Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Differential screening of a human hepatocellular carcinoma complementary DNA library using subtracted probes allowed us to identify a novel gene named HIP whose expression at the transcriptional level was elevated in liver tumors. The protein potentially encoded by the complementary DNA showed 68.5% identity with the bovine pancreatic thread protein and 49% identity with the human reg protein, which has been proposed as a pancreatic islet cell regenerating factor and is identical to the pancreatic stone or pancreatic thread protein. Sequence analysis suggests that the bovine pancreatic thread protein encoding gene is, in fact, the bovine homologue of the HIP gene. Furthermore, data base searches revealed a significant similarity of the HIP and pancreatic stone protein/pancreatic thread protein/reg sequences with the C-type lectin superfamily. The HIP sequence, like pancreatic stone protein/pancreatic thread protein/reg protein, consists of a single carbohydrate recognition domain linked to a signal peptide which would be involved in secretion of the protein. HIP mRNA was expressed at a high level in the tumors of seven of 29 hepatocellular carcinomas. In contrast, HIP mRNA was not detected in nontumorous adjacent areas or in normal adult and fetal liver, suggesting that HIP could be involved in liver cell proliferation or differentiation. HIP mRNA expression is tissue specific, since it is present in the normal small intestine and pancreas, while it could not be evidenced in colon, brain, kidney, or lung. In summary, our results show the existence of a novel family within the superfamily of C-type lectin which may be involved in liver, pancreatic, and intestinal cell proliferation or differentiation.
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PMID:A novel gene (HIP) activated in human primary liver cancer. 132 91

We originally isolated the HIP/PAP gene in a differential screen of a human hepatocellular carcinoma cDNA library. This gene is expressed at high levels in 25% of primary liver cancers but not in nontumorous liver. HIP/PAP belongs to the family of C-type lectins and acts as an adhesion molecule for hepatocytes. In normal adult human tissues, HIP/PAP expression is found in pancreas (exocrine and endocrine cells) and small intestine (Paneth and neuroendocrine cells). In order to gain insight into the possible role of HIP/PAP in vivo, we have investigated the pattern of HIP/PAP expression in the developing postimplantation mouse embryo by in situ hybridization. Detailed analysis of developing mouse embryos revealed that HIP/PAP gene exhibits a restricted expression pattern during development. Thus, HIP/PAP transcripts are first observed within the nervous system from day 14.5 onwards in trigeminal ganglia, dorsal root ganglia, and spinal cord where it appears to be an early specific marker of a subpopulation of motor neurons. At laster stages, HIP/PAP transcripts were detected in intestine and pancreas at day 16.5 but not in embryonic liver. This highly restricted expression pattern suggests that HIP/PAP might participate in neuronal as well as intestinal and pancreatic cell development.
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PMID:HIP/PAP gene, encoding a C-type lectin overexpressed in primary liver cancer, is expressed in nervous system as well as in intestine and pancreas of the postimplantation mouse embryo. 1032 12

Human HIP/PAP is an adhesion protein expressed in normal pancreatic and Paneth cells and overexpressed in hepatocellular carcinoma. HIP/PAP was crystallized using the Hampton Research Crystal Screen and SAmBA software to define the optimal crystallization protocol. The crystals belong to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 30.73, b = 49.35, c = 92.15 A and one molecule in the asymmetric unit. Flash-frozen crystals diffract to 1. 78 A resolution using synchrotron radiation. A molecular-replacement solution was obtained using the human Reg/lithostathine structure and the AMoRe software.
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PMID:Crystallization and preliminary crystallographic study of HIP/PAP, a human C-lectin overexpressed in primary liver cancers. 1041 4

Hepatocarcinoma-intestine-pancreas/pancreatic associated protein (HIP/PAP) gene was identified because of its increased expression in 25% of human hepatocellular carcinoma. HIP/PAP protein, a C-type lectin, binds laminin, acts as an adhesion molecule for hepatocytes, and has also been described as an acute phase secretory protein during acute pancreatitis in humans and rats. We investigated HIP/PAP protein expression in patients with various liver diseases associated with ductular reaction. At the same time, we analyzed patients with hepatocellular carcinoma and cholangiocarcinoma, and tested HIP/PAP protein levels in sera to establish the pattern of secretion. Our data show that HIP/PAP expression was not restricted to hepatocellular carcinoma, but was also detected in cholangiocarcinoma cells as well as in reactive non-malignant bile ductules. In contrast, HIP/PAP protein expression was undetectable in normal mature hepatocytes, but some ductular cells localized at the interface of portal tracts with parenchyma were HIP/PAP immunoreactive in normal liver. Finally, we present evidence that HIP/PAP serum levels were increased in 21/28 (75%) patients with hepatocellular carcinoma, and in 25/51 (49%) patients with nonmalignant cirrhosis. Altogether, these results suggest that HIP/PAP protein may be implicated in hepatocytic and cholangiolar differentiation and proliferation.
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PMID:Hepatocarcinoma-intestine-pancreas/pancreatic associated protein (HIP/PAP) is expressed and secreted by proliferating ductules as well as by hepatocarcinoma and cholangiocarcinoma cells. 1055 Mar 9

New biomarkers of pancreatic adenocarcinoma are needed to improve the early detection of this deadly disease. We performed surface enhanced laser desorption ionization (SELDI) mass spectrometry using ProteinChip technology (Ciphergen Biosystems, Fremont, CA) to screen for differentially expressed proteins in pancreatic juice. Pancreatic juice samples obtained from patients undergoing pancreatectomy for pancreatic adenocarcinoma were compared with juice samples from patients with other pancreatic diseases. We identified a peak approximately 16,570 daltons present in the pancreatic juice from 10/15 (67%) of the patients with pancreatic adenocarcinoma and in the pancreatic juice from 1/7 (17%) of the patients with other pancreatic diseases. Using a ProteinChip immunoassay, we identified this differentially expressed protein as hepatocarcinoma-intestine-pancreas/pancreatitis-associated-protein I (HIP/PAP-I), a protein released from pancreatic acini during acute pancreatitis and overexpressed in hepatocellular carcinoma. We then quantified by ELISA the pancreatic juice HIP/PAP-I levels in 43 patients (28 with pancreatic adenocarcinoma, 15 with other pancreatic diseases) and the serum HIP/PAP-I levels in 98 patients (53 with pancreatic adenocarcinoma, 45 with other pancreatic diseases or healthy individuals). HIP/PAP-I levels were significantly higher in both the pancreatic juice (P < 0.001) and in the serum (P < 0.001) of patients with pancreatic adenocarcinoma compared with the control group. HIP/PAP-I levels were approximately 1000-fold higher in pancreatic juice compared with serum and the magnitude of the difference between the pancreatic adenocarcinoma group and the control group was greater in the pancreatic juice samples (143.75 +/- 235.52 microg/ml versus 6.04 +/- 7.59 microg/ml) than in the serum samples (99.96 +/- 140.66 ng/ml versus 35.25 +/- 28.44 ng/ml). In our study, patients with pancreatic juice HIP/PAP-I levels > or= 20 microg/ml were 21.9 times (95% confidence interval, 3.5-136.5; P < 0.001) more likely to have pancreatic adenocarcinoma than patients with levels <20 microg/ml. Immunolabeling of tissue sections revealed that the HIP/PAP-I protein was strongly expressed in acini adjacent to the invasive adenocarcinoma, but it was only rarely (1/30; 3%) expressed in the neoplastic epithelium, which suggests that the main source of HIP/PAP-I release in the pancreatic juice is acini. This low level of HIP/PAP-I expression in pancreatic adenocarcinoma was confirmed by reverse transcription-PCR: only 1 (5%) of 19 pancreatic cancer cell lines expressed HIP/PAP-I transcripts. Taken together, these data suggest that pancreatic juice measurement of HIP/PAP-I may help to identify patients with pancreatic adenocarcinoma.
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PMID:Identification of hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein I as a biomarker for pancreatic ductal adenocarcinoma by protein biochip technology. 1191 67

The present study attempts to shed more light on the role of hepatocarcinoma-intestine-pancreas/pancreatic associated protein (HIP/PAP) in hepatoma cells. We initially examined, by reverse transcription-polymerase chain reaction (RT-PCR), the HIP/PAP transcripts present in human hepatoma cell lines of different origins and with different grades of differentiation and genetic profiles. We also used DNA sequencing analysis to investigate the structure of the HIP/PAP gene. Further investigation is necessary to define the role of HIP/PAP during the development of human hepatocellular carcinoma and to ascertain whether the use of different transcripts is helpful in regulating HIP/PAP expression in transformed liver cells.
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PMID:Expression of HIP/PAP mRNA in human hepatoma cell lines. 1209 28

HIP/PAP is a C-type lectin overexpressed in hepatocellular carcinoma (HCC). Pleiotropic biological activities have been ascribed to this protein, but little is known about the function of HIP/PAP in the liver. In this study, therefore, we searched for proteins interacting with HIP/PAP by screening a HCC cDNA expression library. We have identified the RII alpha regulatory subunit of cAMP-dependent protein kinase (PKA) as a partner of HIP/PAP. HIP/PAP and RII alpha were coimmunoprecipitated in HIP/PAP expressing cells. The biological relevance of the interaction between these proteins was established by demonstrating, using fractionation methods, that they are located in a same subcellular compartment. Indeed, though HIP/PAP is a protein secreted via the Golgi apparatus we showed that a fraction of HIP/PAP escaped the secretory apparatus and was recovered in the cytosol. Basal PKA activity was increased in HIP/PAP expressing cells, suggesting that HIP/PAP may alter PKA signalling. Indeed, we showed, using a thymidine kinase-luciferase reporter plasmid in which a cAMP responsive element was inserted upstream of the thymidine kinase promoter, that luciferase activity was enhanced in HIP/PAP expressing cells. Thus our findings suggest a novel mechanism for the biological activity of the HIP/PAP lectin.
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PMID:HIP/PAP, a C-type lectin overexpressed in hepatocellular carcinoma, binds the RII alpha regulatory subunit of cAMP-dependent protein kinase and alters the cAMP-dependent protein kinase signalling. 1537 27

Regenerating gene (Reg), first isolated from a regenerating islet cDNA library, encodes a secretory protein with a growth stimulating effect on pancreatic beta cells that ameliorates the diabetes of 90% depancreatized rats and non-obese diabetic mice. Reg and Reg-related genes have been revealed to constitute a multigene family, the Reg family, which consists of four subtypes (types I, II, III, IV) based on the primary structures of the encoded proteins of the genes [Diabetes 51(Suppl. 3) (2002) S462]. Plural type III Reg genes were found in mouse and rat. On the other hand, only one type III REG gene, HIP/PAP (gene expressed in hepatocellular carcinoma-intestine-pancreas/gene encoding pancreatitis-associated protein), was found in human. In the present study, we found a novel human type III REG gene, REG III. This gene is divided into six exons spanning about 3 kilobase pairs (kb), and encodes a 175 amino acid (aa) protein with 85% homology with HIP/PAP. REG III was expressed predominantly in pancreas and testis, but not in small intestine, whereas HIP/PAP was expressed strongly in pancreas and small intestine. IL-6 responsive elements existed in the 5'-upstream region of the human REG III gene indicating that the human REG III gene might be induced during acute pancreatitis. All the human REG family genes identified so far (REG Ialpha, REG Ibeta, HIP/PAP, REG III and REG IV) have a common gene structure with 6 exons and 5 introns, and encode homologous 158-175-aa secretory proteins. By database searching and PCR analysis using a yeast artificial chromosome clone, the human REG family genes on chromosome 2, except for REG IV on chromosome 1, were mapped to a contiguous 140 kb region of the human chromosome 2p12. The gene order from centromere to telomere was 5' HIP/PAP 3'-5' RS 3'-3' REG Ialpha 5'-5' REG Ibeta 3'-3' REG III 5'. These results suggest that the human REG gene family is constituted from an ancestor gene by gene duplication and forms a gene cluster on the region.
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PMID:Molecular cloning, expression and chromosomal localization of a novel human REG family gene, REG III. 1555 4

The Wnt/beta-catenin signaling pathway is activated in many human hepatocellular carcinomas (HCC). We tried to identify the genes involved in carcinogenesis and progression of HCC with beta-catenin mutations. We used PCR-based subtractive hybridization to compare gene expression between malignant and benign components of a human HCC occurring in pre-existing adenoma activated for beta-catenin. Two of the genes identified belong to the Regenerating gene (REG) family. They encode the Regenerating islet-derived 3 alpha (REG3A/HIP/PAP/REG-III) and 1 alpha (REG1A) proteins, both involved in liver and pancreatic regeneration and proliferation. Using siRNA directed against beta-catenin, we demonstrated that REG3A is a target of beta-catenin signaling in Huh7 hepatoma cells. The upregulation of REG3A and REG1A expression is significantly correlated to the beta-catenin status in 42 HCC and 28 hepatoblastomas characterized for their beta-catenin status. Thus, we report strong evidence that both genes are downstream targets of the Wnt pathway during liver tumorigenesis.
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PMID:Overexpression of regenerating islet-derived 1 alpha and 3 alpha genes in human primary liver tumors with beta-catenin mutations. 1631 47

Hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP) protein, a member of the reg family, is constitutively expressed by some specialized epithelial cell subsets in the digestive tract and the pancreas. We performed a detailed analysis of the expression of HIP/PAP protein in normal digestive endocrine cells according to their localization, lineage, and differentiation stage, and in digestive endocrine tumors according to their site of origin and hormonal profile. In both adult and fetal normal tissues, HIP/PAP expression was detected only in endocrine cells of the small intestine, ascending colon, and pancreas. Two different expression patterns were identified: (a) a strong cytoplasmic labeling observed in the endocrine cells of the digestive mucosa and the outer rim of Langerhans islets specialized in the synthesis of glucagon and glucagon-like peptides; (b) a weak cytoplasmic immunoreactivity observed in the other pancreatic endocrine cell populations. HIP/PAP expression was detected in 36 of the 184 cases of digestive endocrine tumors examined; 32 of these cases (89%) were pancreatic. The 2 patterns observed in the normal state were retained: (a) a strong labeling was observed in 5% to 100% of tumor cells in 26 tumors, all expressing glucagon or glucagon-like peptides; (b) a weak labeling was present in 10 tumors, presenting various hormonal profiles. In conclusion, a strong expression of HIP/PAP is characteristic of glucagon-producing normal and neoplastic enteropancreatic endocrine cells. Our results lend further support to the concept that members of the reg family play regulatory roles in various endocrine cell populations and that their expression in endocrine cells is lineage-specific.
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PMID:HIP/PAP, a member of the reg family, is expressed in glucagon-producing enteropancreatic endocrine cells and tumors. 1686 70


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