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NCI CANCERLIT^® Search: Retinoblastoma, Hereditary - June 2002

National Cancer Institute^®
Last Modified: June 1, 2002

Impaired expression and promotor hypermethylation of O6-methylguanine-DNA methyltransferase in retinoblastoma tissues.
Induction of VEGF gene expression by retinoic acid through Sp1-binding sites in retinoblastoma Y79 cells.
Retinoic acid upregulates cone arrestin expression in retinoblastoma cells through a Cis element in the distal promoter region.
Two genetic hits (more or less) to cancer.
Association between telomerase activity and basic fibroblast growth factor up-regulation in retinoblastomas.
Cyclin D1 overexpression in thyroid carcinomas: relation with clinico-pathological parameters, retinoblastoma gene product, and Ki67

Table of Contents

1
UI - 11980845
AU - Choy KW; Pang CP; To KF; Yu CB; Ng JS; Lam DS
TI - Impaired expression and promotor hypermethylation of O6-methylguanine-DNA methyltransferase in retinoblastoma tissues.
SO - Invest Ophthalmol Vis Sci 2002 May;43(5):1344-9
AD - Department of Ophthalmology and Visual Sciences, Hong Kong Eye Hospital, The Chinese University of Hong Kong, 3/F, 147K Argyle Street, Kowloon, Hong Kong, China.
PURPOSE: To investigate the role of epigenetic changes in the promoter region of tumor-suppressor genes in the retinoblastoma genome and to study the disruption of expression of O6-methylguanine-DNA Methyltransferase (MGMT) due to aberrant methylation and its association with retinoblastoma. METHODS: A series of 23 retinoblastoma tissue specimens and 2 retinoblastoma cell lines (Y79 and WERI-Rb1) were subjected to methylation-specific PCR (MSP) analysis of hypermethylated genes identified in human cancers, including p14(ARF), p15(INK4b), p16(INK4a), VHL, and MGMT. Further, the expression of MGMT was studied by immunohistochemistry and, when fresh tissue was available, by Western blot analysis and RT-PCR. RESULTS: Aberrant methylation of at least one MGMT locus was detected in 8 of the 23 tumors (35%), all of which (100%) had impaired or absent expression of MGMT. The remaining 15 tumor specimens were nonmethylated, and, among them, 7 (43%) showed defective expression. No methylation of tumor DNA was found on the p14(ARF), p15(INK4b), p16(INK4a), and VHL genes. Hypermethylation in the MGMT promoter was found to be prominently present in retinoblastoma with poor tissue differentiation, and was more frequently detected among patients with bilateral disease. Production of MGMT was consistent with expression of mRNA. No methylation of MGMT promoter was detected in the two retinoblastoma cell lines (Y79, WERI-Rb1). CONCLUSIONS: The data show a clear association between impaired production of MGMT and hypermethylation of the MGMT promoter, which appeared to relate to early onset and poor differentiation, suggesting that epigenetic silencing of MGMT by methylation of the promoter and reduced expression of MGMT may play an important role in the development and progression of retinoblastoma.

2
UI - 11980848
AU - Akiyama H; Tanaka T; Maeno T; Kanai H; Kimura Y; Kishi S; Kurabayashi M
TI - Induction of VEGF gene expression by retinoic acid through Sp1-binding sites in retinoblastoma Y79 cells.
SO - Invest Ophthalmol Vis Sci 2002 May;43(5):1367-74
AD - Department of Ophthalmology, Gunma University School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan.
PURPOSE: Vascular endothelial growth factor (VEGF) is an angiogenic peptide that has been implicated in many retinopathies. Although all trans-retinoic acid (atRA) has long been known as an essential factor in the visual cycle, the role of atRA in the pathogenesis of retinal disease remains elusive. In this study, we investigated the effects of atRA on expression of the VEGF gene in retinoblastoma Y79 cells. METHODS: Total RNA prepared from Y79 cells, with or without atRA, was subjected to Northern blot analyses. Reporter constructs consisting of the VEGF promoter-luciferase gene were transfected into Y79 cells. Nuclear factors binding to the VEGF promoter were analyzed by electrophoretic mobility shift assays (EMSAs). RESULTS: The levels of VEGF transcripts were increased by atRA in a time- and dose-dependent manner. Progressive deletion and site-specific mutation analyses indicated that atRA increased VEGF promoter activity through a G+C-rich sequence that was shown to be an Sp1-binding site by supershift assays. EMSAs showed that Sp1 binding was increased by atRA stimulation. Although no measurable change was observed in Sp1 mRNA levels, Western blot analysis showed an increase in Sp1 protein levels in the atRA-treated cells. These data suggest that atRA increases Sp1 protein levels by posttranscriptional mechanisms, and elevated levels of Sp1 protein induce the expression of VEGF at the transcriptional level. CONCLUSIONS: atRA induced transcription of the VEGF gene through Sp1-binding sites in Y79 cells. Pharmacologic intervention that inhibits the signals elicited by atRA may be effective in treating VEGF-mediated retinopathies.

3
UI - 11980849
AU - Li A; Zhu X; Craft CM
TI - Retinoic acid upregulates cone arrestin expression in retinoblastoma cells through a Cis element in the distal promoter region.
SO - Invest Ophthalmol Vis Sci 2002 May;43(5):1375-83
AD - Mary D. Allen Laboratory for Vision Research, Doheny Eye Institute, University of Southern California, 1333 San Pablo Street, Los Angeles, CA 90089-9112, USA.
PURPOSE: This study was initiated to investigate the molecular mechanisms of activation of expression of the human cone arrestin (hCAR) gene by retinoic acid (RA), in an in vitro model of retinoblastoma cells. METHODS: Human retinoblastoma Weri-Rb-1 or Y79 cell lines were cultured in the absence or presence of RA analogues with transcription or translation inhibitors for various periods. The mRNAs encoding hCAR, retinoic acid receptor (RAR), and retinoid X receptor (RXR) subtypes were analyzed by Northern blot. Immunoblot analysis of hCAR protein was also performed. The hCAR promoter's activity and its responsiveness to RA treatment was evaluated by transient transfection of the hCAR promotor-luciferase reporter constructs, followed by promoter deletion analysis to map the specific regions responsible for the RA response. RESULTS: In our in vitro model, both all-trans RA and 9-cis RA induced hCAR mRNA in a time- and dose-dependent manner. RA's effect was blocked by either RNA or protein synthesis inhibitors; however, hCAR mRNA's stability was not affected by RA, as determined by RNA decay experiments. Although all RAR and RXR subtypes were detected, only RXRgamma and RARalpha increased dramatically after treatment with RA. An RXR-specific agonist, but not an RAR-specific agonist, also increased hCAR mRNA and protein expression in both Weri-Rb-1 and Y79 cells. RA stimulated hCAR promoter-luciferase activity in transient transfection studies. Subsequently, a region between -852 and -702 of the hCAR promoter, with RA-responsive elements (RAREs), was discovered to be responsible for the RA response. CONCLUSIONS: The hCAR gene is transcriptionally upregulated by RA acting through cis elements within -852 to -702 of the hCAR 5' flanking region. Based on the cumulative data, RXRgamma is most likely the RA receptor subtype involved in hCAR regulation by RA.

4
UI - 11905807
AU - Knudson AG
TI - Two genetic hits (more or less) to cancer.
SO - Nature Rev Cancer 2001 Nov;1(2):157-62
AD - Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. ag_knudson@fccc.edu
Most cancers have many chromosomal abnormalities, both in number and in structure, whereas some show only a single aberration. In the era before molecular biology, cancer researchers, studying both human and animal cancers, proposed that a small number of events was needed for carcinogenesis. Evidence from the recent molecular era also indicates that cancers can arise from small numbers of events that affect common cell birth and death processes.

5
UI - 11911245
AU - Kondo Y; Tanaka Y; Shields JA; Kondo S
TI - Association between telomerase activity and basic fibroblast growth factor up-regulation in retinoblastomas.
SO - Anticancer Res 2001 Nov-Dec;21(6A):3765-72
AD - Center for Surgery Research, The Cleveland Clinic Foundation, OH 44195, USA. Yasuko.Kondo@mssm.edu
BACKGROUND: Telomerase is an enzyme associated with cellular immortality and malignancy in many cell types. On the other hand, growth factors such as basic fibroblast growth factor (bFGF) or platelet-derived growth factor (PDGF) promote tumor growth, whereas the association between telomerase and these growth factors remains unclear. MATERIALS AND METHODS: Telomerase activity and expression of bFGF and PDGF were assayed in 9 retinoblastoma tissues and 2 cell lines (WERI-Rb-1 and Y79). The association of telomerase activity with bFGF or PDGF was investigated. RESULTS: Telomerase activity was detected in three out of nine tissues and both cell lines. Two telomerase highly-positive tissues and WERI-Rb-1 and Y79 cells expressed bFGF. As for the expression of PDGF, only one retinoblastoma tissue with high telomerase was positive. To further determine whether telomerase activity and bFGF are closely associated, we inhibited each expression. Inhibition of telomerase in WERI-Rb-1 cells using the anti-sense treatment suppressed the expression of bFGF and subsequently induced apoptosis after 25 to 30 doublings. When bFGF expression was suppressed by the neutralizing antibody, telomerase activity was not affected nor was apoptosis detected. CONCLUSION: Telomerase may up-regulate the expression of bFGF and protect retinoblastoma cells from cell death, indicating, the possibility that inhibition of telomerase is a promising approach for the treatment of telomerase-positive tumors.

6
UI - 11041450
AU - Basolo F; Caligo MA; Pinchera A; Fedeli F; Baldanzi A; Miccoli P;
TI - Iacconi P; Fontanini G; Pacini F Cyclin D1 overexpression in thyroid carcinomas: relation with clinico-pathological parameters, retinoblastoma gene product, and Ki67 labeling index.
SO - Thyroid 2000 Sep;10(9):741-6
AD - Department of Oncology, University of Pisa, Italy. f.basolo@do.mcd.unipi.it
Cyclin D1 is a G1 cyclin participating in the control of cell cycle progression through interaction with the retinoblastoma gene product (pRB). The overexpression of positive regulators (such as cyclin D1) has been reported in a variety of neoplasms, but their role in thyroid tumorigenesis is yet to be established. In our series of 54 thyroid carcinomas, cyclin D1 overexpression (detected by both immunohistochemistry and by Northern blotting) was correlated with prognostic variables, proliferative activity and pRB. Cyclin D1 overexpression was observed in 35% of thyroid carcinomas with a significantly higher expression of this cyclin in neoplastic tissues than in matched normal parenchyma. In well-differentiated carcinomas, the cyclin D1 mRNA overexpression was inversely correlated with nodal status (p = 0.03), while the protein product was higher in tumors from patients less than 40 than patients over 40 years of age. Inversely, there was no significant correlation with gender and tumor status, pRB and with proliferative activity.

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