Increased Expression of the Retinoblastoma Gene in Human Colorectal Carcinomas Relative to Normal Colonic Mucosa

Gope, Rajalakshmi; Christensen, Mark A.; Thorson, Alan G.; Lynch, Henry T.; Smyrk, Thomas C.; Hodgson, Clague P.; Wildrick, David M.; Gope, Mohan L.; Boman, Bruce M.

doi:10.1093/jnci/82.4.310

Cited by 52 publications

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“…There were significantly more tumours with heterozygous loss on chromosome Ip than within the Rb locus (X2 = 6.7, P<0.01), and there tended to be more tumours with heter- Fearon & Vogelstein, 1990 The retinoblastoma gene acts as a tumour suppressor gene, and is known to be involved in several human malignancies (for reviews, see Benedict et al, 1990;Marshall, 1991). In a cytogenetic study on colorectal carcinomas, a non-random gain of chromosome 13 has been demonstrated (Muleris et al, 1988), and in a smaller colorectal carcinoma study, a significant amplification of the Rb gene was demonstrated both at the DNA and RNA levels (Gope et al, 1990), both studies suggesting that the Rb gene may be involved in colorectal carcinogenesis. The findings of the latter report have recently been confirmed by Lothe et al (1991).…”

Section: Resultsmentioning

confidence: 98%

“…The Rb gene has been shown to suppress tumour development (Bookstein et al, 1990), and the gene is therefore classified as a tumour suppressor gene. Little is known about the involvement of this gene in colorectal tumourigenesis. However, in a small series of colorectal carcinomas, it has recently been reported a significant amplification of the Rb gene (Gope et al, 1990).…”

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confidence: 97%

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Genetic alterations within the retinoblastoma locus in colorectal carcinomas. Relation to DNA ploidy pattern studied by flow cytometric analysis

Meling

Lothe²,

Børresen³

et al. 1991

Br J Cancer

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Alterations within the retinoblastoma (Rb) gene, as detected by the VNTR probe p68RS2.0, and flow cytometric DNA pattern have been analysed in 255 colorectal carcinomas. A total of 35.3% of the tumours had alterations within the Rb gene. Amplification of one allele was demonstrated in 29.5% of the tumours, and loss of heterozygosity was found in 11.5%. No association was found between amplification within the Rb gene and clinicopathological characteristics of the patients. The high frequency of alterations demonstrated within the Rb gene, suggests that this gene is involved in colorectal carcinogenesis with amplification as by far the most abundant genetic alteration. This may imply that the Rb gene has an oncogene-like function in colorectal carcinomas, rather than acting as a tumour suppressor gene. Sixty-three per cent of the carcinomas were DNA aneuploid, and a significant association was demonstrated between amplification within the Rb gene and DNA aneuploidy (P less than 0.01). Two other chromosome loci were analysed, on chromosome 1p (probe pYNZ2) and on chromosome 2p (probe pYNH24), respectively. On chromosome 1p, heterozygous loss was found in 22.2% of the tumours, indicating an involvement of this chromosome in a subset of colorectal carcinomas. Images Figure 1

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Section: Resultsmentioning

confidence: 98%

mentioning

confidence: 97%

Genetic alterations within the retinoblastoma locus in colorectal carcinomas. Relation to DNA ploidy pattern studied by flow cytometric analysis

Meling

Lothe²,

Børresen³

et al. 1991

Br J Cancer

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“…A major difference between the colon and other tissues is the notable lack of RB-1 deletion or mutation in colorectal cancer (Meling et al, 1991;Ali et al, 1993) indicating that the inactivation of RB-1 is not required for the development of colorectal tumorigenesis. In addition, the rise in the level of RB-1 mRNA in colonic tumours compared to that in normal colonic mucosa (Gope et al, 1990), together with the associated increase in pRb phosphorylation (Gope and Gope, 1992) suggest that the active Rb protein is retained and indeed up-regulated in colonic tumorigenesis. This is further supported by the fact that Rb protein associated with elevated levels of transcripts appears to be normal size (4.7 kb) and functional (Ali et al, 1993), inferring that colorectal cancer cells retain functional pRb.…”

Section: Discussionmentioning

confidence: 99%

“…However, loss or inactivation of the RB-1 gene in colorectal tumours is uncommon (Meling et al, 1991;Ali et al, 1993); only up to 11% of colorectal carcinomas show allelic loss on chromosome 13 (Wildrick and Bowman, 1994). Instead, colorectal tumours have been reported to express significantly higher levels of RB-1 mRNA than normal colonic mucosa (Gope et al, 1990). This increase coincides with a 1.5-2.5 fold increase in percentage of pRb phosphorylation (Gope and Gope, 1992), which is thought to be due to over-expression of the Rb-related kinases cdk2 and cdc2 (Yamamoto et al, 1995).…”

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confidence: 95%

Transcriptional down-regulation of the retinoblastoma protein is associated with differentiation and apoptosis in human colorectal epithelial cells

et al. 2001

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SummaryThe aim of this study was to investigate the regulation of Rb protein expression in relation to increased differentiation and induction of apoptosis in colonic epithelial cells. In vivo, Rb protein expression was found to be down-regulated towards the top of the normal colonic crypt, coincident with the region of differentiation and apoptosis, but highly expressed in colonic carcinoma tissue. Using in vitro models to study the regulation of Rb expression in pre-malignant colonic epithelial cells, we have been able to show for the first time that Rb protein expression is transcriptionally down-regulated in differentiated pre-malignant cells (in post-confluent cultures) but not in malignant colorectal epithelial cells. Furthermore, suppression of rb protein function by the HPV-E7 viral oncoprotein increased both spontaneous and DNA damage-induced apoptosis. These results suggest that Rb is able to act as a survival factor in colonic epithelial cells by suppressing apoptosis, and that over-expression of pRb in colorectal tumour cells can cause a loss of sensitivity to apoptotic signalling, resulting in aberrant cell survival and resistance to therapy. targeted inactivation of the RB-1 gene in mouse embryonic fibroblasts induces apoptosis. Therefore, pRb appears to suppress apoptosis in some cell systems, perhaps through the sequestration of the E2F-1 protein, which can induce apoptosis if over-expressed (Qin et al, 1994;Field et al, 1996). In this case, pRb needs to be removed or inactivated before apoptosis can occur. To support this, a 30 kD protein has been detected in apoptotic cells harvested from colon tumour cell lines, CMSV40 fibroblasts and BJA-B lymphocyte cells, suggesting that the Rb protein is cleaved during the apoptotic process (Browne et al, 1994;An and Dou, 1996). Furthermore, cleavage at the C-terminus of pRb results in a p100 and ~5 kDa polypeptide (Chen et al, 1997). The p100 Rb protein can still bind to E2F-1 and inhibit E2F-mediated transcriptional activity, but its anti-apoptotic function is reduced, perhaps through its inability to bind to the oncogene MDM2. Thus the growthsuppressive and anti-apoptotic functions of pRb appear to be distinct from one another. The notion that pRb functions can be separated from one another has been explored previously, and experimental evidence indicates that the multiple functions of pRb can be genetically uncoupled, providing distinct functions in cellcycle control or in tissue-specific gene expression during differentiation (reviewed in Yee et al, 1998). Mice with mutations of the N-terminal region of Rb protein exhibit defects in muscle differentiation, whilst retaining the ability to bind to E2F (Riley et al, 1997). Conversely, cells with pRb mutations in the pocket domain are able to differentiate normally even when E2F binding is abrogated (Sellers et al, 1998).The functional loss of the Rb protein, by deletion or mutation, has been implicated not only in retinoblastoma, but in many types of tumour, including bladder, breast, lung and ovarian ca...

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“…12,14 At the genomic level, allelic loss detected by loss of heterozygosity (LOH) has also been reported in the RB1 region in CRC with widely differing frequencies ranging from 11.5% 15 to as high as 50% of cases studied.…”

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Overexpression of RB1 transcript is significantly correlated with 13q14 allelic imbalance in colorectal carcinomas

Lai

Cheah

Kadam

et al. 2006

Intl Journal of Cancer

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RB1 gene expression has been reported to be upregulated in colorectal carcinomas (CRC) at both the mRNA and protein levels when compared to normal colonic mucosa. However, allelic loss at the genomic level has been detected in CRC with widely differing frequencies ranging from 11.5% to 50%. To determine whether there is indeed a correlation between RB1 allelic imbalance (AI) and expression, a consecutive series of 55 CRC from Singapore patients were analysed by microsatellite analysis, real-time RT-PCR and immunohistochemistry. Microsatellite analysis using 3 RB1 intragenic microsatellite markers and 2 markers flanking RB1 detected AI in 32.7% (18/55) of the cases, in at least 1 locus. The highest AI frequency (22.9%) was observed at the microsatellite marker D13S137 (Cu13), which maps 5 cM distal to RB1. AI was present in both early and late Dukes stages. Real-time RT-PCR revealed that all 40 cases analysed expressed RB1 mRNA, with mRNA overexpression in 37.5% (15/40) and pRB protein expression in 88.2% (30/ 34) of cases. Notably, a statistically significant correlation was found between AI of RB1 and mRNA overexpression of RB1 (p < 0.001, Fishers exact test). These findings provide evidence that despite AI, RB1 expression is not abrogated. Thus, our data suggests that RB1 may play a role in colorectal tumorigenesis through functional regulation of the transcript and protein rather than through its tumour suppressor role by gene inactivation. ' 2006 Wiley-Liss, Inc.Key words: RB1; colorectal cancer; allelic imbalance; expressionThe retinoblastoma gene, RB1, is a well-known tumour suppressor gene that encodes a nucleoprotein (pRB) with a critical role in cell cycle regulation, proliferation, differentiation and apoptosis. Numerous studies have shown frequent loss of RB1 function and either low or no pRb expression in different tumour types, such as pituitary adenomas, 1 glioblastomas, 2,3 hepatocellular carcinomas 4 and sporadic retinoblastomas. 5 In contrast, RB1 gene expression has been reported to be upregulated in colorectal carcinomas (CRC) at both the mRNA and protein levels when compared to normal colonic mucosa.6-13 Consistent with this increased expression, RB1 transcripts and pRb are not truncated or absent in colorectal cancers, suggesting that Rb is functional in CRC. 12,14 At the genomic level, allelic loss detected by loss of heterozygosity (LOH) has also been reported in the RB1 region in CRC with widely differing frequencies ranging from 11.5% 15 to as high as 50% of cases studied.16,17 These differences in frequencies may be because LOH assays actually determine allelic imbalance which may indicate either loss or gain. Increased allelic copy number at polymorphic loci of RB1 has also been documented by densitometric comparisons of Southern blots in 32% of colorectal tumours, 18 as well as by fluorescence in situ hybridization analysis in 44% of colorectal adenomas. 19 The presence of RB1 allelic loss would suggest that its expression would be decreased, contradictory to previous expression stud...

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Increased Expression of the Retinoblastoma Gene in Human Colorectal Carcinomas Relative to Normal Colonic Mucosa

Cited by 52 publications

References 0 publications

Genetic alterations within the retinoblastoma locus in colorectal carcinomas. Relation to DNA ploidy pattern studied by flow cytometric analysis

Genetic alterations within the retinoblastoma locus in colorectal carcinomas. Relation to DNA ploidy pattern studied by flow cytometric analysis

Transcriptional down-regulation of the retinoblastoma protein is associated with differentiation and apoptosis in human colorectal epithelial cells

Overexpression of RB1 transcript is significantly correlated with 13q14 allelic imbalance in colorectal carcinomas

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