Coincident inactivation of 14-3-3σ and p16INK4a is an early event in vulval squamous neoplasia

Gasco, Milena; Sullivan, Alice; Repellin, Claire E.; Brooks, Lucy; Farrell, Patrick J.; Tidy, John; Dunne, Barbara; Gusterson, Barry A.; Evans, David J.; Crook, Tim

doi:10.1038/sj.onc.1205256

Cited by 94 publications

(71 citation statements)

References 18 publications

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“…This protein is a negative regulator of the cell cycle that causes G 2 arrest. 40 Inactivation of this gene by epigenetic silencing appears to be an early event in vulval squamous neoplasia 41 and several other malignancies. [42][43][44] A protein which has thus far not been directly implicated in cancer is Endonuclease III homolog 1 (HNTH1) (cluster 7A, C04i).…”

Section: Discussionmentioning

confidence: 99%

Detection of cancer‐related gene expression profiles in severe cervical neoplasia

Sopov

Magbagbeolu

et al. 2004

Intl Journal of Cancer

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The molecular signatures of 20 severe cervical intraepithelial neoplasia (CIN3) cases and 10 cervical squamous cell cancers were determined to define cancer-related gene expression profiles. RNAs extracted from microdissected tissues were amplified by SMART technology and used as probes for hybridization of commercially available cDNA array filters comprising 1,176 cancer-related genes. Ninetytwo differentially expressed genes were identified by comparison of pooled cDNA from CIN3 vs. cervical cancer. Heterogeneity in expression of this subset of genes was then analyzed for each biopsy using an algorithm for self-organizing maps. For several gene clusters, the expression pattern for CIN3 differed significantly from that of cancer. Moreover, hierarchical clustering revealed significant differences in distribution of CIN and cancer. Several CIN cases were more strongly related to cancer, suggesting that gene expression profiling may be useful for subdividing pathologically indistinguishable precancers into different biologic entities. This approach also provides a basis for the identification of putative prognostic markers and for targeted molecular therapy.

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Section: Discussionmentioning

confidence: 99%

Detection of cancer‐related gene expression profiles in severe cervical neoplasia

Sopov

Magbagbeolu

et al. 2004

Intl Journal of Cancer

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“…Inactivation of p16 has previously been shown to confer a loss of tumour-suppressor function in high-grade gliomas (Nishikawa et al, 1995). Another investigation of the inactivation of p16 INK4a and 14-3-3s suggested the latter as early events in vulval squamous neoplasia (Gacso et al, 2002). Downregulation of 14-3-3s in keratinocytes allows escape from replicative senescence and this is also accompanied by loss of p16 INK4a .…”

Section: Discussionmentioning

confidence: 99%

Minichromosome maintenance (Mcm) proteins, cyclin B1 and D1, phosphohistone H3 and in situ DNA replication for functional analysis of vulval intraepithelial neoplasia

et al. 2003

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Vulval intraepithelial neoplasia (VIN) is defined histopathologically by distinctive abnormalities of cellular maturation and differentiation. To investigate the functional properties of VIN, the expression of several proteins involved in the regulation of the cell cycle as well as in situ DNA replication competence was analysed by immunohistochemistry. Snap-frozen vulval biopsies were graded as normal squamous epithelium (n ¼ 6), undifferentiated HPV positive VIN 1 (n ¼ 3), VIN 2 (n ¼ 8) and VIN 3 (n ¼ 20). Immunohistochemistry was performed using the following markers: cyclin D1 (expressed in middle/late G1), cyclin B1 (expressed in G2/early M), phosphorylated histone H3 (expressed during mitosis) and minichromosome maintenance (Mcm) proteins 2 and 5 (expressed during the cell cycle, but not in differentiated or quiescent cells). In situ DNA replication competence was used to identify S-phase cells. The percentage of positively stained nuclei in three representative microscopic fields was calculated per biopsy. In normal vulva, the expression of all markers was restricted to the proliferative compartment of the basal layer of the epithelium. In contrast in high-grade VIN, the majority of epithelial cells expressed the Mcm proteins from basal to superficial layer. The detection of cyclins B1 and D1, phospho-histone H3 and in situ DNA replication was also found through the full thickness of these lesions but by a lower proportion of the cells. This is consistent with these markers providing a series of 'snapshots' of the cell cycle status of individual cells. The low-grade VIN showed reduced expression of the cell cycle markers in relation to the level of dysplasia. The combination of these analyses establishes that the majority of VIN cells remain in a functional replicative or prereplicative state of the cell cycle. Clinical application of these analyses may provide a basis for improved diagnosis of VIN.

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“…It is induced by DNA damage and appears to be required for maintaining the G 2 /M checkpoint in epithelial cells, and its gene is directly regulated by p53 (Hermeking, 2003). Absent or decreased expression of 14-3-3 s has been found in different cancers, such as vulvar cancer (Gasco et al, 2002), breast cancer (Urano et al, 2002), bladder cancer (Ostergaard et al, 1997) and neuroendocrine lung tumours (Yatabe et al, 2002). Figure 4 Cluster analysis using the expression patterns of 11 identified proteins that are downregulated in both vaginal and cervical carcinoma.…”

Section: Tumour Suppressor Proteins and Oncoproteinsmentioning

confidence: 99%

Differential tissue-specific protein markers of vaginal carcinoma

et al. 2009

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The objective was to identify proteins differentially expressed in vaginal cancer to elucidate relevant cancer-related proteins. A total of 16 fresh-frozen tissue biopsies, consisting of 5 biopsies from normal vaginal epithelium, 6 from primary vaginal carcinomas and 5 from primary cervical carcinomas, were analysed using two-dimensional gel electrophoresis (2-DE) and MALDI-TOF mass spectrometry. Of the 43 proteins identified with significant alterations in protein expression between non-tumourous and tumourous tissue, 26 were upregulated and 17 were downregulated. Some were similarly altered in vaginal and cervical carcinoma, including cytoskeletal proteins, tumour suppressor proteins, oncoproteins implicated in apoptosis and proteins in the ubiquitin -proteasome pathway. Three proteins were uniquely altered in vaginal carcinoma (DDX48, erbB3-binding protein and biliverdin reductase) and five in cervical carcinoma (peroxiredoxin 2, annexin A2, sarcomeric tropomyosin kappa, human ribonuclease inhibitor and prolyl-4-hydrolase beta). The identified proteins imply involvement of multiple different cellular pathways in the carcinogenesis of vaginal carcinoma. Similar protein alterations were found between vaginal and cervical carcinoma suggesting common tumourigenesis. However, the expression level of some of these proteins markedly differs among the three tissue specimens indicating that they might be useful molecular markers.

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Coincident inactivation of 14-3-3σ and p16INK4a is an early event in vulval squamous neoplasia

Cited by 94 publications

References 18 publications

Detection of cancer‐related gene expression profiles in severe cervical neoplasia

Detection of cancer‐related gene expression profiles in severe cervical neoplasia

Minichromosome maintenance (Mcm) proteins, cyclin B1 and D1, phosphohistone H3 and in situ DNA replication for functional analysis of vulval intraepithelial neoplasia

Differential tissue-specific protein markers of vaginal carcinoma

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