. Moreover, telomere lengths were reduced in cells stably expressing this particular RNA sequence, cloned as an shRNA into an eukaryotic expression vector. The cell clone that displayed a telomerase-negative phenotype showed dramatically reduced telomere lengths and stopped proliferation. We observed that the vector was integrated into the cell genome and, despite telomere shortening, cells retained their MSI phenotype. We conclude that we have developed a potent telomerase inhibitor leading to cell death.
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PMID:Telomerase inhibition by an siRNA directed against hTERT leads to telomere attrition in HT29 cells. 1682 Sep 26

Intraductal papillary mucinous neoplasm (IPMN) is a well-established entity in pancreatic neoplasms and a precursor of infiltrating adenocarcinoma. Fascin, an actin-bundling protein involved in cellular motility, is upregulated in many human neoplasms. Its overexpression in pancreatic intraepithelial neoplasia, a pre-cancerous lesion sharing many characteristics with IPMN, has been reported. However, fascin expression in IPMN remains unknown. The aim of this study was to investigate fascin expression in IPMNs and to elucidate its relationship to clinicopathological features, including histological grade and phenotypic subclassification. We evaluated fascin expression by immunohistochemistry in 116 surgical specimens, followed by quantitative analysis of fascin mRNA expression using a laser microdissection system and real-time reverse-transcriptase polymerase chain reaction in eight frozen samples. Fascin expression was significantly higher in borderline neoplasms (25/29, 86%) and carcinomas (37/42, 88%) than in adenomas (23/45, 51%) (P<0.05, respectively), but no difference was observed between borderline neoplasms and carcinomas. With regard to the subclassification, intestinal-type neoplasms (35/39, 90%) were more frequently positive for fascin than gastric-type neoplasms (36/59, 61%) (P<0.05). Two oncocytic-type neoplasms were both fascin-negative. Fascin mRNA expression seemed to be higher in moderately to severely dysplastic epithelium than in mildly dysplastic epithelium (not statistically significant), supporting the immunohistochemical experiments. Our findings suggest that fascin overexpression is involved in the progression of IPMN. Fascin could become a new therapeutic target for inhibition of their progression.
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PMID:Fascin overexpression in intraductal papillary mucinous neoplasms (adenomas, borderline neoplasms, and carcinomas) of the pancreas, correlated with increased histological grade. 1739 45

Previously, we have shown that pancreatic acini release adenosine triphosphate (ATP) and ATP-handling enzymes, and pancreatic ducts express various purinergic P2 receptors. The aim of the present study was to establish whether pancreatic ducts also express adenosine receptors and whether these could be involved in secretory processes, which involve cystic fibrosis transmembrane regulator (CFTR) Cl- channels or Ca2+-activated Cl- channels and H(+)/HCO(-)(3) transporters. Reverse transcriptase polymerase chain reaction analysis on rat pancreatic ducts and human duct cell adenocarcinoma lines showed that they express A1, A2A, A2B, and A3 receptors. Real-time PCR revealed relatively low messenger RNA levels of adenosine receptors compared to beta-actin; the rank order for the receptors was A2A>A2B>or=A3>>A1 for rat pancreas and A2B>A2A>>A3>or=A1 for duct cell lines. Whole-cell patch-clamp recordings on rat pancreatic ducts showed that, in about half of the recordings, adenosine depolarized the membrane voltage, and this was because of the opening of Cl- channels. Using a Cl--sensitive fluorophore and single-cell imaging on duct cell lines, it was found that 58% of PANC-1 cells responded to adenosine, whereas only 9% of CFPAC-1 cells responded. Adenosine elicited Ca2+ signals only in a few rat and human duct cells, which did not seem to correlate with Cl- signals. A2A receptors were localized in the luminal membranes of rat pancreatic ducts, plasma membrane of many PANC-1 cells, but only a few CFPAC-1 cells. Taken together, our data indicate that A2A receptors open Cl- channels in pancreatic ducts cells with functional CFTR. We propose that adenosine can stimulate pancreatic secretion and, thereby, is an active player in the acini-to-duct signaling.
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PMID:Adenosine receptors in rat and human pancreatic ducts stimulate chloride transport. 1805 56

ONECUT1 (HNF-6) is the prototype of a new class of homeodomain transcription factors, that controls the development of pancreatic ducts during mouse development. In the present study, the role of ONECUT1 and its targeted genes TCF2, PKHD1 and CYS1 was analyzed in human pancreatic ductal adenocarcinoma (PDAC). mRNA levels of ONECUT1, TCF2, PKHD1 and CYS1 were measured in pancreatic tissues and pancreatic cancer cell lines by quantitative reverse-transcriptase polymerase chain reaction (QRT-PCR). Protein expression of ONECUT1 and TCF2 was assessed in pancreatic tissues by immunohistochemistry. ONECUT1 was transfected into Panc-1 and T3M4 pancreatic cancer cells and its effects on anchorage-dependent and -independent growth as well as invasion and adhesion were analyzed. Median mRNA levels of ONECUT1, TCF2, PKHD1 and CYS1 were 7.7-, 2.0-, 5.7- and 3.8-fold higher in normal tissues than in PDAC tissues. ONECUT1 protein was expressed in normal acinar and ductal cells, but neither in the cancer cells of PDAC tissues nor in 7 of 8 cultured pancreatic cancer cell lines. There was a significant positive correlation between ONECUT1 and TCF2, CYS1, and PKHD1 mRNA levels in PDAC tissues. Transfection of ONECUT1 into pancreatic cancer cells resulted in up-regulation of the target gene TCF2, a reduction in invasiveness, but no change in adhesion or growth. In conclusion, ONECUT1 expression is lost in pancreatic cancer cells, suggesting a tumor suppressor function in this malignancy.
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PMID:Loss of ONECUT1 expression in human pancreatic cancer cells. 1809 90

The recent identification of fusion genes involving ETS family members in human prostate adenocarcinoma has confirmed the hypothesis that recurrent specific aberrations such as fusion genes may be as frequent in epithelial tumors as they are in leukemias and sarcomas. However, reciprocal translocations with fusion genes are often not detectable in carcinomas by conventional karyotyping because of additional complex chromosomal abnormalities. We retrospectively analyzed a large series of formalin-fixed, paraffin-embedded samples including 55 prostate carcinomas and 11 benign prostate tumors. We identified the fusion gene TMPRSS2-ERG by reverse-transcriptase polymerase chain reaction (RT-PCR) in 40/55 carcinomas (72%). Our study demonstrates that the detection of ETS fusion gene by RT-PCR is feasible on formalin-fixed and paraffin-embedded samples. No significant association between the presence of the fusion gene and any clinical feature, such as preoperative serum prostate-specific antigen (PSA) level (PSA>20 or PSA< or =20), pTNM stage including capsule invasion, seminal vesicle invasion, and lymph nodes metastases, or recurrence was observed in our series.
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PMID:Detection of the TMPRSS2-ETS fusion gene in prostate carcinomas: retrospective analysis of 55 formalin-fixed and paraffin-embedded samples with clinical data. 1847 93

Pancreatic ductal adenocarcinoma (PDAC) shows the worst mortality among the common malignancies and development of novel therapies for PDAC through identification of good molecular targets is an urgent issue. Among dozens of over-expressing genes identified through our gene-expression profile analysis of PDAC cells, we here report CST6 (Cystatin 6 or E/M) as a candidate of molecular targets for PDAC treatment. Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemical analysis confirmed over-expression of CST6 in PDAC cells, but no or limited expression of CST6 was observed in normal pancreas and other vital organs. Knock-down of endogenous CST6 expression by small interfering RNA attenuated PDAC cell growth, suggesting its essential role in maintaining viability of PDAC cells. Concordantly, constitutive expression of CST6 in CST6-null cells promoted their growth in vitro and in vivo. Furthermore, the addition of mature recombinant CST6 in culture medium also promoted cell proliferation in a dose-dependent manner, whereas recombinant CST6 lacking its proteinase-inhibitor domain and its non-glycosylated form did not. Over-expression of CST6 inhibited the intracellular activity of cathepsin B, which is one of the putative substrates of CST6 proteinase inhibitor and can intracellularly function as a pro-apoptotic factor. These findings imply that CST6 is likely to involve in the proliferation and survival of pancreatic cancer probably through its proteinase inhibitory activity, and it is a promising molecular target for development of new therapeutic strategies for PDAC.
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PMID:Over-expression of cysteine proteinase inhibitor cystatin 6 promotes pancreatic cancer growth. 1875 76

The translocation t(11;19)(q21;p13) results in the gene fusion of mucoepidermoid carcinoma translocated 1-mammalian mastermind like 2 genes that is the major chromosomal abnormality observed in mucoepidermoid carcinomas of salivary glands but has not been studied in bronchopulmonary mucoepidermoid carcinoma. To investigate the importance of the mammalian mastermind like 2 gene rearrangement and mucoepidermoid carcinoma translocated 1-mammalian mastermind like 2 fusion gene in bronchopulmonary mucoepidermoid carcinoma tumorigenesis and its differential diagnosis with primary pulmonary non-small-cell carcinomas, we evaluated the presence of the mammalian mastermind like 2 gene rearrangement and the mucoepidermoid carcinoma translocated 1-mammalian mastermind like 2 fusion in formalin-fixed, paraffin-embedded tissue sections from 17 adult bronchopulmonary mucoepidermoid carcinoma, 16 adenosquamous carcinomas, 24 squamous cell carcinomas, and 41 primary adenocarcinomas by fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction. We detected mammalian mastermind like 2 gene rearrangement by fluorescence in situ hybridization analysis in 13 (77%) of 17 bronchopulmonary mucoepidermoid carcinoma cases (10 of 10 being low grade and 3 of 7 being high grade). Reverse transcriptase polymerase chain reaction analysis confirmed positive fluorescence in situ hybridization results in 6 (43%) of 14 mucoepidermoid carcinoma cases. None of the squamous, adenosquamous, or adenocarcinoma cases revealed the mammalian mastermind like 2 gene rearrangement by fluorescence in situ hybridization, and the mucoepidermoid carcinoma translocated 1-mammalian mastermind like 2 fusion product by reverse transcriptase polymerase chain reaction was not identified specifically in our adenosquamous carcinoma cases. In conclusion, our study demonstrates that mammalian mastermind like 2 gene rearrangement and mucoepidermoid carcinoma translocated 1-mammalian mastermind like 2 fusion product can be detected by fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction analysis performed on low- and high-grade primary bronchopulmonary mucoepidermoid carcinoma and can be used to help discriminate low- and high-grade mucoepidermoid carcinoma from adenocarcinoma, adenosquamous carcinoma, and squamous cell carcinoma mimics in histologically challenging cases.
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PMID:Mammalian mastermind like 2 11q21 gene rearrangement in bronchopulmonary mucoepidermoid carcinoma. 1926 6

A proportion of human pulmonary adenocarcinomas has been shown previously to express an antigen related to the Gag protein of a betaretrovirus, Jaagsiekte sheep retrovirus, that causes ovine pulmonary adenocarcinoma. To investigate further the hypothesis that a retrovirus might be present in human lung adenocarcinoma, we examined specimens from patients with lung cancer for evidence of retroviral infection by immunohistochemistry, reverse transcriptase-polymerase chain reaction, immunoblotting and cDNA library screening. Thirty-eight percent of the tumor samples analyzed were positive by immunohistochemistry for Gag-related antigen of Jaagsiekte sheep retrovirus. However, this antigen was not detected by immunoblotting using the same antiserum. In addition, plasma samples from the patients did not contain antibodies reacting with Gag proteins from Jaagsiekte sheep retrovirus or other betaretroviruses on immunoblots. Reverse transcriptase-polymerase chain reaction identified the expression of endogenous betaretroviruses in tumor tissue and in normal lung tissue, but no specific provirus was associated with tumor. Expression library screening did not identify the Gag-reactive antigen. This study has confirmed the expression of a Jaagsiekte sheep retrovirus Gag-related antigen in some human lung tumors but additional evidence of betaretroviral infection was not obtained. While these data do not rule out a role for a retrovirus in human pulmonary adenocarcinomas, they suggest that, if such a virus is present, it is unrelated to known betaretroviruses.
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PMID:Absence of markers of betaretrovirus infection in human pulmonary adenocarcinoma. 2082 71

Primary adenocarcinoma with signet-ring cell component (Ad-SRCC) of the lung has been well characterized clinicopathologically and histologically, but their genetics has rarely been investigated. A recent report suggesting an association between Ad-SRCC and EML4-ALK fusion prompted us to undertake a histological, immunohistochemical, and molecular analysis of 10 cases of primary Ad-SRCC identified out of 699 lung adenocarcinomas (1.4%). Most of the Ad-SRCCs showed characteristic architectural as well as cytological features including cohesive clustering of signet-ring cells, a solid/acinar growth pattern, and alveolar filling at the tumor periphery. Diffuse co-expression of TTF-1 and p63 was observed in half of the Ad-SRCCs, and this immunoprofile has not been recognized previously. Four Ad-SRCCs (40%) harbored ALK translocations detected by reverse-transcriptase polymerase chain reaction, fluorescence in situ hybridization, and immunohistochemistry. One new EML4-ALK fusion variant was identified. One ALK-rearranged tumor showed focal squamous differentiation. None of the present Ad-SRCCs had EGFR or KRAS mutations, regardless of ALK status. This study successfully utilized tumor histology alone to identify a subset of adenocarcinomas showing a high rate of ALK translocation. The characteristic histology, immunoprofile, frequent ALK translocation, and total lack of EGFR or KRAS mutations, may suggest that Ad-SRCC forms a histologically/molecularly coherent subgroup of adenocarcinoma.
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PMID:Frequent ALK rearrangement and TTF-1/p63 co-expression in lung adenocarcinoma with signet-ring cell component. 2103 15


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