Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer

Nature Genetics volume 27, pages 427–430 (2001)Cite this article

Abstract

The existence of tumor-suppressor genes was originally demonstrated by functional complementation through whole-cell and microcell fusion1,2. Transfer of chromosome 11 into a human non-small-cell lung cancer (NSCLC) cell line, A549, suppresses tumorigenicity3. Loss of heterozygosity (LOH) on the long arm of chromosome 11 has been reported in NSCLC and other cancers4,5,6. Several independent studies indicate that multiple tumor-suppressor genes are found in this region, including the gene PPP2R1B at 11q23–24 (ref. 7). Linkage studies of NSCLC are precluded because no hereditary forms are known8,9. We previously identified a region of 700 kb on 11q23.2 that completely suppresses tumorigenicity of A549 human NSCLC cells10. Most of this tumor-suppressor activity localizes to a 100-kb segment by functional complementation. Here we report that this region contains a single confirmed gene, TSLC1, whose expression is reduced or absent in A549 and several other NSCLC, hepatocellular carcinoma (HCC) and pancreatic cancer (PaC) cell lines. TSLC1 expression or suppression is correlated with promoter methylation state in these cell lines. Restoration of TSLC1 expression to normal or higher levels suppresses tumor formation by A549 cells in nude mice. Only 2 inactivating mutations of TSLC1 were discovered in 161 tumors and tumor cell lines, both among the 20 primary tumors with LOH for 11q23.2. Promoter methylation was observed in 15 of the other 18 primary NSCLC, HCC and PaC tumors with LOH for 11q23.2. Thus, attenuation of TSLC1 expression occurred in 85% of primary tumors with LOH. Hypermethylation of the TSLC1 promoter would seem to represent the 'second hit' in NSCLC with LOH.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Localization of a tumor-suppressor gene on 11q23.2.
Figure 2: TSLC1 protein localizes to the cell membrane. Subcellular localization using TSLC1–GFP fusion protein.
Figure 3: Expression of TSLC1 in cancer cell lines.
Figure 4: TSLC1 suppresses tumorigenicity of A549 cells.
Figure 5: Methylation analysis of TSLC1.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Harris, H., Miller, O.J., Klein, G., Worst, P. & Tachibana, T. Suppression of malignancy by cell fusion. Nature 223, 363–368 (1969).

    Article  CAS  PubMed  Google Scholar 

  2. Weissman, B.E. et al. Introduction of a normal human chromosome 11 into a Wilms' tumor cell line controls its tumorigenic expression. Science 236, 175–180 (1987).

    Article  CAS  PubMed  Google Scholar 

  3. Satoh, H. et al. Suppression of tumorigenicity of A549 lung adenocarcinoma cells by human chromosomes 3 and 11 introduced via microcell-mediated chromosome transfer. Mol. Carcinog. 7, 157–164 (1993).

    Article  CAS  PubMed  Google Scholar 

  4. Iizuka, M. et al. Allelic losses in human chromosome 11 in lung cancers. Genes Chromosomes Cancer 13, 40–46 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Rasio, D. et al. Loss of heterozygosity at chromosome 11q in lung adenocarcinoma: identification of three independent regions. Cancer Res. 55, 3988–3991 (1995).

    CAS  PubMed  Google Scholar 

  6. Wang, S.S., Virmani, A., Gazdar, A.F., Minna, J.D. & Evans, G.A. Refined mapping of two regions of loss of heterozygosity on chromosome band 11q23 in lung cancer. Genes Chromosomes Cancer 25, 154–159 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Wang, S.S. et al. Alterations of the PPP2R1B gene in human lung and colon cancer. Science 282, 284–287 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Murakami, Y.S., Brothman, A.R., Leach, R.J. & White, R.L. Suppression of malignant phenotype in a human prostate cancer cell line by fragments of normal chromosomal region 17q. Cancer Res. 55, 3389–3394 (1995).

    CAS  PubMed  Google Scholar 

  9. Thiagalingam, S. et al. Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers. Nature Genet. 13, 343–346 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Murakami, Y. et al. Localization of tumor suppressor activity important in non small cell lung carcinoma on chromosome 11q. Proc. Natl. Acad. Sci. USA 95, 8153–8158 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gomyo, H. et al. A 2-Mb sequence-ready contig map and a novel immunoglobulin superfamily gene IGSF4 in the LOH region of chromosome 11q23.2. Genomics 62, 139–146 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Fogh, J., Fogh, J.M. & Orfeo, T. One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice. J. Natl. Cancer Inst. 59, 221–226 (1977).

    Article  CAS  PubMed  Google Scholar 

  13. Santon, J.B. et al. Effects of epidermal growth factor receptor concentration on tumorigenicity of A431 cells in nude mice. Cancer Res. 46, 4701–4705 (1986).

    CAS  PubMed  Google Scholar 

  14. Ohsaki, Y., Ishida, S., Fujikane, T. & Kikuchi, K. Pentoxifylline potentiates the antitumor effect of cisplatin and etoposide on human lung cancer cell lines. Oncology 53, 327–333 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Aoe, K. et al. Effect of docetaxel with cisplatin or vinorelbine on lung cancer cell lines. Anticancer Res. 19, 291–299 (1999).

    CAS  PubMed  Google Scholar 

  16. Yamori, T., Sato, S., Chikazawa, H. & Kadota, T. Anti-tumor efficacy of paclitaxel against human lung cancer xenografts. Jpn. J. Cancer Res. 88, 1205–1210 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hirai, K., Shimada, H., Ogawa, T. & Taji, S. The spread of human lung cancer cells on collagens and its inhibition by type III collagen. Clin. Exp. Metastasis 9, 517–527 (1991).

    Article  CAS  PubMed  Google Scholar 

  18. Sakai, T. et al. Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. Am. J. Hum. Genet. 48, 880–888 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Merlo, A. et al. 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nature Med. 1, 686–692 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Kane, M.F. et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 57, 808–811 (1997).

    CAS  PubMed  Google Scholar 

  21. Schutte, M. et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res. 57, 3126–3130 (1997).

    CAS  PubMed  Google Scholar 

  22. Kanamori, M. et al. Microsatellite instability and the PTEN1 gene mutation in a subset of early onset gliomas carrying germline mutation or promoter methylation of the hMLH1 gene. Oncogene 19, 1564–1571 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Ihde, D.C. & Minna, J.D. Non-small cell lung cancer. Part I: Biology, diagnosis, and staging. Curr. Probl. Cancer 15, 61–104 (1991).

    CAS  PubMed  Google Scholar 

  24. Murakami, Y. & Sekiya, T. Accumulation of genetic alterations and their significance in each primary human cancer and cell line. Mutat. Res. 400, 421–437 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Ghosh, K. & Ghosh, H.P. Role of the membrane anchoring and cytoplasmic domains in intracellular transport and localization of viral glycoproteins. Biochem. Cell Biol. 77, 165–178 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Orita, M., Suzuki, Y., Sekiya, T. & Hayashi, K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5, 874–879 (1989).

    Article  CAS  PubMed  Google Scholar 

  27. Kukita, Y., Tahira, T., Sommer, S.S. & Hayashi, K. SSCP analysis of long DNA fragments in low pH gel. Hum. Mutat. 10, 400–407 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Frommer, M. et al. A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc. Natl. Acad. Sci. USA 89, 1827–1831 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Veigl, M.L. et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc. Natl. Acad. Sci. USA 95, 8698–8702 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank R.L. White and M. Meuth for discussions, and K. Ghosh, M. Sakamoto, K. Kumada, H. Sakamoto, S. Koizume, T. Fukami and M. Watanabe for materials and technical assistance. This work was supported in part by a Grant-in-Aid for the Second Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health and Welfare, Japan; a Grant-in-Aid for Special Projects for Cancer Research from the Ministry of Education, Science, Sports and Culture of Japan; a Grant from the Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research (OPSR) of Japan; and U.S. Public Health Service award HD-24605 (R.H.R.). M.K., H.F., T.N. and T.K. are recipients of Research Resident Fellowships from the Foundation for Promotion of Cancer Research of Japan.

Author information

Author notes

  1. Masami Kuramochi, Hiroshi Fukuhara and Takahiro Nobukuni: These authors contributed equally to this work.

Authors and Affiliations

  1. Tumor Suppression & Functional Genomics Project, National Cancer Center Research Institute, Tokyo, Japan

    Masami Kuramochi, Hiroshi Fukuhara, Takahiro Nobukuni, Takamasa Kanbe, Tomoko Maruyama, Hara P. Ghosh, Takao Sekiya & Yoshinori Murakami

  2. Department of Physiology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA

    Mathew Pletcher & Roger H. Reeves

  3. Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Minoru Isomura

  4. Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan

    Masataka Onizuka

  5. Department of Urology, Faculty of Medicine, University of Tokyo, Tokyo, Japan

    Tadaichi Kitamura

Authors
  1. Masami Kuramochi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroshi Fukuhara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takahiro Nobukuni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takamasa Kanbe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tomoko Maruyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hara P. Ghosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mathew Pletcher
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Minoru Isomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masataka Onizuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tadaichi Kitamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takao Sekiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Roger H. Reeves
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yoshinori Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yoshinori Murakami.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kuramochi, M., Fukuhara, H., Nobukuni, T. et al. TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer. Nat Genet 27, 427–430 (2001). https://doi.org/10.1038/86934

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/86934

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing