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. 2000 Jan 18;82(2):459–466. doi: 10.1054/bjoc.1999.0943

Suppressed tumorigenicity of human endometrial cancer cells by the restored expression of the DCC gene

H Kato 1, Y Zhou 1, K Asanoma 1, H Kondo 1, Y Yoshikawa 2, K Watanabe 1, T Matsuda 1, N Wake 1, J C Barrett 3
PMCID: PMC2363268  PMID: 10646905

Abstract

To obtain functional evidence for DCC as a tumour suppressor associated with endometrial cancer, the human DCC cDNA encoding a complete open reading frame (ORF) was transfected into highly tumorigenic human endometrial carcinoma cells, HHUA and Ishikawa in which DCC expression was completely deleted. Reconstituted expression of DCC in HHUA had little effect on in vitro growth, but suppressed tumour formation in mice completely. The clones from Ishikawa had abundant DCC expression similar to that in normal endometrium. Their growth in vitro was suppressed and showed apoptotic phenotype. Lower levels of DCC expression in the prolonged passaged clones did not induce apoptosis, but still had the potential to suppress tumorigenicity. These observations imply a role of DCC in regulation of normal endometrial cell growth, and categorize DCC as the tumour suppressor gene for endometrial cancer. © 2000 Cancer Research Campaign

Keywords: tumour suppression, tumour suppressor gene, DCC, endometrial carcinoma, apoptosis

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Selected References

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  1. Brewster S. F., Gingell J. C., Browne S., Brown K. W. Loss of heterozygosity on chromosome 18q is associated with muscle-invasive transitional cell carcinoma of the bladder. Br J Cancer. 1994 Oct;70(4):697–700. doi: 10.1038/bjc.1994.376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Cho K. R., Oliner J. D., Simons J. W., Hedrick L., Fearon E. R., Preisinger A. C., Hedge P., Silverman G. A., Vogelstein B. The DCC gene: structural analysis and mutations in colorectal carcinomas. Genomics. 1994 Feb;19(3):525–531. doi: 10.1006/geno.1994.1102. [DOI] [PubMed] [Google Scholar]
  3. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  4. Clifton D. R., Goss R. A., Sahni S. K., van Antwerp D., Baggs R. B., Marder V. J., Silverman D. J., Sporn L. A. NF-kappa B-dependent inhibition of apoptosis is essential for host cellsurvival during Rickettsia rickettsii infection. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4646–4651. doi: 10.1073/pnas.95.8.4646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Devilee P., van Vliet M., Kuipers-Dijkshoorn N., Pearson P. L., Cornelisse C. J. Somatic genetic changes on chromosome 18 in breast carcinomas: is the DCC gene involved? Oncogene. 1991 Feb;6(2):311–315. [PubMed] [Google Scholar]
  6. Enomoto T., Fujita M., Cheng C., Nakashima R., Ozaki M., Inoue M., Nomura T. Loss of expression and loss of heterozygosity in the DCC gene in neoplasms of the human female reproductive tract. Br J Cancer. 1995 Mar;71(3):462–467. doi: 10.1038/bjc.1995.94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fazeli A., Dickinson S. L., Hermiston M. L., Tighe R. V., Steen R. G., Small C. G., Stoeckli E. T., Keino-Masu K., Masu M., Rayburn H. Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene. Nature. 1997 Apr 24;386(6627):796–804. doi: 10.1038/386796a0. [DOI] [PubMed] [Google Scholar]
  8. Fearon E. R., Cho K. R., Nigro J. M., Kern S. E., Simons J. W., Ruppert J. M., Hamilton S. R., Preisinger A. C., Thomas G., Kinzler K. W. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 1990 Jan 5;247(4938):49–56. doi: 10.1126/science.2294591. [DOI] [PubMed] [Google Scholar]
  9. Gao X., Honn K. V., Grignon D., Sakr W., Chen Y. Q. Frequent loss of expression and loss of heterozygosity of the putative tumor suppressor gene DCC in prostatic carcinomas. Cancer Res. 1993 Jun 15;53(12):2723–2727. [PubMed] [Google Scholar]
  10. Gima T., Kato H., Honda T., Imamura T., Sasazuki T., Wake N. DCC gene alteration in human endometrial carcinomas. Int J Cancer. 1994 May 15;57(4):480–485. doi: 10.1002/ijc.2910570407. [DOI] [PubMed] [Google Scholar]
  11. Hedrick L., Cho K. R., Fearon E. R., Wu T. C., Kinzler K. W., Vogelstein B. The DCC gene product in cellular differentiation and colorectal tumorigenesis. Genes Dev. 1994 May 15;8(10):1174–1183. doi: 10.1101/gad.8.10.1174. [DOI] [PubMed] [Google Scholar]
  12. Höhne M. W., Halatsch M. E., Kahl G. F., Weinel R. J. Frequent loss of expression of the potential tumor suppressor gene DCC in ductal pancreatic adenocarcinoma. Cancer Res. 1992 May 1;52(9):2616–2619. [PubMed] [Google Scholar]
  13. Imamura T., Arima T., Kato H., Miyamoto S., Sasazuki T., Wake N. Chromosomal deletions and K-ras gene mutations in human endometrial carcinomas. Int J Cancer. 1992 Apr 22;51(1):47–52. doi: 10.1002/ijc.2910510110. [DOI] [PubMed] [Google Scholar]
  14. Keino-Masu K., Masu M., Hinck L., Leonardo E. D., Chan S. S., Culotti J. G., Tessier-Lavigne M. Deleted in Colorectal Cancer (DCC) encodes a netrin receptor. Cell. 1996 Oct 18;87(2):175–185. doi: 10.1016/s0092-8674(00)81336-7. [DOI] [PubMed] [Google Scholar]
  15. Kennedy T. E., Serafini T., de la Torre J. R., Tessier-Lavigne M. Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord. Cell. 1994 Aug 12;78(3):425–435. doi: 10.1016/0092-8674(94)90421-9. [DOI] [PubMed] [Google Scholar]
  16. Klingelhutz A. J., Hedrick L., Cho K. R., McDougall J. K. The DCC gene suppresses the malignant phenotype of transformed human epithelial cells. Oncogene. 1995 Apr 20;10(8):1581–1586. [PubMed] [Google Scholar]
  17. Lei J., Zou T. T., Shi Y. Q., Zhou X., Smolinski K. N., Yin J., Souza R. F., Appel R., Wang S., Cymes K. Infrequent DPC4 gene mutation in esophageal cancer, gastric cancer and ulcerative colitis-associated neoplasms. Oncogene. 1996 Dec 5;13(11):2459–2462. [PubMed] [Google Scholar]
  18. Mehlen P., Rabizadeh S., Snipas S. J., Assa-Munt N., Salvesen G. S., Bredesen D. E. The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis. Nature. 1998 Oct 22;395(6704):801–804. doi: 10.1038/27441. [DOI] [PubMed] [Google Scholar]
  19. Neuman W. L., Wasylyshyn M. L., Jacoby R., Erroi F., Angriman I., Montag A., Brasitus T., Michelassi F., Westbrook C. A. Evidence for a common molecular pathogenesis in colorectal, gastric, and pancreatic cancer. Genes Chromosomes Cancer. 1991 Nov;3(6):468–473. doi: 10.1002/gcc.2870030609. [DOI] [PubMed] [Google Scholar]
  20. Oshimura M., Kugoh H., Koi M., Shimizu M., Yamada H., Satoh H., Barrett J. C. Transfer of a normal human chromosome 11 suppresses tumorigenicity of some but not all tumor cell lines. J Cell Biochem. 1990 Mar;42(3):135–142. doi: 10.1002/jcb.240420304. [DOI] [PubMed] [Google Scholar]
  21. Reale M. A., Hu G., Zafar A. I., Getzenberg R. H., Levine S. M., Fearon E. R. Expression and alternative splicing of the deleted in colorectal cancer (DCC) gene in normal and malignant tissues. Cancer Res. 1994 Aug 15;54(16):4493–4501. [PubMed] [Google Scholar]
  22. Ronnett B. M., Burks R. T., Cho K. R., Hedrick L. DCC genetic alterations and expression in endometrial carcinoma. Mod Pathol. 1997 Jan;10(1):38–46. [PubMed] [Google Scholar]
  23. Saegusa M., Hashimura M., Hara A., Okayasu I. Loss of expression of the gene deleted in colon carcinoma (DCC) is closely related to histologic differentiation and lymph node metastasis in endometrial carcinoma. Cancer. 1999 Jan 15;85(2):453–464. doi: 10.1002/(sici)1097-0142(19990115)85:2<453::aid-cncr25>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  24. Scheck A. C., Coons S. W. Expression of the tumor suppressor gene DCC in human gliomas. Cancer Res. 1993 Dec 1;53(23):5605–5609. [PubMed] [Google Scholar]
  25. Serafini T., Colamarino S. A., Leonardo E. D., Wang H., Beddington R., Skarnes W. C., Tessier-Lavigne M. Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell. 1996 Dec 13;87(6):1001–1014. doi: 10.1016/s0092-8674(00)81795-x. [DOI] [PubMed] [Google Scholar]
  26. Shibata D., Reale M. A., Lavin P., Silverman M., Fearon E. R., Steele G., Jr, Jessup J. M., Loda M., Summerhayes I. C. The DCC protein and prognosis in colorectal cancer. N Engl J Med. 1996 Dec 5;335(23):1727–1732. doi: 10.1056/NEJM199612053352303. [DOI] [PubMed] [Google Scholar]
  27. Takagi Y., Kohmura H., Futamura M., Kida H., Tanemura H., Shimokawa K., Saji S. Somatic alterations of the DPC4 gene in human colorectal cancers in vivo. Gastroenterology. 1996 Nov;111(5):1369–1372. doi: 10.1053/gast.1996.v111.pm8898652. [DOI] [PubMed] [Google Scholar]
  28. Takeichi M. The cadherins: cell-cell adhesion molecules controlling animal morphogenesis. Development. 1988 Apr;102(4):639–655. doi: 10.1242/dev.102.4.639. [DOI] [PubMed] [Google Scholar]
  29. Thiagalingam S., Lengauer C., Leach F. S., Schutte M., Hahn S. A., Overhauser J., Willson J. K., Markowitz S., Hamilton S. R., Kern S. E. Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers. Nat Genet. 1996 Jul;13(3):343–346. doi: 10.1038/ng0796-343. [DOI] [PubMed] [Google Scholar]
  30. White E. Life, death, and the pursuit of apoptosis. Genes Dev. 1996 Jan 1;10(1):1–15. doi: 10.1101/gad.10.1.1. [DOI] [PubMed] [Google Scholar]
  31. Yamada H., Sasaki M., Honda T., Wake N., Boyd J., Oshimura M., Barrett J. C. Suppression of endometrial carcinoma cell tumorigenicity by human chromosome 18. Genes Chromosomes Cancer. 1995 May;13(1):18–24. doi: 10.1002/gcc.2870130104. [DOI] [PubMed] [Google Scholar]
  32. Yun Z., Menter D. G., Nicolson G. L. Involvement of integrin alphavbeta3 in cell adhesion, motility, and liver metastasis of murine RAW117 large cell lymphoma. Cancer Res. 1996 Jul 1;56(13):3103–3111. [PubMed] [Google Scholar]

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