Negative regulation of G1/S transition by the candidate bladder tumour suppressor gene DBCCR1

Nishiyama, Hiroyuki; Gill, Jason H.; Pitt, Eva; Kennedy, Wendy; Knowles, Margaret A.

doi:10.1038/sj.onc.1204432

Cited by 50 publications

(38 citation statements)

References 22 publications

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“…Previous cell cycle studies suggested that DBCCR1 has growth-suppressing and antiproliferative activities mediated via modulation of the G 1 checkpoint. Overexpression of DBCCR1 caused a slower G 1 transition rather than G 1 arrest and did not affect apoptosis (Nishiyama et al, 2001). Although these functional studies and the high rate of DBCCR1 hypermethylation in oral squamous cell carcinomas support the candidacy of DBCCR1 as a tumour suppressor at 9q33, additional studies are required to unravel its possible role in oral malignant development.…”

Section: Discussionmentioning

confidence: 99%

Loss of heterozygosity at 9q33 and hypermethylation of the DBCCR1 gene in oral squamous cell carcinoma

Worm

Guldberg

et al. 2004

Br J Cancer

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The DBCCR1 gene at chromosome 9q33 has been identified as a candidate tumour suppressor, which is frequently targeted by promoter hypermethylation in bladder cancer. Here, we studied the possible involvement of DBCCR1 in the development of oral squamous cell carcinoma. DNA from 34 tumours was examined for loss of heterozygosity (LOH) at three markers surrounding DBCCR1 and for hypermethylation of the DBCCR1 promoter, using methylation-specific PCR and methylation-specific melting-curve analysis. LOH was found in 10 of 31 cases (32%), and DBCCR1 hypermethylation was present in 15 of 34 cases (44%). Hypermethylation of DBCCR1 was also present in three of seven epithelial tissues adjacent to the tumours, including two hyperplastic and one histologically normal epithelia. Furthermore, of four oral leukoplakias with dysplasia, one showed LOH at 9q33 and two showed DBCCR1 hypermethylation. These data suggest that LOH at 9q33 and hypermethylation of the DBCCR1 promoter are frequent and possibly early events in oral malignant development. Oral cancer comprises about 3% of all newly diagnosed cancer cases in the Western countries. Despite advances in therapy, the 5-year survival rate after diagnosis is still poor and remains B50% (Landis et al, 1999;Silverman, 2001). Clinically, oral carcinomas often develop in a two-step process. The first step is characterised by the appearance of potentially malignant lesions such as leukoplakias and erythroplakias, and the second step is characterised by the development of carcinomas. However, clinical and histopathological features are insufficient measures for predicting the prognosis of potentially malignant lesions (Warnakulasuriya, 2000(Warnakulasuriya, , 2001. Furthermore, a recent study indicated that clinically and histologically normal mucosa adjacent to tumours may harbour patches of genetically altered cells (Braakhuis et al, 2003). It is, therefore, important to find molecular markers for identifying the minor fraction of oral lesions that will develop into carcinoma.Loss of heterozygosity (LOH) at multiple chromosome regions and genetic and epigenetic alterations of several proto-oncogenes and tumour suppressor genes have been demonstrated in oral carcinomas, including alterations of the TP53, p16, p15, MGMT, Ecadherin genes and RAS (Califano et al, 1996;Partridge et al, 1999;Williams, 2000;Ogi et al, 2002;Viswanathan et al, 2003). In addition, our previous study showed that hypermethylation of the ABO gene promoter was associated with loss of expression of A/B antigen in approximately one-third of oral squamous cell carcinomas (Gao et al, 2004). LOH at 9q34, in which the ABO gene is located, was also a frequent event in these tumours. However, a number of tumours from AO and BO heterozygotes showed deletion of the O allele, which does not encode a functional glycosyltransferase, suggesting the existence of an additional tumour suppressor gene on chromosome 9q. The DBCCR1 (deleted in bladder cancer chromosomal region candidate 1) gene at chromosome 9q33 was identified as...

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Section: Discussionmentioning

confidence: 99%

Loss of heterozygosity at 9q33 and hypermethylation of the DBCCR1 gene in oral squamous cell carcinoma

Worm

Guldberg

et al. 2004

Br J Cancer

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“…As the name implies, the gene is frequently deleted in bladder cancer, which has also been reported to be associated with asbestos exposure (22,23). DBC1 has been shown to inhibit cell proliferation by negative regulation of the G 1 -S transition (24). In our previous expression array analysis, we detected low expression of DBC1 in both normal lung and .…”

Section: Chromosomal Microsatellitementioning

confidence: 99%

Molecular Alterations at 9q33.1 and Polyploidy in Asbestos-Related Lung Cancer

Nymark

Kettunen²,

Aavikko³

et al. 2009

Clinical Cancer Research

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Purpose: Asbestos causes DNA damage and the fibers, together with tobacco smoke, have a synergistic effect on lung cancer risk. We recently identified 18 chromosomal regions that showed differences in DNA copy number between the lung tumors of asbestos-exposed and nonexposed patients. One of the previously identified asbestos-associated chromosomal regions at 9q was further analyzed for allelic imbalance and DNA copy number alterations (CNA) in the lung tumors of asbestos-exposed and nonexposed patients. In addition, the ploidy level of the tumors was studied. Experimental Design: Allelic imbalance was analyzed at 9q31.3-34.3 with 15 microsatellite markers in 52 lung tumor samples from asbestos-exposed and nonexposed patients. CNA at 9q32-34.3 were characterized by fluorescent in situ hybridization (FISH) with six bacterial artificial chromosome probes in 95 lung tumors. The ploidy level was analyzed in 100 lung tumors with FISH using three to five centromere probes. Results: Allelic imbalance at 9q31.3-q34.3 was found in all asbestos-exposed patient tumors (100%, 17 of 17) compared with 64% (14 of 22) in the nonexposed cases (P = 0.005). The most significant difference was detected at 9q33.1 (P = 0.002). FISH results showed that also CNA were more frequent at 9q33.1in the three major histologic types of non^small-cell lung tumors of exposed patients, and the association showed a dose-dependent trend (P = 0.03). Furthermore, we detected more frequent polyploidy among the exposed (48%, 28 of 58) than among the nonexposed (29%, 12 of 42) patient tumors (P < 0.05). Conclusions:These results provide a basis for the development of a method to identify asbestos-related lung cancer on a molecular level.

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“…In addition to LOH studies, evidence supporting the hypothesis that DBCCR1 is a tumor suppressor gene includes chromosome copy number changes detected by fluorescence in situ hybridization (FISH) (Stadler et al, 2001), absence of DBCCR1 mRNA expression in tumor cell lines and bladder tumors, and the existence of a bladder tumor (Nishiyama et al, 1999) and a bladder tumor cell line with homozygous deletions at the DBCCR1 locus (9p33) (Fujiwara et al, 2001).Transfection and expression of DBCCR1 in NIH/3T3 cells resulted in an increase in the proportion of cells in the G1 phase of the cell cycle (Nishiyama et al, 2001). This phenomenon was observable only under serum starvation conditions and the mechanism of action remains unclear.…”

Section: Introductionmentioning

confidence: 99%

DBCCR1 mediates death in cultured bladder tumor cells

2004

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Chromosome 9, which is often partially or fully reduced to homozygosity in bladder cancer cells, harbors several tumor suppressor loci including deleted in bladder cancer chromosome region 1 (DBCCR1) at 9q32-33. To study DBCCR1 function, stable cell lines, inducible for DBCCR1 expression by tetracycline, were made, but the DBCCR1 protein was not expressed at detectable levels. To understand the fate of DBCCR1-expressing cells, human bladder tumor cells were transiently transfected with an expression vector containing DBCCR1 fused to enhanced green fluorescent protein (EGFP). Initially, DBCCR1-EGFP-expressing cells demonstrated diffuse cytoplasmic green fluorescence with nuclear exclusion patterns. After time, the intensity level of green fluorescence increased and a granular distribution of protein became visible in the cells. At this point, cells rounded up and detached from the tissue culture dish. Cells transfected with a control vector, containing only EGFP, and partial DBCCR1-EGFP fusion constructs did not demonstrate this behavior. DBCCR1-mediated cell death in cultured tumor cells was independent of caspase-3 activation and did not result in detectable DNA strand breaks by TUNEL staining that are hallmarks of the classical apoptotic pathway.

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Negative regulation of G1/S transition by the candidate bladder tumour suppressor gene DBCCR1

Cited by 50 publications

References 22 publications

Loss of heterozygosity at 9q33 and hypermethylation of the DBCCR1 gene in oral squamous cell carcinoma

Loss of heterozygosity at 9q33 and hypermethylation of the DBCCR1 gene in oral squamous cell carcinoma

Molecular Alterations at 9q33.1 and Polyploidy in Asbestos-Related Lung Cancer

DBCCR1 mediates death in cultured bladder tumor cells

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