Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1994 Dec;70(6):1060–1066. doi: 10.1038/bjc.1994.449

Inhibition of gastric cancer cell proliferation by antisense oligonucleotides targeting the messenger RNA encoding proliferating cell nuclear antigen.

C Sakakura 1, A Hagiwara 1, H Tsujimoto 1, K Ozaki 1, T Sakakibara 1, T Oyama 1, M Ogaki 1, T Takahashi 1
PMCID: PMC2033708  PMID: 7981055

Abstract

Proliferating cell nuclear antigen (PCNA) is a nuclear protein that regulates DNA synthesis by DNA polymerase delta, and is essential for DNA replication. PCNA expression level is related to the malignancy of gastric cancer cells. Seven different gastric cancer cell lines and two kinds of control cell lines were treated with antisense oligonucleotides complementary to the messenger RNA of PCNA. Treatment of each gastric cancer cell line with antisense oligonucleotides at concentration of 10-40 microM inhibited the cell growth, colony formation and PCNA protein production in a dose-dependent manner, but only affected normal cells slightly. A random sequence oligomer showed no effect. These results show that PCNA is essential for gastric cancer cell proliferation and that the use of synthetic oligonucleotides is an effective way of producing antisense-mediated changes in the behaviour of human gastric cancers.

Full text

PDF
1060

Images in this article

1061Figure 2
on p.1061
1064Figure 5
on p.1064
1065Figure 6
on p.1065

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Agrawal S., Temsamani J., Tang J. Y. Pharmacokinetics, biodistribution, and stability of oligodeoxynucleotide phosphorothioates in mice. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7595–7599. doi: 10.1073/pnas.88.17.7595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bravo R., Frank R., Blundell P. A., Macdonald-Bravo H. Cyclin/PCNA is the auxiliary protein of DNA polymerase-delta. Nature. 1987 Apr 2;326(6112):515–517. doi: 10.1038/326515a0. [DOI] [PubMed] [Google Scholar]
  3. Bravo R., Macdonald-Bravo H. Induction of the nuclear protein 'cyclin' in quiescent mouse 3T3 cells stimulated by serum and growth factors. Correlation with DNA synthesis. EMBO J. 1984 Dec 20;3(13):3177–3181. doi: 10.1002/j.1460-2075.1984.tb02276.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Calabretta B. Inhibition of protooncogene expression by antisense oligodeoxynucleotides: biological and therapeutic implications. Cancer Res. 1991 Sep 1;51(17):4505–4510. [PubMed] [Google Scholar]
  5. Celis J. E., Celis A. Cell cycle-dependent variations in the distribution of the nuclear protein cyclin proliferating cell nuclear antigen in cultured cells: subdivision of S phase. Proc Natl Acad Sci U S A. 1985 May;82(10):3262–3266. doi: 10.1073/pnas.82.10.3262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chiang M. Y., Chan H., Zounes M. A., Freier S. M., Lima W. F., Bennett C. F. Antisense oligonucleotides inhibit intercellular adhesion molecule 1 expression by two distinct mechanisms. J Biol Chem. 1991 Sep 25;266(27):18162–18171. [PubMed] [Google Scholar]
  7. Furth M. E., Aldrich T. H., Cordon-Cardo C. Expression of ras proto-oncogene proteins in normal human tissues. Oncogene. 1987 Mar;1(1):47–58. [PubMed] [Google Scholar]
  8. Hagiwara A., Takahashi T., Kojima O., Sawai K., Yamaguchi T., Yamane T., Taniguchi H., Kitamura K., Noguchi A., Seiki K. Prophylaxis with carbon-adsorbed mitomycin against peritoneal recurrence of gastric cancer. Lancet. 1992 Mar 14;339(8794):629–631. doi: 10.1016/0140-6736(92)90792-2. [DOI] [PubMed] [Google Scholar]
  9. Hagiwara A., Takahashi T., Kojima O., Yamaguchi T., Sasabe T., Lee M., Sakakura C., Shoubayashi S., Ikada Y., Hyon S. H. Pharmacologic effects of cisplatin microspheres on peritoneal carcinomatosis in rodents. Cancer. 1993 Feb 1;71(3):844–850. doi: 10.1002/1097-0142(19930201)71:3<844::aid-cncr2820710330>3.0.co;2-h. [DOI] [PubMed] [Google Scholar]
  10. Hawley P., Gibson I. The detection of oligodeoxynucleotide molecules following uptake into mammalian cells. Antisense Res Dev. 1992 Summer;2(2):119–127. doi: 10.1089/ard.1992.2.119. [DOI] [PubMed] [Google Scholar]
  11. Iversen P. L., Zhu S., Meyer A., Zon G. Cellular uptake and subcellular distribution of phosphorothioate oligonucleotides into cultured cells. Antisense Res Dev. 1992 Fall;2(3):211–222. doi: 10.1089/ard.1992.2.211. [DOI] [PubMed] [Google Scholar]
  12. Jaskulski D., Gatti C., Travali S., Calabretta B., Baserga R. Regulation of the proliferating cell nuclear antigen cyclin and thymidine kinase mRNA levels by growth factors. J Biol Chem. 1988 Jul 25;263(21):10175–10179. [PubMed] [Google Scholar]
  13. Jaskulski D., deRiel J. K., Mercer W. E., Calabretta B., Baserga R. Inhibition of cellular proliferation by antisense oligodeoxynucleotides to PCNA cyclin. Science. 1988 Jun 10;240(4858):1544–1546. doi: 10.1126/science.2897717. [DOI] [PubMed] [Google Scholar]
  14. MULLIGAN R. M., REMBER R. R. Histogenesis and biologic behavior of gastric carcinoma: study of one hundred thirty-eight cases. AMA Arch Pathol. 1954 Jul;58(1):1–25. [PubMed] [Google Scholar]
  15. Masui H., Kamrath H., Apell G., Houston L. L., Mendelsohn J. Cytotoxicity against human tumor cells mediated by the conjugate of anti-epidermal growth factor receptor monoclonal antibody to recombinant ricin A chain. Cancer Res. 1989 Jul 1;49(13):3482–3488. [PubMed] [Google Scholar]
  16. Masui H., Kawamoto T., Sato J. D., Wolf B., Sato G., Mendelsohn J. Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res. 1984 Mar;44(3):1002–1007. [PubMed] [Google Scholar]
  17. Ming S. C. Gastric carcinoma. A pathobiological classification. Cancer. 1977 Jun;39(6):2475–2485. doi: 10.1002/1097-0142(197706)39:6<2475::aid-cncr2820390626>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
  18. Speir E., Epstein S. E. Inhibition of smooth muscle cell proliferation by an antisense oligodeoxynucleotide targeting the messenger RNA encoding proliferating cell nuclear antigen. Circulation. 1992 Aug;86(2):538–547. doi: 10.1161/01.cir.86.2.538. [DOI] [PubMed] [Google Scholar]
  19. Sporn M. B., Roberts A. B. Autocrine growth factors and cancer. 1985 Feb 28-Mar 6Nature. 313(6005):745–747. doi: 10.1038/313745a0. [DOI] [PubMed] [Google Scholar]
  20. Steele C., Cowsert L. M., Shillitoe E. J. Effects of human papillomavirus type 18-specific antisense oligonucleotides on the transformed phenotype of human carcinoma cell lines. Cancer Res. 1993 May 15;53(10 Suppl):2330–2337. [PubMed] [Google Scholar]
  21. Szczylik C., Skorski T., Nicolaides N. C., Manzella L., Malaguarnera L., Venturelli D., Gewirtz A. M., Calabretta B. Selective inhibition of leukemia cell proliferation by BCR-ABL antisense oligodeoxynucleotides. Science. 1991 Aug 2;253(5019):562–565. doi: 10.1126/science.1857987. [DOI] [PubMed] [Google Scholar]
  22. Travali S., Ku D. H., Rizzo M. G., Ottavio L., Baserga R., Calabretta B. Structure of the human gene for the proliferating cell nuclear antigen. J Biol Chem. 1989 May 5;264(13):7466–7472. [PubMed] [Google Scholar]
  23. Wachter L., Jablonski J. A., Ramachandran K. L. A simple and efficient procedure for the synthesis of 5'-aminoalkyl oligodeoxynucleotides. Nucleic Acids Res. 1986 Oct 24;14(20):7985–7994. doi: 10.1093/nar/14.20.7985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Yasui W., Hata J., Yokozaki H., Nakatani H., Ochiai A., Ito H., Tahara E. Interaction between epidermal growth factor and its receptor in progression of human gastric carcinoma. Int J Cancer. 1988 Feb 15;41(2):211–217. doi: 10.1002/ijc.2910410209. [DOI] [PubMed] [Google Scholar]
  25. Yonemura Y., Kimura H., Fushida S., Tugawa K., Nakai Y., Kaji M., Fonseca L., Yamaguchi A., Miyazaki I. Analysis of proliferative activity using anti-proliferating cell nuclear antigen antibody in gastric cancer tissue specimens obtained by endoscopic biopsy. Cancer. 1993 Apr 15;71(8):2448–2453. doi: 10.1002/1097-0142(19930415)71:8<2448::aid-cncr2820710804>3.0.co;2-v. [DOI] [PubMed] [Google Scholar]
  26. Yoshida K., Kyo E., Tsujino T., Sano T., Niimoto M., Tahara E. Expression of epidermal growth factor, transforming growth factor-alpha and their receptor genes in human gastric carcinomas; implication for autocrine growth. Jpn J Cancer Res. 1990 Jan;81(1):43–51. doi: 10.1111/j.1349-7006.1990.tb02505.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Yoshida K., Tsuda T., Matsumura T., Tsujino T., Hattori T., Ito H., Tahara E. Amplification of epidermal growth factor receptor (EGFR) gene and oncogenes in human gastric carcinomas. Virchows Arch B Cell Pathol Incl Mol Pathol. 1989;57(5):285–290. doi: 10.1007/BF02899093. [DOI] [PubMed] [Google Scholar]
  28. Zamecnik P. C., Stephenson M. L. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci U S A. 1978 Jan;75(1):280–284. doi: 10.1073/pnas.75.1.280. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES