Expression of sex steroid receptor genes and comodulation with retinoid signaling in normal human uroepithelial cells and bladder cancer cell lines

Waliszewski, Przemysław; Waliszewska, Miroslawa; Hemstreet, George P.; Hurst, Robert E.

doi:10.1016/s1078-1439(98)00011-8

Cited by 10 publications

(6 citation statements)

References 24 publications

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“…One explanation for these differences may be the well-known influence of androgens on the development of bladder cancer (46). The correlation could also result from a higher fraction of smokers in the male population.…”

Section: Discussionmentioning

confidence: 99%

HERV-K and LINE-1 DNA Methylation and Reexpression in Urothelial Carcinoma

Kreimer¹,

Schulz²,

Koch³

et al. 2013

Front. Oncol.

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Changes in DNA methylation frequently accompany cancer development. One prominent change is an apparently genome-wide decrease in methylcytosine that is often ascribed to DNA hypomethylation at retroelements comprising nearly half the genome. DNA hypomethylation may allow reactivation of retroelements, enabling retrotransposition, and causing gene expression disturbances favoring tumor development. However, neither the extent of hypomethylation nor of retroelement reactivation are precisely known. We therefore assessed DNA methylation and expression of three major classes of retroelements (LINE-1, HERV-K, and AluY) in human urinary bladder cancer tissues and cell lines by pyrosequencing and quantitative reverse transcription–polymerase chain reaction, respectively. We found substantial global LINE-1 DNA hypomethylation in bladder cancer going along with a shift toward full-length LINE-1 expression. Thus, pronounced differences in LINE-1 expression were observed, which may be promoted, among others, by LINE-1 hypomethylation. Significant DNA hypomethylation was found at the HERV-K_22q11.23 proviral long terminal repeat (LTR) in bladder cancer tissues but without reactivation of its expression. DNA methylation of HERVK17, essentially absent from normal urothelial cells, was elevated in cell lines from invasive bladder cancers. Accordingly, the faint expression of HERVK17 in normal urothelial cells disappeared in such cancer cell lines. Of 16 additional HERV-Ks, expression of 7 could be detected in the bladder, albeit generally at low levels. Unlike in prostate cancers, none of these showed significant expression changes in bladder cancer. In contrast, expression of the AluYb8 but not of the AluYa5 family was significantly increased in bladder cancer tissues. Collectively, our findings demonstrate a remarkable specificity of changes in expression and DNA methylation of retroelements in bladder cancer with a significantly different pattern from that in prostate cancer.

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Section: Discussionmentioning

confidence: 99%

HERV-K and LINE-1 DNA Methylation and Reexpression in Urothelial Carcinoma

Kreimer¹,

Schulz²,

Koch³

et al. 2013

Front. Oncol.

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“…Shen and colleagues (22) previously reported increased proliferation in the RT4 UCB cell line treated with the non-selective ER agonist estradiol; but higher expression of ERα than ERβ in this cell line raises the possibility that ERα activation was responsible. Another study investigating estradiol in a UCB cell line expressing predominantly ERβ observed no growth effects (31). Here, we demonstrated that selective ERβ activation by DPN in the bladder cancer cells predominantly expressing ERβ increased proliferation in all cases (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Several prior studies of SERMs have described conflicting growth inhibitory effects in bladder cancer cell lines or murine xenografts (21–23,31). We found that tamoxifen treatment alone significantly inhibited growth (Fig.…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor-β expression and pharmacological targeting in bladder cancer

et al. 2013

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A role for estrogen signaling in urothelial carcinoma of the bladder (UCB) is suggested to be associated with more advanced disease with worse outcomes in women. Estrogen receptor β (ERβ) is the predominant receptor in bladder tissues. We aimed to ascertain whether ERβ correlates with clinicopathological predictors of aggressive bladder cancer and worse survival outcomes. ERβ was measured by immunohistochemistry in malignant and adjacent benign bladder tissues in patients (N=72) with UCB who underwent radical cystectomy. ERβ expression was tested for statistical association with clinicopathological variables and patient survival. ERβ expression was determined in bladder cancer cell lines, and the effects of the selective estrogen modulator tamoxifen and the ERβ agonist diarylpropionitrile on cell growth were determined. The ERβ level was significantly higher in malignant vs. benign urothelium (P<0.001) and was strongly associated with aggressive tumor histology characterized by lymphovascular (P=0.008) and perineural (P=0.006) invasion, and clinical histories of pelvic irradiation (P=0.005), hydronephrosis (P=0.022) and no intravesical chemotherapy (P=0.038). All patients with a high (>70%) percentage of ERβ positivity in tissue with >3-month follow-up developed recurrent disease (P=0.009). Higher ERβ level was predictive of worse recurrence-free and overall survival following cystectomy, after adjustment for tumor stage, and remained significantly associated with recurrence-free survival in the multivariable analysis including tumor stage, nodal stage and lymphovascular invasion. Activation of ERβ in bladder cancer cell lines led to significant increases in proliferation, while pharmacological inhibition with tamoxifen blocked cell growth. Our study supports a role for ERβ in aggressive UCB. Pharmacological targeting of ERβ warrants further investigation as a therapeutic strategy in UCB.

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“…This combination suggests loss of epithelial differentiation. Bladder cancer cells were earlier demonstrated to contain both functional androgen and estrogen receptors without regard to the sex of the donor [ 34 , 35 ] while myogenin was primary expressed in rhabdomyosarcomas [ 36 , 37 ]. Identification of myogenin expression in bladder cancer cell lines is novel, and further research will be needed to determine if this transcription factor is actually active.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the interaction of extracellular matrix and phenotype of bladder cancer cells

et al. 2006

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BackgroundThe extracellular matrix has a major effect upon the malignant properties of bladder cancer cells both in vitro in 3-dimensional culture and in vivo. Comparing gene expression of several bladder cancer cells lines grown under permissive and suppressive conditions in 3-dimensional growth on cancer-derived and normal-derived basement membrane gels respectively and on plastic in conventional tissue culture provides a model system for investigating the interaction of malignancy and extracellular matrix. Understanding how the extracellular matrix affects the phenotype of bladder cancer cells may provide important clues to identify new markers or targets for therapy.MethodsFive bladder cancer cell lines and one immortalized, but non-tumorigenic, urothelial line were grown on Matrigel, a cancer-derived ECM, on SISgel, a normal-derived ECM, and on plastic, where the only ECM is derived from the cells themselves. The transcriptomes were analyzed on an array of 1186 well-annotated cancer derived cDNAs containing most of the major pathways for malignancy. Hypervariable genes expressing more variability across cell lines than a set expressing technical variability were analyzed further. Expression values were clustered, and to identify genes most likely to represent biological factors, statistically over-represented ontologies and transcriptional regulatory elements were identified.ResultsApproximately 400 of the 1186 total genes were expressed 2 SD above background. Approximately 100 genes were hypervariable in cells grown on each ECM, but the pattern was different in each case. A core of 20 were identified as hypervariable under all 3 growth conditions, and 33 were hypervariable on both SISgel and Matrigel, but not on plastic. Clustering of the hypervariable genes showed very different patterns for the same 6 cell types on the different ECM. Even when loss of cell cycle regulation was identified, different genes were involved, depending on the ECM. Under the most permissive conditions of growth where the malignant phenotype was fully expressed, activation of AKT was noted. TGFβ1 signaling played a major role in the response of bladder cancer cells to ECM. Identification of TREs on genes that clustered together suggested some clustering was driven by specific transcription factors.ConclusionThe extracellular matrix on which cancer cells are grown has a major effect on gene expression. A core of 20 malignancy-related genes were not affected by matrix, and 33 were differentially expressed on 3-dimensional culture as opposed to plastic. Other than these genes, the patterns of expression were very different in cells grown on SISgel than on Matrigel or even plastic, supporting the hypothesis that growth of bladder cancer cells on normal matrix suppresses some malignant functions. Unique underlying regulatory networks were driving gene expression and could be identified by the approach outlined here.

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Expression of sex steroid receptor genes and comodulation with retinoid signaling in normal human uroepithelial cells and bladder cancer cell lines

Cited by 10 publications

References 24 publications

HERV-K and LINE-1 DNA Methylation and Reexpression in Urothelial Carcinoma

HERV-K and LINE-1 DNA Methylation and Reexpression in Urothelial Carcinoma

Estrogen receptor-β expression and pharmacological targeting in bladder cancer

Analysis of the interaction of extracellular matrix and phenotype of bladder cancer cells

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