Complexity, Retinoid-Responsive Gene Networks, and Bladder Carcinogenesis

Hurst, Robert E.; Waliszewski, Przemysław; Waliszewska, Miroslawa; Bonner, Rebecca B.; Benbrook, Doris M.; Dar, Arindam; Hemstreet, George P.

doi:10.1007/978-1-4615-4737-2_35

Cited by 13 publications

(18 citation statements)

References 53 publications

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“…The majority of actions of retinoids are thought to be mediated by two different families of nuclear receptors, RA receptors and retinoid X receptors, each consisting of three receptor types ␣, ␤, and ␥ (17). The expression profile of these receptors in bladder cancer has been explored previously in vitro for several human bladder carcinoma cell lines (9,18). The RA receptors and retinoid X receptors act as ligand-activated transcription factors to regulate the expression of a number of retinoidresponsive genes (19).…”

Section: Introductionmentioning

confidence: 99%

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Boorjian¹,

Tickoo²,

Mongan³

et al. 2004

Clinical Cancer Research

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Purpose: Retinoids, which include vitamin A (retinol; ROL) and its derivatives, have been investigated in the treatment of bladder cancer. We have shown that expression of the enzyme lecithin:ROL acyltransferase (LRAT), which converts ROL to retinyl esters, is reduced in several human cancers. Here we evaluated expression of LRAT protein and mRNA in normal and malignant bladder tissue specimens from human patients. We also examined the effect of retinoids on LRAT expression in bladder cancer cell lines.Experimental Design: We evaluated 49 bladder cancer specimens for LRAT protein expression using immunohistochemistry with affinity-purified antibodies to human LRAT. LRAT mRNA expression was assessed using reverse transcription-PCR in bladder specimens from an additional 16 patients. We examined the effect of retinoic acid and ROL on LRAT mRNA expression in five human bladder cancer cell lines.Results: LRAT protein was detected throughout the nonneoplastic bladder epithelium in all of the specimens. In bladder tumors, LRAT protein expression was reduced compared with the nonneoplastic epithelium or was completely absent in 7 of 32 (21.9%) superficial tumors versus 16 of 17 (94.1%) invasive tumors (P < 0.001). All of the nonneoplastic bladder specimens tested (11 of 11) showed LRAT mRNA expression, compared with 5 of 8 (62%) superficial tumors and 0 of 5 (0%) invasive tumors (P ‫؍‬ 0.001). Three of five human bladder cancer cell lines expressed LRAT mRNA independent of retinoid exposure, whereas in two cell lines LRAT mRNA expression was induced by retinoid treatment.Conclusions: We report a significant reduction in LRAT expression in bladder cancer. Moreover, we demonstrate an inverse correlation of LRAT mRNA and protein expression with increasing tumor stage. These data suggest that loss of LRAT expression is associated with invasive bladder cancer.

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Section: Introductionmentioning

confidence: 99%

Reduced Lecithin

Boorjian¹,

Tickoo²,

Mongan³

et al. 2004

Clinical Cancer Research

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“…[32][33] Rationale of the present study was based on the mutual relationship of the bladder and retinoids as evident from: (1) The expression of not only the complete retinoid signal transduction cascade, synthesizing and catabolising enzymes but also retinoid storing ability. [34][35][36][37][38] (2) Abnormalities at the genetic and epigenetic levels involving these components correlated unfavorable bladder cancer prognosis and early disease. [34][35][36][37][38][39][40][41][42] (3) Epidemiologic studies connected the disease predisposition and/or prevention to abnormal plasma retinoid levels.…”

Section: Discussionmentioning

confidence: 99%

“…[34][35][36][37][38] (2) Abnormalities at the genetic and epigenetic levels involving these components correlated unfavorable bladder cancer prognosis and early disease. [34][35][36][37][38][39][40][41][42] (3) Epidemiologic studies connected the disease predisposition and/or prevention to abnormal plasma retinoid levels. [43][44][45] Bilharzial patients and bladder cancer patients with squamous cell carcinoma, the most prevalent type in Egypt, showed significantly lower levels of vitamin A than normal male subjects.…”

Section: Discussionmentioning

confidence: 99%

The effectiveness of retinoic acid treatment in bladder cancer: Impact on recurrence, survival and TGFα and VEGF as end-point biomarkers.

Hameed

2008

Cancer Biology & Therapy

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Introduction and aims: Being best-studied superficial bladder cancer (SBC) chemopreventives, retinoids' negative studies and toxicity were stumbling. With proper understanding of retinoid metabolism, we aimed at investigating combined ketoconazole (a strong inhibitor of retinoic acid-catabolizing cytochrome P450s) all-trans retinoic acid (Keto-atRA) SBC treatment. VEGF and TGFα levels are end-point pathogenetic biomarkers involved in early SBC.Results: Keto-atRA treatment significantly improved survival time and decreased recurrence rate compared to control disease group, with tolerable and reversible side-effects. Treatment normalized induced levels of VEGF and TGFα with a positive correlation between these cytokines.Material and methods: Seven days after TURT visible tumor(s), combined atRA 1 mg/kg for five days a week + Keto 200 mg twice daily for five days a week for three months were given to 16 patients with SBC stages Ta and T1 with various grades. Three months follow up/20 months used white light cystoscopy and urinary cytology. Recurrence rate and survival time were compared to a retrospective group of 25 patients of comparable age, stage and grade with TURT as sole treatment for SBC. VEGF and TGFα were measured in urine and serum of 12 normal subjects and treated patients. Samples were collected just before TURT, one week after TURT, at the end of one month and at the end of three months of treatment.Conclusions: The combination and schedule used for KetoatRA therapy effectively reduced recurrence rate and increased survival time of SBC patients probably through reduction of VEGF and TGFα as major mitogenic/angiogenic factors; possibly by eliminating malignant cells that produce them.

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“…Two members of the cellular retinoic acid-binding proteins (CRABPs) exist in the cytosol for specific binding to retinoic acid (RA), designated as CRABP-I and CRABP-II. In the parental cell line 5637, CRABP-I has been previously reported as nonexpressed (Hurst et al, 1999). In line with this report, we measured CRABP-I expression, which was just above the detection level of the microarrays in all clones, whereas CRABP-II was expressed at much higher levels and 2.2-fold overexpressed in clone D. Furthermore, the expression profiles of small, proline-rich proteins (SPRR1B and SPRR2B) were nearly identical to the expression profile of MTs and SERPINB5 (Figure 3, top right panel).…”

Section: Discussionmentioning

confidence: 99%

“…SPRR1B is induced during keratinocyte differentiation and is downregulated by retinoids (Marvin et al, 1992). Retinoid signalling has been suggested to be a frequent target of inactivation in bladder carcinogenesis (Hurst et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

DBC1 re-expression alters the expression of multiple components of the plasminogen pathway

et al. 2005

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Deleted in bladder cancer 1 (DBC1) is a candidate gene for the bladder tumour suppressor locus at 9q33.1. The function of the gene is currently unknown but a crossspecies sequence comparison suggests an important role, as it is highly evolutionarily conserved. Here, we transfected a nonexpressing human bladder cancer cell line with a set of human DBC1 cDNA constructs. The effect on global expression patterns was assessed using cDNA microarrays. The cell clone with the lowest level of DBC1 expression showed induced expression of 26 genes including plasminogen activator inhibitor 2 (SERPINB5; 4.6-fold), heparin-binding EGF-like growth factor precursor (DTR; 4.2-fold), small proline-rich protein 2B (SPRR2B; 3.6-fold), metallothionein 1 isoforms (MT1B/ MT1A/MT-1F; from 2.9-to 3.2-fold), tissue-type plasminogen activator precursor (PLAT; 2.8-fold) and urokinase-type plasminogen activator precursor (PLAU; 2.7-fold). In clustering analysis, both PLAT and PLAU clustered with the functionally related urokinase plasminogen activator surface receptor (PLAUR; 1.9-fold). Furthermore, 14 human bladder tumours were analysed by real-time quantitative PCR using gene-specific primers for selected (n ¼ 20) genes. The expression levels of SERPINB5, PLAU, PLAUR and MT1 correlated with the DBC1 levels, suggesting previously unknown involvement of DBC1 in the urokinase-plasminogen pathway.

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Complexity, Retinoid-Responsive Gene Networks, and Bladder Carcinogenesis

Cited by 13 publications

References 53 publications

Reduced Lecithin

Reduced Lecithin

The effectiveness of retinoic acid treatment in bladder cancer: Impact on recurrence, survival and TGFα and VEGF as end-point biomarkers.

DBC1 re-expression alters the expression of multiple components of the plasminogen pathway

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