Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metastases in the nervous system represent an important and growing problem in the clinical practice, being the cause of a great mortality in the developed countries. This article reviews the few data available on the molecular mechanisms involved in the pathogenesis of these tumours, leading to oncogene activation, inactivation of tumour suppressor genes, not only by the classical mechanisms, but also by the tumour cell epigenetic balance alteration. We conclude that all this knowledge will lead in the future to a better diagnosis, treatment and clinic evolution of these patients.
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PMID:[Metastasis tumors of the central nervous system: molecular biology]. 1563 95

The human gene, human giant larvae (Hugl-1/Llg1/Lgl1) has significant homology to the Drosophila tumour suppressor gene lethal(2)giant larvae (lgl). The lgl gene codes for a cortical cytoskeleton protein, Lgl, that binds Myosin II and is involved in maintaining cell polarity and epithelial integrity. The human protein, Hugl-1 contains several conserved functional domains found in Lgl, suggesting that these proteins may have closely related functions. Whether loss of Hugl expression plays a role in human tumorigenesis has so far not been extensively investigated. Thus, we evaluated tumour tissues from 94 patients undergoing surgery for colorectal cancer (CRC) for loss of Hugl-1 transcription and compared our findings with the clinical data from each of these patients. We found that Hugl-1 was lost in 75% of tumour samples and these losses were associated with advanced stage and particularly with lymph node metastases. Reduced Hugl-1 expression during the adenoma-carcinoma sequence occurring as early as in colorectal adenomas was detected by both immunohistochemical and reverse transcription-polymerase chain reaction analysis. Functional assays with ecdysone-inducible cell lines revealed that Hugl-1 expression increased cell adhesion and decreased cell migration. Our studies thus indicate that downregulation of Hugl-1 contributes to CRC progression.
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PMID:Reduced expression of Hugl-1, the human homologue of Drosophila tumour suppressor gene lgl, contributes to progression of colorectal cancer. 1573 78

Using oligonucleotide microarray analysis, THY1, mapping close to a previously defined 11q22-23 nasopharyngeal carcinoma (NPC) critical region was identified as showing consistent downregulated expression in the tumour segregants, as compared to their parental tumour-suppressing microcell hybrids (MCHs). Gene expression and protein analyses show that THY1 was not expressed in the NPC HONE1 recipient cells, tumour segregants, and other NPC cell lines; THY1 was exclusively expressed in the non-tumourigenic MCHs. The mechanism of THY1 gene inactivation in these cell lines was attributed to hypermethylation. Clinical study showed that in 65% of NPC specimens there was either downregulation or loss of THY1 gene expression. Using a tissue microarray and immunohistochemical staining, 44% of the NPC cases showed downregulated expression of THY1 and 9% lost THY1 expression. The frequency of THY1 downregulated expression in lymph node metastatic NPC was 63%, which was significantly higher than in the primary tumour (33%). After transfection of THY1 gene into HONE1 cells, a dramatic reduction of colony formation ability was observed. These findings suggest that THY1 is a good candidate tumour suppressor gene in NPC, which is significantly associated with lymph node metastases.
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PMID:THY1 is a candidate tumour suppressor gene with decreased expression in metastatic nasopharyngeal carcinoma. 1600 74

The vast majority of invasive breast tumors are ductal and lobular breast carcinomas. Despite the many similarities, some clinical follow-up data and the patterns of metastases suggest that these histological subtypes of breast cancer are biologically distinct. Few papers, however, describe immunohistochemical markers useful for differentiation of these carcinomas. Many investigations suggest that E cadherin protein expression is lost in lobular but not in ductal carcinoma. The absence of E-CD, as a partial loss of epithelial differentiation, may account for the extended spread of lobular carcinoma in situ and the peculiar diffuse invasion mode of invasive lobular carcinoma. Some investigations report the significance of E-CD associated proteins alpha-, beta-, gamma-catenin expression, as well as the usefulness of cytokeratins 5, 6, 8, 7 and thrombospondin in differentiating histological types of breast invasive carcinomas. Several reports have suggested the possibility that invasive ductal and lobular cancers differ with respect to expression of antigens involved in proliferation and cell cycle regulation. It has been shown that vascular endothelial growth factor expression, also the expression of maspin, a tumour suppressor gene product, is higher in ductal, than in lobular carcinoma. Expression of NKX3.1, a member of the NK-class of homeodomain, is highly restricted and is found primarily in lobular carcinoma. Some histological and immunohistochemical characteristics of pleomorphic lobular carcinoma are also discussed.
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PMID:Differentiation of tumours of ductal and lobular origin: I. Proteomics of invasive ductal and lobular breast carcinomas. 1617 Mar 89

EphB2, a receptor tyrosine kinase regulated by the beta-catenin/Tcf4 complex, is expressed in the proliferative compartment of mouse intestine and regulates bidirectional migration of intestinal precursor cells in the crypt-villus axis through repulsive interaction with Ephrin-B ligands. Recently, it has been shown that reduction of EphB activity accelerates colon tumour progression in the Apc(Min/+) mice. In this study, we examined the expression of EphB2 in normal colon, adenomas, primary colorectal cancers (CRCs), lymph node metastases and liver metastases using immunohistochemistry on tissue microarrays. In addition, EphB2 was overexpressed in SW480 colon cancer cells to study its effect in vitro. We found that EphB2 was expressed in 100% of normal colon crypt base cells, 78% of adenomas, 55.4% of primary CRCs, 37.8% of lymph node metastases and 32.9% of liver metastases (all differences were statistically significant at P < 0.001 compared with primary CRCs). Patients with CRCs that lose EphB2 expression had more advanced tumour stage (P = 0.005), poor differentiation (P < 0.001), poor overall survival (P = 0.005) and disease-free survival (P = 0.001), with the latter being independent of tumour stage. In vitro studies showed that overexpression of EphB2 inhibited colon cancer cell growth in colony formation assay and activation of EphB2 receptor inhibited colon cancer cell adhesion and migration. Our data demonstrated a progressive loss of EphB2 expression in each critical step of colon carcinogenesis, including the onset of invasion, dedifferentiation and metastasis which are paralleled by adverse patient outcome. EphB2 may achieve its tumour suppressor function through regulation of cell survival, adhesion and migration.
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PMID:Reduced expression of EphB2 that parallels invasion and metastasis in colorectal tumours. 1627 70

The recent discoveries of the RNA-mediated interference system in cells could explain all of the known features of human carcinogenesis. A key, novel idea, proposed here, is that the cell has the ability to recognise a mutated protein and/or mRNA. Secondly, the cell can generate its own short interfering RNA (siRNA) using an RNA polymerase to destroy mutated mRNA, even when only a single base pair in the gene has mutated. The anti-sense strand of the short RNA molecule (called sicRNA), targets the mutated mRNA of an oncogene or a tumour suppressor. The resulting double stranded RNA, using the RNA-induced silencing complex in the cytoplasm dices the mutated mRNA. In cancer-prone tissues, during cell mitosis, the sicRNA complex can move into the nucleus to target the mutated gene. The sicRNA, possibly edited by dsRNA-specific adenosine deaminase, converting adenosines to inosines, can be retained in the nucleus, with enhanced destructive capability. The sicRNA triggers the assembly of protein complexes leading to epigenetic modification of the promoter site of the mutant gene, specifically methylation of cytosines. In some instances, instead of methylation, the homologous DNA is degraded, leading to loss of heterozygosity. The factors controlling these two actions are unknown but the result is gene silencing or physical destruction of the mutant gene. The cell survives dependent on the functioning of the single, wild-type allele. An error in RNAi defence occurs when the sicRNA enters the nucleus and targets the sense strand of the wrong DNA. The sicRNA, because of the similarity of its short sequence and relaxed stringency, can target other RNAs, which are being transcribed. This can result in the methylation of the wrong promoter site of a gene or LOH of that region. In the vast majority of these cases, the aberrant hybridisations will have no effect on cell function or apoptosis eliminates non-viable cells. On a rare occasion, a preneoplastic cell is initiated when aberrant hybridisations switches on/off a gene involved in apoptosis, as well as a gene involved in cell proliferation and DNA damage surveillance. Genetic instability results when the sicRNA competes for a repeat sequence in the centromere or telomere, leading to gross chromosomal rearrangements. A malignancy develops when the sicRNAs fortuitously targets a microRNA (miRNA) or activates a transcription factor, resulting in the translation of a large number of new genes, alien to that tissue. This leads to dedifferentiation of the tissue, a resculpting of the histone code, chromosomal rearrangements, along a number of specific pathways, the gain of immortality and the dissemination of a metastatic cancer.
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PMID:The dialectics of cancer: A theory of the initiation and development of cancer through errors in RNAi. 1635 27

Maspin is a member of the serpin family of protease inhibitors. It is a 42 kDa cytoplasmic protein that is reported to have tumour suppressor activity. The loss of maspin gene expression is correlated with increased invasiveness and the risk of metastases in breast cancer. We studied maspin expression in primary melanoma lesions obtained from 76 patients. Immunostaining of 5 pm sections for maspin expression was obtained using the citrate antigen retrieval method. The extent of immunostaining was scored by recording the proportion of immunoreactive cells and the intensity of immunostaining. Our results demonstrated that maspin expression was down-regulated in intermediate thickness and thick melanoma lesions compared with thin lesions. These results suggest that loss of maspin expression might play a role in melanoma progression, invasion and metastatic dissemination. Further studies are needed to clarify the clinicopathological significance of maspin expression in melanoma.
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PMID:Decreased immunoreactive maspin expression in intermediate thickness and thick primary melanoma lesions. 1660 23

Pancreatic cancer, which is responsible for >90% of exocrine pancreatic tumours, is typically a disease of the elderly (> or =70 years of age). However, older patients are less likely to be staged than younger patients despite having a worse overall 5-year survival rate than their younger counterparts. Various radiological, ultrasonographic and endoscopic investigations are used not only as diagnostic tools but also to accurately stage the cancer for possible surgery. Many patients with pancreatic cancer have mutations of the K-ras oncogene, and various tumour suppressor genes are also inactivated. Pancreas resection can be performed in elderly resectable patients without excess mortality, even in those >80 years of age. However, treatment for locally advanced, unresectable and metastatic pancreatic cancer is palliative. Fluorouracil-based chemoradiation for locally advanced or unresectable cancer, and gemcitabine for patients with metastatic disease, can result in clinical benefits. Placement of a stent in the biliary tract has been shown to improve symptoms of obstructive jaundice or ascites, as well as quality of life. As molecular targets are identified, interventions with targeted specific agents may improve tumour control. However, further studies will be needed to demonstrate whether or not various agents targeting signal transduction pathways or nuclear transcription factors are useful for elderly patients with advanced pancreatic cancer.
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PMID:Current treatment strategies for pancreatic cancer in the elderly. 1682 93

Parathyroid carcinoma (PC) is an uncommon finding, accounting for only 1-2% of patients with primary hyperparathyroidism (HPT), but a relatively higher incidence has been reported in Italy and Japan. The etiology of the tumour remains unclear, but molecular analysis studies have hypothesised the involvement of mutations of several genes in the pathogenesis of PC, including the oncogene cyclin Dl or PRADI located at the chromosome 13, the retinoblastoma and the p53 tumour suppressor gene. The clinical presentation of patients with PC is mainly related to the increased secretion of PTH rather than to the tumour burden. The pre-operative diagnosis of malignancy is very difficult to obtain, and, thus, intra-operative recognition of PC is mandatory. However, reliable signs of malignancy are rarely detectable. Probably, only vascular invasion, that correlates with tumour recurrence and metastases, should be considered useful in confirming malignancy, although both Ki-67 and Cyclin D1 have been recently used to aid in the definitive diagnosis. The en bloc resection of the tumour, together with ipsilateral thyroid lobe and adjacent structures, only if involved, avoiding any capsular rupture of the mass, represents the gold standard of surgical treatment of patients. Although the PC has traditionally been considered as a radioresistant tumour, there are some retrospective data holding a possible benefit from post-operative irradiation. No cytotoxic regimen with proven efficacy is currently available for patients with PC, but since hypercalcemia is ultimately the most frequent cause of death, several studies have suggested the usefulness of bisphosphonates (i.e., clodronate, pamidronate and zoledronate), calcitonin, and calcimimetic agents (i.e., cinacalcet) in patients with PC and severe hypercalcemia. In conclusion, PC is a rare malignancy and the NCDB survey reports an overall five- and ten-year survival rate of 85% and 49%, respectively. However, it is very difficult to predict the clinical behaviour of patients with PC and probably the ultimate prognosis depends on successful resection of the tumour at the initial surgery.
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PMID:Parathyroid cancer: etiology, clinical presentation and treatment. 1721 44

The four GPI-anchored cell adhesion molecules that exemplify the IgLON family are most highly expressed in the nervous system and associate to form up to six different heterodimeric 'Diglons' that can modify cell adhesion and inhibit axon migration. Recently, two members, OPCML and LSAMP, were identified as putative tumour suppressor genes in ovarian and renal carcinomas respectively. In this study, we investigated OPCML expression in nonneoplastic brain tissue and 35 brain tumours (18 glioblastoma multiformes, five anaplastic gliomas, five meningiomas, six metastases and one medulloblastoma) and four glioma cell lines using quantitative reverse transcriptase polymerase chain reaction (RT-PCR). OPCML was highly expressed in cerebellum, less so in cerebral cortex, frontal lobe and meninges and was significantly reduced or absent in 83% of brain tumours and all cell lines compared with nonneoplastic whole brain. Two OPCML splice variants have been identified in humans, termed alpha1 and alpha2, but the latter has not been demonstrated in human neural tissues. Using PCR with specific primers, nonneoplastic brain and 3/6 of tested brain tumours expressed both splice variants, whereas the remaining brain tumours only expressed the alpha2 variant. Hypermethylation of the alpha1 OPCML promoter, associated with down-regulation of expression in ovarian tumours, did not correlate with expression levels in the subset of brain tumours tested, implying transcription of OPCML from an alternative promoter or a different mechanism of down-regulation. This study demonstrates that OPCML down-regulation occurs in the majority of brain tumours tested, warranting further investigation of OPCML and other IgLONs in the development and progression of brain tumours.
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PMID:Expression of cellular adhesion molecule 'OPCML' is down-regulated in gliomas and other brain tumours. 1723 10


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