• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of brjcancerBJC HomepageBJC Advance online publicationBJC Current IssueSubmitting an article to BJCWeb feeds
Br J Cancer. Jul 1999; 80(9): 1312–1321.
PMCID: PMC2363067

DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas

Abstract

Since DNA methylation is considered an important mechanism for silencing of retroelements in the mammalian genome, hypomethylation in human tumours may lead to their reactivation. The methylation status of LINE-1 retroposons was determined in 73 samples of urinary bladder cancers, 34 specimens of renal cell carcinoma and in the corresponding normal tissues by Southern blot analysis. LINE-1 sequences were strongly methylated in normal tissues and were significantly hypomethylated in 69 (95%) urothelial carcinomas, but in none of the renal carcinomas. Hypomethylation in bladder cancers was independent of stage and tended to increase with grade. The methylation status of HERV-K proviral DNA in normal and transformed urothelial cells paralleled that of LINE-1 sequences (r2 = 0.87). It was shown by ligation-mediated polymerase chain reaction that hypomethylation also extended to the LINE-1 promoter sequence located at the 5′-ends of full-length elements which is repressed by methylation in somatic tissues. Accordingly, full-length LINE-1 transcripts were detected by Northern blot analysis in two urothelial carcinoma cell lines. In contrast, transcripts from HERV-K proviruses were restricted to teratocarcinoma cell lines. Our data indicate that genome-wide DNA hypomethylation is an early change in urothelial carcinoma, but is absent from renal cell carcinoma. The coordinate changes of LINE-1 and HERV-K DNA methylation suggest that hypomethylation in urothelial cancer affects a variety of different retroelements to similar extents. We speculate that decreased methylation of LINE-1 retroelements, in particular, may contribute to genomic instability in specific human tumours such as urothelial carcinoma by rendering these normally repressed sequences competent for transcription and recombination. © 1999 Cancer Research Campaign

Keywords: bladder cancer, renal cancer, retrotransposon, methylcytosine, chromosome instability

Full Text

The Full Text of this article is available as a PDF (281K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Alves G, Tatro A, Fanning T. Differential methylation of human LINE-1 retrotransposons in malignant cells. Gene. 1996 Oct 17;176(1-2):39–44. [PubMed]
  • Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res. 1998;72:141–196. [PubMed]
  • Bedford MT, van Helden PD. Hypomethylation of DNA in pathological conditions of the human prostate. Cancer Res. 1987 Oct 15;47(20):5274–5276. [PubMed]
  • Bratthauer GL, Fanning TG. Active LINE-1 retrotransposons in human testicular cancer. Oncogene. 1992 Mar;7(3):507–510. [PubMed]
  • Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R. DNA hypomethylation leads to elevated mutation rates. Nature. 1998 Sep 3;395(6697):89–93. [PubMed]
  • Clifford SC, Prowse AH, Affara NA, Buys CH, Maher ER. Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene and allelic losses at chromosome arm 3p in primary renal cell carcinoma: evidence for a VHL-independent pathway in clear cell renal tumourigenesis. Genes Chromosomes Cancer. 1998 Jul;22(3):200–209. [PubMed]
  • Dombroski BA, Scott AF, Kazazian HH., Jr Two additional potential retrotransposons isolated from a human L1 subfamily that contains an active retrotransposable element. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6513–6517. [PMC free article] [PubMed]
  • Feinberg AP, Gehrke CW, Kuo KC, Ehrlich M. Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res. 1988 Mar 1;48(5):1159–1161. [PubMed]
  • Feng Q, Moran JV, Kazazian HH, Jr, Boeke JD. Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition. Cell. 1996 Nov 29;87(5):905–916. [PubMed]
  • Goelz SE, Vogelstein B, Hamilton SR, Feinberg AP. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science. 1985 Apr 12;228(4696):187–190. [PubMed]
  • Gonzalez-Zulueta M, Bender CM, Yang AS, Nguyen T, Beart RW, Van Tornout JM, Jones PA. Methylation of the 5' CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. Cancer Res. 1995 Oct 15;55(20):4531–4535. [PubMed]
  • Götzinger N, Sauter M, Roemer K, Mueller-Lantzsch N. Regulation of human endogenous retrovirus-K Gag expression in teratocarcinoma cell lines and human tumours. J Gen Virol. 1996 Dec;77(Pt 12):2983–2990. [PubMed]
  • Grimm MO, Jürgens B, Schulz WA, Decken K, Makri D, Schmitz-Dräger BJ. Inactivation of tumor suppressor genes and deregulation of the c-myc gene in urothelial cancer cell lines. Urol Res. 1995;23(5):293–300. [PubMed]
  • Hata K, Sakaki Y. Identification of critical CpG sites for repression of L1 transcription by DNA methylation. Gene. 1997 Apr 21;189(2):227–234. [PubMed]
  • Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S, Samid D, Duan DS, Gnarra JR, Linehan WM, et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9700–9704. [PMC free article] [PubMed]
  • Herman JG, Merlo A, Mao L, Lapidus RG, Issa JP, Davidson NE, Sidransky D, Baylin SB. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res. 1995 Oct 15;55(20):4525–4530. [PubMed]
  • Holmes SE, Dombroski BA, Krebs CM, Boehm CD, Kazazian HH., Jr A new retrotransposable human L1 element from the LRE2 locus on chromosome 1q produces a chimaeric insertion. Nat Genet. 1994 Jun;7(2):143–148. [PubMed]
  • Jarrard DF, Bova GS, Ewing CM, Pin SS, Nguyen SH, Baylin SB, Cairns P, Sidransky D, Herman JG, Isaacs WB. Deletional, mutational, and methylation analyses of CDKN2 (p16/MTS1) in primary and metastatic prostate cancer. Genes Chromosomes Cancer. 1997 Jun;19(2):90–96. [PubMed]
  • Jürgens B, Schmitz-Dräger BJ, Schulz WA. Hypomethylation of L1 LINE sequences prevailing in human urothelial carcinoma. Cancer Res. 1996 Dec 15;56(24):5698–5703. [PubMed]
  • Kazazian HH, Jr, Moran JV. The impact of L1 retrotransposons on the human genome. Nat Genet. 1998 May;19(1):19–24. [PubMed]
  • Laird PW, Jaenisch R. The role of DNA methylation in cancer genetic and epigenetics. Annu Rev Genet. 1996;30:441–464. [PubMed]
  • Liu J, Nau MM, Zucman-Rossi J, Powell JI, Allegra CJ, Wright JJ. LINE-I element insertion at the t(11;22) translocation breakpoint of a desmoplastic small round cell tumor. Genes Chromosomes Cancer. 1997 Mar;18(3):232–239. [PubMed]
  • Löwer R, Löwer J, Tondera-Koch C, Kurth R. A general method for the identification of transcribed retrovirus sequences (R-U5 PCR) reveals the expression of the human endogenous retrovirus loci HERV-H and HERV-K in teratocarcinoma cells. Virology. 1993 Feb;192(2):501–511. [PubMed]
  • Löwer R, Löwer J, Kurth R. The viruses in all of us: characteristics and biological significance of human endogenous retrovirus sequences. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5177–5184. [PMC free article] [PubMed]
  • Löwer R, Tönjes RR, Korbmacher C, Kurth R, Löwer J. Identification of a Rev-related protein by analysis of spliced transcripts of the human endogenous retroviruses HTDV/HERV-K. J Virol. 1995 Jan;69(1):141–149. [PMC free article] [PubMed]
  • Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB, Sidransky D. 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1995 Jul;1(7):686–692. [PubMed]
  • Miki Y, Nishisho I, Horii A, Miyoshi Y, Utsunomiya J, Kinzler KW, Vogelstein B, Nakamura Y. Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. Cancer Res. 1992 Feb 1;52(3):643–645. [PubMed]
  • Miller OJ, Schnedl W, Allen J, Erlanger BF. 5-Methylcytosine localised in mammalian constitutive heterochromatin. Nature. 1974 Oct 18;251(5476):636–637. [PubMed]
  • Moran JV, Holmes SE, Naas TP, DeBerardinis RJ, Boeke JD, Kazazian HH., Jr High frequency retrotransposition in cultured mammalian cells. Cell. 1996 Nov 29;87(5):917–927. [PubMed]
  • Morse B, Rotherg PG, South VJ, Spandorfer JM, Astrin SM. Insertional mutagenesis of the myc locus by a LINE-1 sequence in a human breast carcinoma. Nature. 1988 May 5;333(6168):87–90. [PubMed]
  • Nagarajan L, Lange B, Cannizzaro L, Finan J, Nowell PC, Huebner K. Molecular anatomy of a 5q interstitial deletion. Blood. 1990 Jan 1;75(1):82–87. [PubMed]
  • Pomykala HM, Bohlander SK, Broeker PL, Olopade OI, Díaz MO. Breakpoint junctions of chromosome 9p deletions in two human glioma cell lines. Mol Cell Biol. 1994 Nov;14(11):7604–7610. [PMC free article] [PubMed]
  • Santourlidis S, Florl A, Ackermann R, Wirtz HC, Schulz WA. High frequency of alterations in DNA methylation in adenocarcinoma of the prostate. Prostate. 1999 May 15;39(3):166–174. [PubMed]
  • Schulz WA. DNA methylation in urological malignancies (review). Int J Oncol. 1998 Jul;13(1):151–167. [PubMed]
  • Skowronski J, Fanning TG, Singer MF. Unit-length line-1 transcripts in human teratocarcinoma cells. Mol Cell Biol. 1988 Apr;8(4):1385–1397. [PMC free article] [PubMed]
  • Steigerwald SD, Pfeifer GP, Riggs AD. Ligation-mediated PCR improves the sensitivity of methylation analysis by restriction enzymes and detection of specific DNA strand breaks. Nucleic Acids Res. 1990 Mar 25;18(6):1435–1439. [PMC free article] [PubMed]
  • Swergold GD. Identification, characterization, and cell specificity of a human LINE-1 promoter. Mol Cell Biol. 1990 Dec;10(12):6718–6729. [PMC free article] [PubMed]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...