157 research outputs found
Diagnostic significance of high mobility group I(Y) protein expression in intraductal papillary mucinous tumors of the pancreas
No full textIntroduction: Overexpression of the high mobility group I(Y), [HMGI(Y)], gene/proteins has been demonstrated in many types of human malignancies, suggesting that HMGI(Y) may play a vital role in the oncogenic transformation of cells. Aims: To analyze HMGI(Y) expression in intraductal papillary mucinous tumor (IPMT) of the pancreas to verify whether determination of the HMGI(Y) expression level could provide any diagnostic advantages in the pathological diagnosis of IPMT. Methodology: Thirty-three different lesions from 25 patients with IPMT, including 20 with mild dysplasia, 7 with moderate dysplasia, and 6 with carcinoma, were analyzed immunohistochemically with use of an HMGI(Y)-specific antibody. Results: Immunohistochemical analysis revealed that, although no significant immunoreactivity was found in cases of normal pancreatic duct or mild dysplasia, 28.6% (2/7) of moderate dysplasia showed multifocal immunoreactivity with moderate intensity. In contrast, in 50% (3/6) of the cases of carcinoma, intense multifocal or diffuse immunoreactivity Occurred, almost equivalent to that observed in cases of duct cell carcinoma, whereas in the remaining, 3 cases of carcinoma only a faint focal immunoreactivity Occurred. Histologic examination revealed that these HMGI(Y)-positive carcinomas had an invasive growth pattern, whereas the HMGI(Y)-negative carcinomas were either carcinomas in situ or tumors with minimal invasion. Thus, an increased expression level of HMGI(Y) proteins was closely associated with the malignant phenotype in IPMT. Conclusion: On the basis of these findings, we propose that HMGI(Y) proteins could play an important role(s) in a multistage process of carcinogenesis of IPMT and that the HMGI(Y) protein level could serve as a potential diagnostic marker, which may enable the identification Of tumor Cells with potential to be biologically malignant
Pancreatic duct cell carcinomas express high levels of high mobility group I(Y) proteins
No full textThe high mobility group I (HMGI) family of proteins in mammals belongs to a group of nonhistone nuclear proteins known as architectural transcriptional factors. They function in vivo as both structural components of chromatin and auxiliary gene transcription factors. In an earlier study (N, Abe et nl., Cancer Res., 59: 1169-1174, 1999), we demonstrated that the expression level of the HMGI(Y) gene/proteins was significantly increased in colorectal adenocarcinoma and colorectal adenoma with severe cellular atypia, In the current study, we analyzed HMGI(Y) expression in several human pancreatic lesions to investigate (a) whether HMGI(Y) overexpression is also observed in pancreatic carcinoma, and (b) the role of HMGI(Y) in the diagnosis of pancreatic neoplasms. To this end, HMGI(Y) expression was determined at the protein level by immunohistochemistry using a HMGI(Y)-specific antibody in 6 surgically resected specimens of nonneoplastic tissue (4 specimens of normal pancreatic tissue and 2 specimens of chronic pancreatitis tissue), 8 pancreatic cystic neoplasms (5 intraductal papillary mucinous adenomas, 1 serous cystadenoma, and 2 solid pseudopapillary tumors), and 15 duct cell carcinomas of the pancreas. Immunohistochemical analysis revealed intense nuclear staining in the pancreatic carcinoma cells, whereas only very faint nuclear staining was seen in the nonneoplastic cells. There was a strong correlation between HMGI(Y) protein overexpression and a diagnosis of carcinoma (P = 0.000018). Thus, an increased expression level of the HMGI(Y) proteins was clearly associated with the malignant phenotype in pancreatic tissue. In addition, a low level of protein expression was also apparent in two of the cystic neoplasms that exhibited cellular atypia, but not in those that did not exhibit cellular atypia, Based on these findings, we propose that the HMGI(Y) proteins could be closely associated with tumorigenesis in the pancreas and that HMGI(Y) could serve as a potential diagnostic molecular marker for distinguishing pancreatic malignancies unambiguously from normal tissue or benign lesions
High mobility group A1 is expressed in metastatic adenocarcinoma to the liver and intrahepatic cholangiocarcinoma, but not in hepatocellular carcinoma: its potential use in the diagnosis of liver neoplasms.
No full textHigh mobility group A1 is expressed in metastatic adenocarcinoma to the liver and intrahepatic cholangiocarcinoma, but not in hepatocellular carcinoma: its potential use in the diagnosis of liver neoplasms
No full textBackground. An increased level of high mobility group A (HMGA) gene/protein expression has been demonstrated to be associated with many human neoplasms originating from a variety of tissues. However, HMGA1 expression has not yet been studied in hepatic tumors. In this study, we analyzed HMGA1 expression in hepatic primary and metastatic tumors in order to verify whether determination of the HMGA1 expression level could provide any diagnostic advantages in the pathological diagnosis of hepatic tumors. Methods. Twenty samples of hepatocellular carcinoma, 5 samples of intrahepatic cholangiocarcinoma, and 21 samples of metastatic adenocarcinoma to the liver (15 metastatic tumors from colorectal carcinoma and 6 metastatic tumors from pancreatic carcinoma) were analyzed immunohistochemically using an HMGA1-specific antibody. Results. While no significant nuclear immunoreactivity was found in hepatocytes of non-neoplastic liver tissue, 40% (2/5) of intrahepatic cholangiocarcinomas, 53.3% (8/15) of metastatic lesions from colorectal carcinoma, and 100% (6/6) of metastatic lesions from pancreatic carcinoma showed positive immunoreactivity. In contrast, all 20 samples of hepatocellular carcinoma were negative for HMGA1 nuclear immunoreactivity. Thus, hepatocellular carcinoma represents the first case of malignant neoplasia in which HMGA1 expression is not induced, which presents a striking contrast to several previous studies demonstrating the significance of increased HMGA gene/protein levels in carcinogenesis and/or tumor progression. Conclusions. Based on these findings, we conclude that the HMGA1 protein level could serve as a potential diagnostic marker that may enable the differential diagnosis between hepatocellular carcinoma and intrahepatic cholangiocarcinoma or metastatic adenocarcinoma to the liver
High mobility group A1 is expressed in metastatic adenocarcinoma to the liver and intrahepatic cholangiocarcinoma, but not in hepatocellular carcinoma: its potential use in the diagnosis of liver neoplasms.
No full textHyperthermophilic archaea as a source for novel enzyme discovery
No full textThe Archaea are a group of microorganisms that are phylogenetically distinct to the Bacteria and Eucarya. Their size and shape resemble bacteria, but display stark differences in the structure of their membrane lipids and machinery that are responsible for DNA replication and transcription. In addition, Archaea seem to utilize metabolic pathways that differ to previously recognized, classical pathways in bacteria and eukaryotes. Based on the genome sequences of the Archaea, there are many cases in which a particular metabolic pathway seems to be absent or incomplete. The search for these “missing” pathways or enzymes has been an exciting field of research in the Archaea, and has led to the discovery of structurally novel enzymes or enzymes with novel activity. Until now, we have been focused on the metabolism of the hyperthermophilic archaeon Thermococcus kodakarensis. The organism is an obligate anaerobe and heterotroph, utilizing a wide range of organic compounds including peptides/amino acids, starch and maltooligosaccharides, and organic acids such as pyruvate. By searching for missing genes, we have identified a structurally novel fructose-1,6-bisphosphatase [1], a key enzyme in gluconeogenesis, and enzymes with novel activity, such as pantoate kinase and phosphopantothenate synthetase, both involved in coenzyme A biosynthesis in T. kodakarensis [2].
A number of genes predicted to encode kinases are present on the T. kodakarensis genome. Although more than half display similarity to characterized enzymes high enough to predict their substrates, there are still nearly 20 genes whose substrates are unknown. One of them turned out to be a myo-inositol 3-kinase [3]. Another was found to display an ADP-dependent ribose-1-phosphate kinase activity, which participates in a pentose bisphosphate pathway, a previously unidentified route to direct the ribose moieties of nucleosides to central carbon metabolism [4]. Another kinase was identified through studies on serine and cysteine metabolism in T. kodakarensis. The protein was initially annotated as a chromosome-partitioning protein ParB, but displayed ADP-dependent serine kinase activity. The enzyme was necessary for the conversion of Ser to Cys in vivo, and is most likely involved in Ser assimilation in this archaeon [5]. The structure of the enzyme explains the specificity of the enzyme towards Ser and ADP, and raises the possibility that structurally related proteins may also be present not only in archaea but also in bacteria [6]. These studies indicate the potential of archaea as a source for novel enzyme discovery demonstrate various means to identify gene function through genome sequence information.
[1] Rashid N, Imanaka H, Kanai T, Fukui T, Atomi H, Imanaka T. A novel candidate for the true fructose-1,6-bisphosphatase in archaea. J. Biol. Chem., 277(34):30649-30655, 2002.
[2] Yokooji Y, Tomita H, Atomi H, Imanaka T. Pantoate kinase and phosphopantothenate synthetase, two novel enzymes necessary for CoA biosynthesis in the Archaea. J. Biol. Chem., 284(41):28137-28145, 2009.
[3] Sato T, Fujihashi M, Miyamoto Y, Kuwata K, Kusaka E, Fujita H, Miki K, Atomi H. An uncharacterized member of the ribokinase family in Thermococcus kodakarensis exhibits myo-inositol kinase activity. J. Biol. Chem., 288(29):20856-20867, 2013.
[4] Aono R, Sato T, Imanaka T, Atomi H. A pentose bisphosphate pathway for nucleoside degradation in Archaea. Nat. Chem. Biol., 11(5):355-360, 2015.
[5] Makino Y, Sato T, Kawamura H, Hachisuka SI, Takeno R, Imanaka T, Atomi H. An archaeal ADP-dependent serine kinase involved in cysteine biosynthesis and serine metabolism. Nat. Commun., 7:13446, 2016.
[6] Nagata R, Fujihashi M, Kawamura H, Sato T, Fujita T, Atomi H, Miki K. Structural study on the reaction mechanism of a free serine kinase involved in cysteine biosynthesis. ACS Chem. Biol. Article ASAP, 2017. doi:10.1021/acschembio.7b00064
An increased high-mobility group A2 expression level is associated with malignant phenotype in pancreatic exocrine tissue
No full textThe altered form of the high-mobility group A2 (HMGA2) gene is somehow related to the generation of human benign and malignant tumours of mesenchymal origin. However, only a few data on the expression of HMGA2 in malignant tumour originating from epithelial tissue are available. In this study, we examined the HMGA2 expression level in pancreatic carcinoma, and investigated whether alterations in the HMGA2 expression level are associated with a malignant phenotype in pancreatic tissue. High-mobility group A2 mRNA and protein expression was determined in eight surgically resected specimens of non-neoplastic tissue (six specimens of normal pancreatic tissue and two of chronic pancreatitis tissue) and 27 pancreatic carcinomas by highly sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) techniques and immunohistochemical staining, respectively. Reverse transcriptase-polymerase chain reaction analysis revealed the expression of the HMGA2 gene in non-neoplastic pancreatic tissue, although its expression level was significantly lower than that in carcinoma. Immunohistochemical analysis indicated that the presence of the HMGA2 gene in non-neoplastic pancreatic tissue observed in RT-PCR reflects its abundant expression in islet cells, together with its focal expression in duct epithelial cells. Intense and multifocal or diffuse HMGA2 immunoreactivity was noted in all the pancreatic carcinoma examined. A strong correlation between HMGA2 overexpression and the diagnosis of carcinoma was statistically verified. Based on these findings, we propose that an increased expression level of the HMGA2 protein is closely associated with the malignant phenotype in the pancreatic exocrine system, and accordingly, HMGA2 could serve as a potential diagnostic molecular marker for distinguishing pancreatic malignant cells from non-neoplastic pancreatic exocrine cells
An increased high-mobility group A2 expression level is associated with malignant phenotype in pancreatic exocrine tissue.
No full textAn increased high-mobility group A2 expression level is associated with malignant phenotype in pancreatic exocrine tissue.
No full textStructural Determination and Chemical Synthesis of the N-Glycan from the Hyperthermophilic Archaeon Thermococcus kodakarensis
No full textAsparagine-linked protein glycosylations (N-glycosylations) are one of the most abundant post-translational modifications and are essential for various biological phenomena. Herein, we describe the isolation, structural determination, and chemical synthesis of the N-glycan from the hyperthermophilic archaeon Thermococcus kodakarensis. The N-glycan from the organism possesses a unique structure including myo-inositol, which has not been found in previously characterized N-glycans. In this structure, myo-inositol is highly glycosylated and linked with a disaccharide unit through a phosphodiester. The straightforward synthesis of this glycan was accomplished through diastereoselective phosphorylation and phosphodiester construction by SN2 coupling. Considering the early divergence of hyperthermophilic organisms in evolution, this study can be expected to open the door to approaching the primitive function of glycan modification at the molecular level
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