Transcriptional activation of H-ras, K-ras and N-ras proto-oncogenes in human bladder tumors

Vageli, Dimitra P.; Kiaris, Hippokratis; Delakas, Dimitrios; Anezinis, Ploutarchos; Cranidis, Angelos; Spandidos, Demetrios Α.

doi:10.1016/0304-3835(96)04372-8

Cited by 53 publications

(30 citation statements)

References 19 publications

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“…First, overexpression of ras protooncogene occurs frequently in human bladder tumors. Vageli et al (1996) quanti®ed the ras transcripts in paired tumor and adjacent normal tissue and found ras overexpression in about 40% of tumor specimens. Others found ras overexpression at the protein level in more than 50% of the bladder tumors (Dunn et al, 1988;Ye et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation

et al. 2001

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Urothelial tumors develop along two distinctive phenotypic pathways (super®cial papillary non-invasive tumors versus¯at carcinoma in situ lesions), with markedly di erent biological behavior and prognosis. Although multiple genetic alterations have been identi®ed in human bladder cancer, their cause ± e ect relationship with the two pathways has not been ®rmly established. Using a urothelium-speci®c promoter of the uroplakin II gene, we showed earlier in transgenic mice that the urothelial expression of SV40T antigen, which inactivates p53 and pRb, induced carcinoma in situ and invasive and metastatic bladder cancer. In striking contrast, we demonstrate here that the urothelial expression of an activated Ha-ras in transgenic mice caused urothelial hyperplasia and super®cial papillary non-invasive bladder tumors. These results provide strong, direct experimental evidence that the two phenotypical pathways of bladder tumorigenesis are caused by distinctive genetic defects. Our results indicate that Ha-ras activation can induce urothelial proliferation in vivo; and that urothelial hyperplasia is a precursor of low-grade, super®cial papillary bladder tumors. Our transgenic models provide unique opportunities to study the detailed molecular events underlying di erent types of bladder neoplasms, and can serve as useful preclinical models for evaluating the in vivo e cacy of preventive and therapeutic agents that act on various signaling pathways in bladder cancer.

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Section: Discussionmentioning

confidence: 99%

Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation

et al. 2001

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“…HER3 and HER4 quantifications were previously determined by same method by amplifying a 365 and 265 bp fragment, respectively (Memon et al, 2004). Beta-actin mRNA was used as an endogenous RNA control, which has been used as control gene in various studies on bladder cancer (Vageli et al, 1996;Chiu et al, 2002) as well as on breast cancer (Agudo et al, 2004). Specificity was verified by the size of the PCR product on agarose gel electrophoresis and nucleotide sequencing using a 310 genetic analyser (Applied Biosystems).…”

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confidence: 99%

The relation between survival and expression of HER1 and HER2 depends on the expression of HER3 and HER4: a study in bladder cancer patients

et al. 2006

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Increased expression of the epidermal growth factor (EGF) receptors, HER1 and HER2 are related to poor prognosis in most cancers studied. Recently, a high expression of the two remaining receptors of the EGF system, HER3 and HER4 has been related to a favourable prognosis. However, prognostic significance of HER1 and HER2 receptors in bladder cancer is controversial and the effect of the expression of different combinations of these receptors on patient survival is not well understood. Therefore, we examined the mRNA expression of all four EGF receptors with real-time polymerase chain reaction in biopsies from 88 patients with bladder cancer, where the survival was followed for a median of 38.5 months (range 1 -117 months). Expression of HER1 and HER2 alone showed no correlation with survival. However, a high expression of HER1 together with high expression of HER3 and HER4 correlated to a better prognosis compared to the high expression of HER1 together with low expression of HER3 and HER4 (P ¼ 0.0006). Also, a significantly longer survival was observed in patients expressing high HER2 when coexpressed with high HER3 and HER4, as compared to the survival in patients with tumours expressing high HER2 but low HER3 and HER4 (P ¼ 0.0005). Our results suggest that the final outcome of patients with high HER1-and HER2-expressing tumours depends on the expression of HER3 and HER4.

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“…Molecular genetic and immunopathological analyses of bladder cancer have identified abnormalities in a number of chromosomes and genes that appear to be implicated in the development and progression of such tumours. These include activation of the H-RAS oncogene (Fujita et al, 1987;Burchill et al, 1994;Hong et al, 1996;Vageli et al, 1996), increased expression of epidermal growth factor receptor (Neal et al, 1990) and inactivation of the retinoblastoma gene (Lipponen and Liukkonen, 1995) as well as frequent abnormalities of the TP53 tumour-suppressor gene.TP53 is a key gene in carcinogenesis, being involved in cell cycle control and preservation of genomic integrity. It co-ordinates the cellular response to DNA damage and other cellular stresses by inducing cell cycle arrest (Livingstone et al, 1992) Correspondence to: J Lunec (Lowe et al, 1993;Fujiwara et al, 1994), depending on the severity of damage and cell type.…”

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Alterations of TP53 in microdissected transitional cell carcinoma of the human urinary bladder: high frequency of TP53 accumulation in the absence of detected mutations is associated with poor prognosis

Abdel-Fattah

Challen²,

Griffiths³

et al. 1998

Br J Cancer

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NE2 4HH; 3Department of Pathology, Freeman Hospital, Freeman Rd, Newcastle upon Tyne NE7 7DN, UK Summary We have used microdissection of paraffin-embedded histological sections and polymerase chain reaction (PCR)-based direct DNA sequencing for 54 transitional cell carcinoma (TCC) of the bladder, to examine critically the association between TP53 nuclear accumulation determined by immunohistochemistry and the presence of TP53 mutations, and to examine their relationship to tumour stage and grade, as well as patient survival. There was a significant association between the presence of TP53-positive nuclei (> 10%) and a higher histological stage and grade (P = 0.0115, P = 0.0151 respectively; Fisher's exact). A significant association between TP53 gene mutations and TP53 nuclear reactivity in more than 10% of tumour cell nuclei was also observed (P = 0.0003; Fisher's exact). Mutations were detected in 18/54 (33%) cases together with the wild-type sequence when analysed from bulk frozen samples, with significant clustering of mutations in exons 7 and 8. The microdissection method distinguished more clearly between heterozygous and/or homozygous alterations of the TP53 tumour-suppressor gene, and clearly showed frequent accumulation of TP53 in the absence of mutations. When microdissecting immunonegative regions from the same paraffin sections, three out of ten samples showed the identical mutations detected in the immunopositive regions. There was a significant association between TP53 immunoreactivity in more than 50% of tumour cell nuclei and decreased survival among all patients (P = 0.0325; log-rank test). The patients with TP53 mutations showed a trend for a shorter survival period; however, the association was not statistically significant at the 95% confidence level (P = 0.132; log-rank test). In conclusion, our observations show that accumulation of TP53 occurs frequently in the absence of mutations, and that such accumulation is nevertheless associated with poor survival when it occurs in a high proportion (> 50%) of tumour cell nuclei.Keywords: TP53; mutation; immunohistochemistry; bladder cancer; microdissection Ten thousand individuals per year in England and Wales develop bladder cancer and 5800 die as a result of the disease (Office of Population Census Statistics, 1993). A total of 90% of bladder tumours are transitional cell carcinoma (TCC), whereas less common histological types include squamous cell carcinoma, adenocarcinoma and sarcoma. Molecular genetic and immunopathological analyses of bladder cancer have identified abnormalities in a number of chromosomes and genes that appear to be implicated in the development and progression of such tumours. These include activation of the H-RAS oncogene (Fujita et al, 1987;Burchill et al, 1994;Hong et al, 1996;Vageli et al, 1996), increased expression of epidermal growth factor receptor (Neal et al, 1990) and inactivation of the retinoblastoma gene (Lipponen and Liukkonen, 1995) as well as frequent abnormalities of the TP53 tumour-suppressor gene.TP53 is ...

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Transcriptional activation of H-ras, K-ras and N-ras proto-oncogenes in human bladder tumors

Cited by 53 publications

References 19 publications

Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation

Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation

The relation between survival and expression of HER1 and HER2 depends on the expression of HER3 and HER4: a study in bladder cancer patients

Alterations of TP53 in microdissected transitional cell carcinoma of the human urinary bladder: high frequency of TP53 accumulation in the absence of detected mutations is associated with poor prognosis

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