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PubMed1996

Expression of cyclin D1 and EMS1 in bladder tumours; relationship with chromosome 11q13 amplification.

11q13 amplifications have been found in several cancers, including bladder tumours. However, the biological significance of this genetic alteration is not yet fully understood. To get more insight into the role of 11q13 amplification in bladder tumour development, we have studied the level of amplification and expression of 4 (protoonco)genes lying within the amplicon; cyclin D1, FGF3, FGF4 and EMS1 DNA amplification was found in 5/46 tumours. There was no correlation between amplification and clinico-pathological data. No expression of FGF3 and FGF4 was detected whereas both cyclin D1 and EMS1 were expressed at higher level in tumours with amplifications. Thus cyclin D1 and EMS1, but not FGF3 and FGF4, are likely to play a pathogenic role in the 11q13 amplification in bladder cancer. However, amplification is not the unique way of activation of these genes. Indeed, in situ hybridisation and Northern blot analysis have shown that most bladder tumours have a fair to high expression of cyclin D1 and EMS1 in contrast to normal urothelium with a moderate expression. Interestingly, a trend towards higher expression occurs in superficial versus invasive tumours (8.8 +/- 2.0 versus 1.9 +/- 0.4; P approximately equal to 13% for cyclin D1 and 4.5 +/- 1.4 versus 2.0 +/- 0.4; P approximately equal to 8% for EMS1). Moreover, the 9 tumours with low expression are all highly malignant, leading to the hypothesis that the tumours developing through a cyclin D1/EMS1 independent pathway are more aggressive.

Carcinoma, Squamous Cell↗
PubMed2001

Microsatellite instability, expression of hMSH2 and hMLH1 and HPV infection in cervical cancer and their clinico-pathological association.

Infection with specific genotypes of human papillomavirus (HPV) has been strongly implicated in cervical carcinogenesis. However, HPV infection alone is insufficient for malignant transformation of the cervical epithelium. An alteration of microsatellite repeats is the result of slippage owing to strand misalignment during DNA replication and is referred to as microsatellite instability (MSI). These defects in DNA repair pathways have been related to human carcinogenesis; however, the role of MSI in the tumorigenesis of cervical cancer remains unclear. The clinical and pathological features of cervical cancers which are MSI-positive have also not been fully characterized. This study investigated the prevalence of MSI in cervical cancer and its relationship to clinico-pathological characteristics and HPV infection. Polymerase chain reaction-based microsatellite assay combined with tissue microdissection was used to examine for MSI in 50 cervical squamous cell carcinomas in Hong Kong women. In addition, the immunohistochemical staining was performed to determine the expression of major DNA mismatch repair genes, hMSH2 and hMLH1. Six cases (12%) displayed a low frequency of MSI (MSL-L) showing MSI at one locus only in 5 loci examined. Seven cases (14%) showed a high frequency of MSI (MSI-H) having MSI at 2 or more loci. Grouping MSI-L and MSI-H cases together as MSI-positive, statistical analysis of HPV infection, tumor grade, clinical stage and clinical status failed to disclose differences between MSI-positive and MSI-negative cases (p > 0.05). However, MSI-H correlated with advanced stage of disease (p < 0.05). Individuals with MSI-H tumors appeared to have reduced overall survival compared to individuals with MSI-L and MSI-negative tumors, but the difference was not statistically significant (p = 0.059). An absence of either MSH2 or MLH1 expression was observed in 2 MSI-L and 4 MSI-H cases, respectively. The results suggest that MSI is present in a subgroup of cervical squamous cell carcinomas, and defects resulting in MSI may be related to tumor progression and possibly poor prognosis in cervical cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Reduced expression of hMSH2 protein is correlated to poor survival for soft tissue sarcoma patients.

BACKGROUND: Deregulation of DNA mismatch repair is a common mechanism for the development of hereditary nonpolyposis colon carcinoma and related familiar cancers, but it also plays a role in the tumorigenesis of sporadic cancers. Although the protein expression of the two main components of DNA mismatch repair, hMSH2 and hMLH1, has been described in soft tissue sarcoma (STS) patients, its prognostic impact is yet to be determined. METHODS: The authors investigated the expression of the DNA repair proteins hMSH2 and hMLH1 by Western blot analysis in tumor samples of 57 STS patients. The correlation between the expression of hMSH2/hMLH1 and survival was studied in a Cox proportional hazards regression model, which was adjusted for the prognostic effects of staging, tumor entity, and radicality of tumor resection. RESULTS: Nine of 57 STS (16%) showed reduced expression of hMSH2 and reduced expression of hMLH1 was detected in seven STS patients (12%). In a Kaplan-Meier analysis, the median survival for patients with reduced expression of the hMSH2 protein was 18 months, whereas the patients with a normal expression of hMSH2 survived for an average of 68 months. A multivariate Cox proportional hazards regression model revealed a significant correlation between the reduced expression of the hMSH2 protein and poor survival (relative risk = 4.7; 95% confidence interval [CI]: 1.3-17.2; P = 0.019). CONCLUSIONS: Reduced expression of the hMSH2 protein is an independent negative prognostic factor for STS patients.

Adaptor Proteins, Signal Transducing↗
PubMed2003

The neuroblastoma amplified gene, NAG: genomic structure and characterisation of the 7.3 kb transcript predominantly expressed in neuroblastoma.

Amplification of the MYCN oncogene in neuroblastoma is associated with poor prognosis. The amplified unit of DNA can be up to 1 Mb in size and so could contain additional genes which affect tumour phenotype. The neuroblastoma amplified gene (NAG) gene was initially located 400 kb telomeric to MYCN at 2p24 and reported to be co-amplified in 5/8 (63%) cell lines and 9/13 (70%) tumours. The sequence of a 4.5 kb transcript was proposed from the analysis of overlapping cDNA clones. However, our Northern blot hybridisation experiments indicate that the main RNA species expressed in neuroblastoma is 7-8 kb in size. We describe for the first time the cloning and sequencing of the 7.3 kb transcript of the NAG gene together with its precise genomic location and full exon structure. The 5' end of the gene is located 30 kb telomeric to DDX1, with the two genes lying in opposite orientations. The 52 exons of the 7.3 kb transcript cover 420 kb of genomic DNA. In vitro translation studies confirmed the protein coding potential of the transcript. Co-amplification of the entire NAG gene with MYCN was found in 1/6 (17%) neuroblastoma cell lines and 10/50 (20%) primary tumours. Previous studies had measured co-amplification of only the 5' end of the gene, nearest to MYCN. In this study, co-amplification of the NAG gene was found to be significantly associated with low disease stage in MYCN-amplified tumours (P=0.0063).

Base Sequence↗
PubMed1995

Differentiation and tumor progression.

Clinical and experimental experience indicate that differentiation and malignancy are inversely correlated. However, more recent experimental studies using mouse and human keratinocyte systems have demonstrated that complete or even substantial loss in overall epithelial differentiation is not a prerequisite for malignant growth of cancer cells. Major defects in differentiation are also not a prerequisite for premalignant stages, in particular for cell immortalization, which is considered an early and essential step in the transformation process. Moreover, progressive dedifferentiation, often associated with advanced tumor stages, is also found in immortalized cell lines which are, however, nontumorigenic. On the other hand, malignant cell lines may have maintained a high degree of their normal differentiation program and sensitivity to differentiation modulators. However, to date no transformed keratinocyte cell lines with completely normal differentiation have been observed. Since epidermal keratinization is a very complex process involving many different parameters and is fully expressed only under in vivo conditions, an exact and quantitative comparison of such ill-defined phenomena (differentiation and malignancy) is still problematic. Obviously, both phenomena are under separate control and not causally linked. Nevertheless, a better understanding of factors and mechanisms regulating differentiation and of their disturbance in carcinogenesis would offer new possibilities to design novel tumor therapeutic strategies in the field of differentiation therapy.

Biomarkers↗
PubMed2006

A truncated isoform of TMEFF2 encodes a secreted protein in prostate cancer cells.

The transmembrane protein TMEFF2, also known as tomoregulin or TENB2, has been proposed as a potential immunotherapeutic target for the treatment of prostate cancer. Much attention has focused on its limited tissue distribution, with strong expression seen only in the brain and the prostate. Here we describe the identification of a novel splice variant of TMEFF2 expressed both in the normal prostate and in prostate cancer. This variant encodes an isoform of TMEFF2 that is truncated after the first four coding exons, eliminating both the EGF-like and the transmembrane domains. Fusion of GFP to this isoform demonstrated that this variant transcript produces a truncated TMEFF2 protein (TMEFF2-S). In contrast to full-length TMEFF2-GFP, the truncated TMEFF2-S-GFP fusion protein was enriched in cytosolic granules, showed no staining at the plasma membrane, and was secreted into the medium of transfected cells grown in tissue culture. These results indicate that a truncated isoform of TMEFF2 is expressed from this locus. This secreted form of TMEFF2 may functionally interact with full-length TMEFF2, or its binding partners, and may also influence current immune-based treatment strategies.

Alternative Splicing↗
PubMed1998

FHIT in human cancer.

Explore the source record for details and available documents.

Acid Anhydride Hydrolases↗
PubMedDate not supplied

Down-regulation of survivin by antisense oligonucleotides increases apoptosis, inhibits cytokinesis and anchorage-independent growth.

Survivin, a member of the inhibitor of apoptosis protein (IAP) family, is detected in most common human cancers but not in adjacent normal cells. Previous studies suggest that survivin associates with the mitotic spindle and directly inhibits caspase activity. To further investigate the function of survivin, we used a survivin antisense (AS) oligonucleotide to downregulate survivin expression in normal and cancer cells. We found that inhibition of survivin expression increased apoptosis and polyploidy while decreasing colony formation in soft agar. Immunohistochemistry showed that cells without survivin can initiate the cleavage furrow and contractile ring, but cannot complete cytokinesis, thus resulting in multinucleated cells. These findings indicate that survivin plays important roles in a late stage of cytokinesis, as well as in apoptosis.

Apoptosis↗
PubMed2005

Elevated expression of survivin-splice variants predicts a poor outcome for soft-tissue sarcomas patients.

The aim of this study was to investigate the level and the prognostic value of the expression of different survivin transcript variants--survivin, survivin-DeltaEx3 and survivin-2B--in tumours of 76 soft tissue sarcoma (STS) patients. The expression of survivin transcript variants in STS tissue samples and in 12 nonmalignant control tissues was analysed by quantitative RT-PCRs. Expression levels of all survivin transcript variants were strongly elevated in STS compared to normal tissues. A positive correlation between expression of splice variants and tumour stage was found (P=0.02; chi2 test). The multivariate Cox's proportional hazards regression model revealed a 7.3-fold increased risk of tumour-related death for patients with survivin-DeltaEx3 overexpressing tumours (P=0.007). The effect of surivivin (wildtype variant) and survivin-2B was less pronounced but still significant (2.2- and 1.9-fold, resp., P<0.05 each). Our results show for the first time that mRNA expression of survivin-variants is significantly correlated to a poor prognosis for STS patients, and we suggest expression of survivin splice variants together with tumour stage as independent predictor of survival.

Biomarkers, Tumor↗
PubMed2004

Inflammation-associated cell cycle-independent block of apoptosis by survivin in terminally differentiated neutrophils.

Survivin has received great attention due to its expression in many human tumors and its potential as a therapeutic target in cancer. Survivin expression has been described to be cell cycle-dependent and restricted to the G2-M checkpoint, where it inhibits apoptosis in proliferating cells. In agreement with this current view, we found that survivin expression was high in immature neutrophils, which proliferate during differentiation. In contrast with immature cells, mature neutrophils contained only little or no survivin protein. Strikingly, these cells reexpressed survivin upon granulocyte/macrophage colony-stimulating factor (CSF) or granulocyte CSF stimulation in vitro and under inflammatory conditions in vivo. Moreover, survivin-deficient mature neutrophils were unable to increase their lifespan after survival factor exposure. Together, our findings demonstrate the following: (a) overexpression of survivin occurs in primary, even terminally differentiated cells and is not restricted to proliferating cells; and (b) survivin acts as an inhibitor of apoptosis protein in a cell cycle-independent manner. Therefore, survivin plays distinct and independent roles in the maintenance of the G2-M checkpoint and in apoptosis control, and its overexpression is not restricted to proliferating cells. These data provide new insights into the regulation and function of survivin and have important implications for the pathogenesis, diagnosis, and treatment of inflammatory diseases and cancer.

Animals↗
PubMed2005

Plastins: versatile modulators of actin organization in (patho)physiological cellular processes.

Many actin-binding proteins are expressed in eukaryotic cells. These polypeptides assist in stabilizing and rearranging the organization of the actin cytoskeleton in response to external stimuli, or during cell migration and adhesion. Here we review a particular set of actin-binding proteins called plastins. Plastins (also called fimbrins) belong to a subclass of actin-binding proteins known as actin bundling proteins. Three isoforms have been characterized in mammals: T-plastin is expressed in cells from solid tissue, whereas L-plastin occurs predominantly in hematopoietic cells. The third isoform, I-plastin, is specifically expressed in the small intestine, colon and kidney. These proteins share the unique property of cross-linking actin filaments into tight bundles. Although plastins are primarily involved in regulation of the actin cytoskeleton, they possess some unique features. For instance, they are implicated in invasion by pathogenic bacteria such as Shigella flexneri and Salmonella typhimurium. Also, L-plastin plays an important role in leukocyte function. T-plastin, on the other hand, is possibly involved in DNA repair. Finally, both T- and L-plastin are implicated in several diseases, and L-plastin is considered to be a valuable marker for cancer.

Biomarkers, Tumor↗