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.

  • Original Paper
  • Published:

Introduction of wild-type patched gene suppresses the oncogenic potential of human squamous cell carcinoma cell lines including A431

Oncogene volume 21, pages 2670–2678 (2002)Cite this article

Abstract

Defects in a developmental signaling pathway involving the mammalian homologue of the Drosophila segment polarity gene, patched are associated with human tumors such as basal cell carcinoma, medulloblastoma and squamous cell carcinoma. Loss of heterozygosity (LOH) in some of these tumor cells suggests that patched functions as a tumor suppressor gene. To evaluate the biological significance of patched mutations in human sporadic tumor cells, we constructed a VSV-G pseudotyped retrovirus vector carrying the wild-type patched gene and transduced it into two human squamous cell carcinoma (SCC) cell lines, A431 and KA, that express only mutant patched mRNA. When SSC cells were transduced with Ptc virus, colony forming activity in soft agar was drastically reduced and these cells recovered anchorage independent growth when Sonic hedgehog (Shh), the ligand of Patched (Ptc), was added into the soft agar culture. Expression of exogenous patched, however, had no effect on anchorage independent growth of Ras-transformed NIH3T3 cells or SCC cell line, NA, which expresses wild-type patched mRNA. Cyclopamine, a specific inhibitor of the Shh/Ptc/Smo signaling pathway, efficiently suppressed anchorage independent growth of A431 and KA cells. These results indicate that loss of patched function plays a major role in the acquisition of oncogenic potential in these SCCs and further that Ptc virus would be an effective reagent for suppressing tumorigenicity of such SCCs.

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
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Akimaru H, Chen Y, Dai P, Hon DX, Nonak M, Smolik SM, Armstrong S, Goodman RH, Ishii S . 1997 Nature 386: 735–738

  • Ahmadian A, Ren ZP, Williams C, Ponten F, Odeberg J, Ponten J, Uhlen M, Lundeberg J . 1998 Oncogene 17: 1837–1843

  • Aszterbaum M, Epstein J, Oro A, Douglas V, LeBott P, Scott MP, Epstein Jr EH . 1999 Nat. Med. 5: 1285–1291

  • Arai T, Matsumoto K, Saitoh K, Ui M, Ito T, Murakami M, Kanegae Y, Saito I, Cosset FL, Takeuchi Y, Iba H . 1998 J. Virol. 72: 1115–1121

  • Arai T, Takada M, Ui M, Iba H . 1999 Virology 260: 109–115

  • Bale AE . 2000 Nature 406: 944–945

  • Cooper MK, Porter JA, Young KE, Beachy PA . 1998 Science 280: 1603–1607

  • Dahmane N, Lee J, Robins P, Heller P, Ruiz i Altaba A . 1997 Nature 389: 870–881

  • Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M, Ishii S . 1999 J. Biol. Chem. 247: 8143–8152

  • Fan H, Oro AE, Scott MP, Khavari PA . 1997 Nat. Med. 3: 788–792

  • Gailani MR, Bale SJ, Leffell DJ, DiGiovanna JJ, Peck GL, Poliak S, Drum MA, Pastakia B, McBride OW, Kase R, Greene M, Mulvihill JJ, Bale AE . 1992 Cell 69: 111–117

  • Gailani MR, Stahle-Backdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, Unden AB, Dean M, Brash DE, Bale AE, Toftgard R . 1996 Nat. Genet. 14: 78–81

  • Goodrich LV, Johnson RL, Milenkovic L, McMahon JA, Scott MP . 1996 Genes Dev. 10: 301–312

  • Goodrich LV, Milenkovic L, Higgins KM, Scott MP . 1997 Science 277: 1109–1113

  • Goodrich LV, Scott MP . 1998 Neuron 21: 1243–1257

  • Hahn H, Wojnowski L, Zimmer AM, Hall J, Miller G, Zimmer A . 1998 Nat. Med. 4: 619–622

  • Hahn H, Wojnowski L, Miller G, Zimmer A . 1999 J. Mol. Med. 77: 459–468

  • Incardona JP, Gaffield W, Kapur RP, Roelink H . 1998 Development 125: 3553–3562

  • Incardona JP, Gaffield W, Lange Y, Cooney A, Pentchev PG, Liu S, Watson JA, Kapur RP, Roelink H . 2000 Dev. Biol. 224: 440–452

  • Ingham PW . 1998 EMBO J. 17: 3505–3511

  • Ito T, Yamauchi M, Nishina M, Yamamichi N, Mizutani T, Ui M, Murakami M, Iba H . 2001 J. Biol. Chem. 276: 2852–2857

  • Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Mayers RM, Cox DR, Epstein Jr EH, Scott MP . 1996 Science 272: 1668–1671

  • Johnson RL, Scott MP . 1998 Curr. Opin. Genet. Dev. 8: 450–456

  • Karpen HE, Bukowski JT, Hughes T, Gratton JP, Sessa WC, Gailani MR . 2001 J. Biol. Chem. 276: 19503–19511

  • Kinzler KW, Bigner SH, Bigner DD, Trent JM, Law ML, O'Brien SJ, Wong AJ, Vogelstein B . 1987 Science 236: 70–73

  • Kralova J, Liss AS, Bargmann W, Bose Jr HR . 1998 Mol. Cell. Biol. 18: 2997–3009

  • Kwok TT, Mok CH, Menton-Brennan L . 1994 Cancer Res. 54: 2834–2836

  • Lee J, Platt KA, Censullo P, Ruiz i Altaba A . 1997 Development 124: 2537–2552

  • Lench NJ, Telford EAR, High AS, Marham AF, Wicking C, Wainwright BJ . 1997 Hum. Genet. 100: 497–502

  • Levanat S, Gorlin RJ, Fallet S, Johnson DR, Fantasia JE, Bale AE . 1996 Nat. Genet. 12: 85–87

  • Liu CZ, Yang JT, Yoon JW, Villavicencio E, Pfendler K, Walterhouse D, Iannaccone P . 1998 Gene 209: 1–11

  • Maesawa C, Tamura G, Iwaya T, Ogasawara S, Ishida K, Sato N, Nishizuka S, Suzuki Y, Ikeda K, Aoki K, Saito K, Satodate R . 1998 Genes Chromosomes Cancer 21: 276–279

  • Marigo V, Scott MP, Johnson RL, Goodrich LV, Tabin CJ . 1996a Development 122: 1225–1233

  • Marigo V, Davey RA, Zuo Y, Cunningham JM, Tabin CJ . 1996b Nature 384: 176–179

  • Merlino GT, Xu YH, Ishii S, Clark AJL, Semba K, Toyoshima K, Yamamoto T, Pastan I . 1984 Science 224: 417–419

  • Michimukai E, Kitamura N, Zhang Y, Wang H, Hiraishi Y, Sumi KS, Hayashido Y, Toratani S, Okamoto T . 2001 In Vitro Cell Dev. Biol. Anim. 37: 459–464

  • Murakami M, Ui M, Iba H . 1999 Cell Growth Differ. 10: 333–342

  • Okazaki S, Ito T, Ui M, Watanabe T, Yoshimatsu K, Iba H . 1998 Biochem. Biophys. Res. Commun. 250: 347–353

  • Okuno H, Suzuki T, Yoshida T, Hashimoto Y, Curran T, Iba H . 1991 Oncogene 6: 1491–1497

  • Palm K, Salin-Nordstrom T, Levesque MF, Neuman T . 2000 Mol. Brain Res. 78: 192–195

  • Pietsch T, Waha A, Koch A, Kraus J, Alberecht S, Tonn J, Sorensen N, Berthold F, Henk B, Schmandt N, Wolf HK, von Deimling A, Wainwright B, Chenevix-Trench G, Wistler OD, Wicking C . 1997 Cancer Res. 57: 2085–2088

  • Ping XL, Ratner D, Zhang H, Wu XL, Zhang MJ, Chen FF, Silvers DN, Peacock M, Tsou HC . 2001 J. Invest. Dermatol. 116: 614–616

  • Raffel C, Jenkins RB, Frederick L, Hebrink D, Alderete B, Flts DW, James CD . 1997 Cancer Res. 57: 842–845

  • Ruiz i Altaba A . 1998 Development 125: 2203–2212

  • Ruppert JM, Vogelstein B, Kinzler KW . 1991 Mol. Cell. Biol. 11: 1724–1728

  • Sasaki H, Nishizaki Y, Hui C, Nakafuku M, Kondoh H . 1999 Development 126: 3915–3924

  • Smyth I, Wicking C, Wainwright B, Chenevix-Trench G . 1998 Hum. Genet. 102: 598–601

  • Stone DM, Hynes M, Armanini M, Swanson TA, Gu Q, Johnson RL, Scott MP, Pennica D, Goddard A, Phillip H, Noll M, Hooper JE, de Sauvage F, Rosenthal A . 1996 Nature 384: 129–134

  • Suzuki T, Murakami M, Onai N, Fukuda E, Hashimoto Y, Sonobe MH, Kameda T, Ichinose M, Miki K, Iba H . 1994 J. Virol. 68: 3527–3535

  • Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Millenkovic L, Scott MP, Beachy PA . 2000 Nature 406: 1005–1009

  • Ui M, Takada M, Arai T, Matsumoto K, Yamada K, Nakahata T, Nishiwaki T, Furukawa Y, Tokino T, Nakamura Y, Iba H . 1999 Gene Ther. 6: 1670–1678

  • Ui M, Mizutani T, Takada M, Arai T, Ito T, Murakami M, Koike C, Watanabe T, Yoshimatsu K, Iba H . 2000 Biochem. Biophys. Res. Commun. 278: 97–105

  • Unden AB, Zaphiropoulos PG, Bruce K, Toftgard R, Stahle-Backdahl M . 1997 Cancer Res. 57: 2336–2340

  • Ullrich A, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam W, Lee J, Yanden Y, Libermann YA, Schlessinger J, Downward J, Mayes ELV, Whittle N, Waterfield MD, Seeburg PH . 1984 Nature 309: 418–425

  • Villavicencio EH, Walterhouse DO, Iannaccone PA . 2000 Am. Hum. Genet. 67: 1047–1054

  • Vorechovsky I, Unden AB, Standstedt B, Toftgard R, Stahle-Backdahl M . 1997 Cancer Res. 57: 4677–4681

  • Wang B, Fallon JF, Beachy PA . 2000 Cell 100: 423–434

  • Wetmore C, Eberhart DE, Curran T . 2000 Cancer Res. 60: 2239–2246

  • Wolter M, Reifenberger J, Sommer C, Ruzicka T, Refenberger G . 1997 Cancer Res. 57: 2582–2585

  • Xie J, Johnson RL, Zhang X, Bare JW, Waldman FM, Cogen PH, Menon AG, Warren RS, Chen LC, Scott MP, Epstein Jr EH . 1997 Cancer Res. 57: 2369–2377

  • Zurawel RH, Allen C, Chippa S, Cato W, Biegel J, Cogen P, de Sauvage F, Raffel C . 2000a Genes Chromosomes Cancer 27: 44–51

  • Zurawel RH, Allen C, Wechsler-Reya R, Scott MP, Raffel C . 2000b Genes Chromosomes Cancer 28: 77–81

Download references

Acknowledgements

We thank Dr C Tabin (Harvard University) for providing chicken patched gene, Dr A Bale (Yale University) for providing anti-Ptc polyclonal antibody and Dr W Gaffield (Western Regional Research Center) for supplying cyclopamine. We also thanks Dr H Kimura and Dr T Curran (St. Jude Children's Research Hospital) for their helpful advice on conditions for Western-blotting. We are grateful to Ms M Takada for her excellent technical support. This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Culture and Technology, Japan.

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, Division of Host-Parasite Interaction, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai Minato-ku Tokyo, 108-8639, Japan

    Chika Koike, Taketoshi Mizutani, Taiji Ito, Yasuhito Shimizu, Nobutake Yamamichi, Takashi Kameda & Hideo Iba

  2. Department of Molecular Oral Medicine and Maxillofacial Surgery 1, Faculty of Dentistry, Hiroshima University, 1-2-3 Kasumi Minami-ku Hiroshima, 734-8553, Japan

    Eiji Michimukai, Naoya Kitamura & Tetsuji Okamoto

Authors
  1. Chika Koike
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Taketoshi Mizutani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Taiji Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasuhito Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nobutake Yamamichi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takashi Kameda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eiji Michimukai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Naoya Kitamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tetsuji Okamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hideo Iba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hideo Iba.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Koike, C., Mizutani, T., Ito, T. et al. Introduction of wild-type patched gene suppresses the oncogenic potential of human squamous cell carcinoma cell lines including A431. Oncogene 21, 2670–2678 (2002). https://doi.org/10.1038/sj.onc.1205370

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205370

Keywords

This article is cited by

Search

Advanced search

Quick links