Abstract
Lung cancer is a heterogeneous disease categorized into multiple subtypes of cancers which likely arise from distinct patterns of genetic alterations and disruptions. Precedent exists for a role of β-catenin, a downstream component of the Wnt signaling pathway that serves as a transcriptional co-activator with TCF/LEF, in several human cancers including colon carcinomas. In this study, we observed that β-catenin was highly and uniformly expressed in a panel of NSCLC cell lines and primary lung tumors. By contrast, γ-catenin was weakly expressed or absent in several NSCLC cell lines and immunohistochemical analysis of primary NSCLC tumors revealed negligible to weak γ-catenin staining in ∼30% of the specimens. Treatment of NSCLC cells expressing reduced γ-catenin protein with 5-aza-2′-deoxycytidine (5aza2dc), a DNA methylation inhibitor, or trichostatin A (TSA), a histone deacetylase inhibitor, increased γ-catenin protein content in NSCLC cells with low γ-catenin expression. Significantly, the activity of a β-catenin/TCF-dependent luciferase reporter was markedly elevated in the NSCLC cell lines that underexpressed γ-catenin relative to those lines that highly expressed γ-catenin. Moreover, transfection of these cells with a γ-catenin expression plasmid reduced the elevated TCF activity by 85% and strongly inhibited cell growth on tissue culture plastic as well as anchorage-independent growth in soft agar. This study shows that γ-catenin can function as an inhibitor of β-catenin/TCF-dependent gene transcription and highlights γ-catenin as a potentially novel tumor suppressor protein in a subset of human NSCLC cancers.
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References
Adjei A . 2001 J. Natl. Cancer Inst. 93: 1062–1074
Bates RC, Buret A, van Helden DF, Horton MA, Burns GF . 1994 J. Cell Biol. 125: 403–415
Beekman A, Helfrich B, Bunn Jr PA, Heasley LE . 1998 Cancer Res. 58: 910–913
Brabletz T, Jung A, Dag S, Hlubek F, Kirchner T . 1999 Am. J. Pathol. 155: 1033–1038
Calvo R, West J, Franklin W, Erickson P, Bemis L, Li E, Helfrich B, Bunn P, Roche J, Brambilla E, Rosell R, Gemmill RM, Drabkin HA . 2000 Proc. Natl. Acad. Sci. USA 97: 12776–12781
Crawford HC, Fingleton BM, Rudolph-Owen LA, Goss KJ, Rubinfeld B, Polakis P, Matrisian LM . 1999 Oncogene 18: 2883–2891
de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A, Perret C . 1998 Proc. Natl. Acad. Sci. USA 95: 8847–8851
Fukuchi T, Sakamoto M, Tsuda H, Maruyama K, Nozawa S, Hirohashi S . 1998 Cancer Res. 58: 3526–3528
Graziano SL, Gamble GP, Newman NB, Abbott LZ, Rooney M, Mookherjee S, Lamb ML, Kohman LJ, Poiesz BJ . 1999 J. Clin. Oncol. 17: 668–675
Greenlee R, Hill-Harmon MB, Murray T, Thun M . 2001 CA Cancer J. Clin. Oncol. 51: 15–36
He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW . 1998 Science 281: 1509–1518
Howe LR, Subbaramaiah K, Brown AM, Dannenberg AJ . 2001 Endocr. Relat. Cancer 8: 97–114
Hsieh ET, Shepherd FA, Tsao MS . 2000 Lung Cancer 29: 151–157
Huber OKR, McLaughlin J, Ohsugi M, Herrmann BG, Kemler R . 1996 Mech. Dev. 59: 3–10
Karnovsky A, Klymkowsky MW . 1995 PNAS 92: 4522–4526
Kinzler KW, Vogelstein B . 1996 Cell 87: 159–170
Kolligs FT, Kolligs B, Hajra KM, Hu G, Tani M, Cho KR, Fearon ER . 2000 Genes Dev. 14: 1319–1331
Landau NR, Littman DR . 1992 J. Virol. 66: 5110–5113
Miravet S, Piedra J, Miro F, Itarte E, Garcia de Herreros A, Dunach M . 2002 J. Biol. Chem. 277: 1884–1891
Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW . 1997 Science 275: 1787–1790
Nicholson RI, Gee JM, Harper ME . 2001 Eur. J. Cancer 37: Suppl 4 9–15
Ohsaki Y, Tanno S, Fujita Y, Toyoshima E, Fujiuchi S, Nichigaki Y, Ishida S, Nagase A, Miyokawa N, Hirata S, Kikuchi K . 2000 Oncol. Rep. 7: 603–607
Ozawa M, Baribault H, Kemler R . 1989 EMBO J. 8: 1711–1717
Pantel K, Passlick B, Vogt J, Stosiek P, Angstwurm M, Seen-Hibler R, Hassinger K, Thetter O, Izbicki JR, Riethmuller G . 1998 J. Clin. Oncol. 16: 1407–1413
Parker H, Li Z, Sheinin H, Lauzon G, Pasdar M . 1998 Cell Motility Cytoskel. 40: 87–100
Pear WS, Nolan GP, Scott ML, Baltimore D . 1993 Proc. Natl. Acad. Sci. USA 90: 8392–8396
Pennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, Lee J, Brush J, Taneyhill LA, Deuel B, Lew M, Watanabe C, Cohen RL, Melhem MF, Finley GG, Quirke P, Goddard AD, Hillan KJ, Gurney AL, Botstein D, Levine AJ . 1998 Proc. Natl. Acad. Sci. USA 95: 14717–14722
Pirinen RT, Hirvikoski P, Johansson RT, Hollmen S, Kosma VM . 2001 J. Clin. Pathol. 54: 391–395
Polakis P . 2000 Genes Dev. 14: 1837–1851
Potter E, Braun S, Lehmann U, Brabant G . 2001 Eur. J. Endocrinol. 145: 625–633
Rimm DL, Caca K, Hu G, Harrison FB, Fearon ER . 1999 Am. J. Pathol. 154: 325–329
Sadot E, Simcha I, Shtutman M, Ben-Ze'ev A, Geiger B . 1998 Proc. Natl. Acad. Sci. USA 95: 15339–15344
Sekido Y, Fong KM, Minna JD . 1998 Biochim. Biophys. Acta 1378: F21–F59
Shtutman M, Zhurinsky J, Simcha I, Albanese C, d'Amico M, Pestell R, Ben-Ze'ev A . 1999 Proc. Natl. Acad. Sci. USA 96: 5522–5527
Simcha I, Geiger B, Yehuda-Levenberg S, Salomon D, Ben-Ze'ev A . 1996 J. Cell Biol. 133: 199–209
Soengas MS, Capodieci P, Polsky D, Mora J, Esteller M, Opitz-Araya X, McCombie R, Herman JG, Gerald WL, Lazebnik YA, Cordon-Cardo C, Lowe SW . 2001 Nature 409: 207–211
Tetsu O, McCormick F . 1999 Nature 398: 422–426
Toyoyama H, Nuruki K, Ogawa H, Yanagi M, Matsumoto H, Nishijima H, Shimotakahara T, Aikou T, Ozawa M . 1999 Oncol. Rep. 6: 81–85
Ueda M, Gemmill RM, West J, Winn R, Sugita M, Tanaka N, Ueki M, Drabkin HA . 2001 Br. J. Cancer 85: 64–68
Westra WH, Baas IO, Hruban RH, Askin FB, Wilson K, Offerhaus GJ, Slebos RJ . 1996 Cancer Res. 56: 2224–2228
Zhurinsky J, Shtutman M, Ben-Ze'ev A . 2000 Mol. Cell. Biol. 20: 4238–4252
Acknowledgements
These studies were supported by NIH grants DK19928 and CA58187 to LE Heasley and a VA Career Development Award 0001 to RA Winn. We appreciate the generous gifts of pCDNA3-dnTCF (a human Tcf-4E with an in frame N terminal deletion of amino acids 2–53) and pCDNA3-CA-β-catenin expression vectors (Myc-tagged human β-catenin with an in-frame N-terminal deletion of amino acids 29–48) from Drs Osamu Tetsu and Frank McCormick and the pCDNA3-γ-catenin expression vector kindly provided by Dr Eric Fearon. We also thank Dan Merrick and Raphael Nemenoff for many helpful discussions. In addition, we also greatly appreciate assistance with the immunofluorescence experiments by Barbara Helfrich and immunohistochemistry by Mysan Le.
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Winn, R., Bremnes, R., Bemis, L. et al. γ-Catenin expression is reduced or absent in a subset of human lung cancers and re-expression inhibits transformed cell growth. Oncogene 21, 7497–7506 (2002). https://doi.org/10.1038/sj.onc.1205963
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DOI: https://doi.org/10.1038/sj.onc.1205963
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