Genes Involved in Differentiation, Stem Cell Renewal, and Tumorigenesis Are Modulated in Telomerase-immortalized Human Urothelial Cells

Overview

Journal Mol Cancer Res

Specialty Cell Biology

Date 2008 Jul 23

PMID 18644980

Citations 29

Authors

Emma J Chapman

Gavin Kelly

Margaret A Knowles

Affiliations

Soon will be listed here.

Abstract

The expression of hTERT, the catalytic subunit of telomerase, immortalizes normal human urothelial cells (NHUC). Expression of a modified hTERT, without the ability to act in telomere maintenance, did not immortalize NHUC, confirming that effects at telomeres are required for urothelial immortalization. Previous studies indicate that inhibition of telomerase has an immediate effect on urothelial carcinoma (UC) cell line viability, before sufficient divisions to account for telomere attrition, implicating non-telomere effects of telomerase in UC. We analyzed the effects of telomerase on gene expression in isogenic mortal and hTERT-transduced NHUC. hTERT expression led to consistent alterations in the expression of genes predicted to be of phenotypic significance in tumorigenesis. A subset of expression changes were detected soon after transduction with hTERT and persisted with continued culture. These genes (NME5, PSCA, TSPYL5, LY75, IGFBP2, IGF2, CEACAM6, XG, NOX5, KAL1, and HPGD) include eight previously identified as polycomb group targets. TERT-NHUC showed overexpression of the polycomb repressor complex (PRC1 and PRC4) components, BMI1 and SIRT1, and down-regulation of multiple PRC targets and genes associated with differentiation. TERT-NHUC at 100 population doublings, but not soon after transduction, showed increased saturation density and an attenuated differentiation response, indicating that these are not acute effects of telomerase expression. Some of the changes in gene expression identified may contribute to tumorigenesis. Expression of NME5 and NDN was down-regulated in UC cell lines and tumors. Our data supports the concept of both telomere-based and non-telomere effects of telomerase and provides further rationale for the use of telomerase inhibitors in UC.

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References

Tseng Y, Butte A, Kokkotou E, Yechoor V, Taniguchi C, Kriauciunas K . Prediction of preadipocyte differentiation by gene expression reveals role of insulin receptor substrates and necdin. Nat Cell Biol. 2005; 7(6):601-11. DOI: 10.1038/ncb1259. View

Glinsky G, Berezovska O, Glinskii A . Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J Clin Invest. 2005; 115(6):1503-21. PMC: 1136989. DOI: 10.1172/JCI23412. View

Bracken A, Dietrich N, Pasini D, Hansen K, Helin K . Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 2006; 20(9):1123-36. PMC: 1472472. DOI: 10.1101/gad.381706. View

Gil J, Bernard D, Peters G . Role of polycomb group proteins in stem cell self-renewal and cancer. DNA Cell Biol. 2005; 24(2):117-25. DOI: 10.1089/dna.2005.24.117. View

van Leenders G, Dukers D, Hessels D, van den Kieboom S, Hulsbergen C, Witjes J . Polycomb-group oncogenes EZH2, BMI1, and RING1 are overexpressed in prostate cancer with adverse pathologic and clinical features. Eur Urol. 2006; 52(2):455-63. DOI: 10.1016/j.eururo.2006.11.020. View

Gentleman R, Carey V, Bates D, Bolstad B, Dettling M, Dudoit S . Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 2004; 5(10):R80. PMC: 545600. DOI: 10.1186/gb-2004-5-10-r80. View

Furuyama T, Banerjee R, Breen T, Harte P . SIR2 is required for polycomb silencing and is associated with an E(Z) histone methyltransferase complex. Curr Biol. 2004; 14(20):1812-21. DOI: 10.1016/j.cub.2004.09.060. View

Tateishi K, Ohta M, Kanai F, Guleng B, Tanaka Y, Asaoka Y . Dysregulated expression of stem cell factor Bmi1 in precancerous lesions of the gastrointestinal tract. Clin Cancer Res. 2006; 12(23):6960-6. DOI: 10.1158/1078-0432.CCR-06-0449. View

Maruyama K, Usami M, Aizawa T, Yoshikawa K . A novel brain-specific mRNA encoding nuclear protein (necdin) expressed in neurally differentiated embryonal carcinoma cells. Biochem Biophys Res Commun. 1991; 178(1):291-6. DOI: 10.1016/0006-291x(91)91812-q. View

10.

Nakada Y, Taniura H, Uetsuki T, Yoshikawa K . Characterization and chromosomal mapping of a human Necdin pseudogene. Gene. 2000; 245(1):185-91. DOI: 10.1016/s0378-1119(00)00012-3. View

11.

Liu L, Berletch J, Green J, Pate M, Andrews L, Tollefsbol T . Telomerase inhibition by retinoids precedes cytodifferentiation of leukemia cells and may contribute to terminal differentiation. Mol Cancer Ther. 2004; 3(8):1003-9. View

12.

Taniura H, Matsumoto K, Yoshikawa K . Physical and functional interactions of neuronal growth suppressor necdin with p53. J Biol Chem. 1999; 274(23):16242-8. DOI: 10.1074/jbc.274.23.16242. View

13.

Nowak K, Kerl K, Fehr D, Kramps C, Gessner C, Killmer K . BMI1 is a target gene of E2F-1 and is strongly expressed in primary neuroblastomas. Nucleic Acids Res. 2006; 34(6):1745-54. PMC: 1421501. DOI: 10.1093/nar/gkl119. View

14.

Choi J, Southworth L, Sarin K, Venteicher A, Ma W, Chang W . TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program. PLoS Genet. 2008; 4(1):e10. PMC: 2211538. DOI: 10.1371/journal.pgen.0040010. View

15.

Chapman E, Hurst C, Pitt E, Chambers P, Aveyard J, Knowles M . Expression of hTERT immortalises normal human urothelial cells without inactivation of the p16/Rb pathway. Oncogene. 2006; 25(36):5037-45. DOI: 10.1038/sj.onc.1209513. View

16.

Matsumoto K, Taniura H, Uetsuki T, Yoshikawa K . Necdin acts as a transcriptional repressor that interacts with multiple guanosine clusters. Gene. 2001; 272(1-2):173-9. DOI: 10.1016/s0378-1119(01)00544-3. View

17.

Al-Tubuly A, Spijker R, Pignatelli M, Kirkland S, Ritter M . Inhibition of growth and enhancement of differentiation of colorectal carcinoma cell lines by MAb MR6 and IL-4. Int J Cancer. 1997; 71(4):605-11. DOI: 10.1002/(sici)1097-0215(19970516)71:4<605::aid-ijc16>3.0.co;2-a. View

18.

Bahrenberg G, Brauers A, Joost H, Jakse G . Reduced expression of PSCA, a member of the LY-6 family of cell surface antigens, in bladder, esophagus, and stomach tumors. Biochem Biophys Res Commun. 2000; 275(3):783-8. DOI: 10.1006/bbrc.2000.3393. View

19.

Nosrati M, Li S, Bagheri S, Ginzinger D, Blackburn E, Debs R . Antitumor activity of systemically delivered ribozymes targeting murine telomerase RNA. Clin Cancer Res. 2004; 10(15):4983-90. DOI: 10.1158/1078-0432.CCR-04-0134. View

20.

Takazaki R, Nishimura I, Yoshikawa K . Necdin is required for terminal differentiation and survival of primary dorsal root ganglion neurons. Exp Cell Res. 2002; 277(2):220-32. DOI: 10.1006/excr.2002.5558. View