Intraepithelial p63-dependent expression of distinct components of cell adhesion complexes in normal esophageal mucosa and squamous cell carcinoma
Corresponding Author
Amélie Thépot
Molecular Carcinogenesis Group and Epigenetics Group, IARC, Lyon, France
Banque de Tissus et cellules, Hôpital E. Herriot, Lyon, France
Tel.: 33-4-72-73-84-62, Fax: 33-4-72-73-83-22
Group of Molecular Carcinogenesis and Biomarkers, IARC, 150 cours Albert Thomas, 69372 Lyon Cedex 08, FranceSearch for more papers by this authorAgnès Hautefeuille
Molecular Carcinogenesis Group and Epigenetics Group, IARC, Lyon, France
Search for more papers by this authorMarie-Pierre Cros
Molecular Carcinogenesis Group and Epigenetics Group, IARC, Lyon, France
Search for more papers by this authorBehnoush Abedi-Ardekani
Molecular Carcinogenesis Group and Epigenetics Group, IARC, Lyon, France
Search for more papers by this authorAurélia Pétré
Molecular Carcinogenesis Group and Epigenetics Group, IARC, Lyon, France
Search for more papers by this authorOdile Damour
Banque de Tissus et cellules, Hôpital E. Herriot, Lyon, France
Search for more papers by this authorVladimir Krutovskikh
Molecular Carcinogenesis Group and Epigenetics Group, IARC, Lyon, France
Search for more papers by this authorCorresponding Author
Pierre Hainaut
Molecular Carcinogenesis Group and Epigenetics Group, IARC, Lyon, France
Tel.: 33-4-72-73-84-62, Fax: 33-4-72-73-83-22
Group of Molecular Carcinogenesis and Biomarkers, IARC, 150 cours Albert Thomas, 69372 Lyon Cedex 08, FranceSearch for more papers by this authorCorresponding Author
Amélie Thépot
Molecular Carcinogenesis Group and Epigenetics Group, IARC, Lyon, France
Banque de Tissus et cellules, Hôpital E. Herriot, Lyon, France
Tel.: 33-4-72-73-84-62, Fax: 33-4-72-73-83-22
Group of Molecular Carcinogenesis and Biomarkers, IARC, 150 cours Albert Thomas, 69372 Lyon Cedex 08, FranceSearch for more papers by this authorAgnès Hautefeuille
Molecular Carcinogenesis Group and Epigenetics Group, IARC, Lyon, France
Search for more papers by this authorMarie-Pierre Cros
Molecular Carcinogenesis Group and Epigenetics Group, IARC, Lyon, France
Search for more papers by this authorBehnoush Abedi-Ardekani
Molecular Carcinogenesis Group and Epigenetics Group, IARC, Lyon, France
Search for more papers by this authorAurélia Pétré
Molecular Carcinogenesis Group and Epigenetics Group, IARC, Lyon, France
Search for more papers by this authorOdile Damour
Banque de Tissus et cellules, Hôpital E. Herriot, Lyon, France
Search for more papers by this authorVladimir Krutovskikh
Molecular Carcinogenesis Group and Epigenetics Group, IARC, Lyon, France
Search for more papers by this authorCorresponding Author
Pierre Hainaut
Molecular Carcinogenesis Group and Epigenetics Group, IARC, Lyon, France
Tel.: 33-4-72-73-84-62, Fax: 33-4-72-73-83-22
Group of Molecular Carcinogenesis and Biomarkers, IARC, 150 cours Albert Thomas, 69372 Lyon Cedex 08, FranceSearch for more papers by this authorAbstract
TP63 gene is a member of TP53 tumor suppressor gene family that encodes several protein isoforms involved in the process of epithelial stratification and in epithelial-mesenchyme interactions. TP63 is amplified in a significant proportion of squamous cell carcinoma of the esophagus (ESCC), resulting in the hyper-expression of ΔNp63 as the major p63 isoform. To better understand the contribution of this high expression to tumorigenesis, we have analyzed the impact of intraepithelial p63 expression on the expression of cell adhesion complexes in normal esophagus and in ESCC cell lines. Cells expressing p63 showed an adhesion pattern characterized by lack of tight junctions and presence of adherens junctions. Cell differentiation was accompanied by a decrease in p63 and by a shift to adhesion patterns involving tight junctions. Silencing of p63 mRNA in ESCC cell lines resulted in a similar shift, characterized by increased expression of component of tight junctions, decreased cell-to-cell communication and downregulation of cell proliferation. These results indicate that ΔNp63 may contribute to esophageal squamous carcinogenesis by maintaining cell adhesion patterns compatible with cell proliferation.
Supporting Information
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IJC_25221_sm_suppfig1.tif577.5 KB | Supporting Figure 1 |
IJC_25221_sm_suppfig2.tif339.1 KB | Supporting Figure 2 |
IJC_25221_sm_suppfig3.tif55 KB | Supporting Figure 3 |
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References
- 1 Osada M, Park HL, Nagakawa Y, Yamashita K, Fomenkov A, Kim MS, Wu G, Nomoto S, Trink B, Sidransky D. Differential recognition of response elements determines target gene specificity for p53 and p63. Mol Cell Biol 2005; 14: 6077–89.
- 2 Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dötsch V, Andrews NC, Caput D, McKeon F. p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell 1998; 2: 305–16.
- 3 Levrero M, De Laurenzi V, Costanzo A, Gong J, Wang JY, Melino G. The p53/p63/p73 family of transcription factors: overlapping and distinct functions. J Cell Sci 2000; 113: 1661–70.
- 4 Rinne T, Brunner HG, van Bokhoven H. p63-associated disorders. Cell Cycle 2007; 6: 262–8.
- 5 Geddert H, Kiel S, Heep HJ, Gabbert HE, Sarbia M. The role of p63 and ΔNp63 (p40) protein expression and gene amplification in esophageal carcinogenesis. Hum Pathol 2003; 34: 850–6.
- 6 Moll UM, Slade N. p63 and p73: roles in development and tumor formation. Mol Cancer Res 2004; 2: 371–86.
- 7 Patturajan M, Nomoto S, Sommer M, Fomenkov A, Hibi K, Zangen R, Poliak N, Califano J, Trink B, Ratovitski E, Sidransky D. DeltaNp63 induces beta-catenin nuclear accumulation and signaling. Cancer Cell 2002; 1: 369–79.
- 8 Higashikawa K, Yoneda S, Tobiume K, Saitoh M, Taki M, Mitani Y, Shigeishi H, Ono S, Kamata N. DeltaNp63alpha-dependent expression of Id-3 distinctively suppresses the invasiveness of human squamous cell carcinoma. Int J Cancer 2009; 124: 2837–44.
- 9 Higashikawa K, Yoneda S, Tobiume K, Taki M, Shigeishi H, Kamata N. Snail-induced down-regulation of DeltaNp63alpha acquires invasive phenotype of human squamous cell carcinoma. Cancer Res 2007; 67: 9207–13.
- 10 Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 1999; 398: 708–13.
- 11 Yang A, Schweitzer R, Sun D, Kadhad M, Walker N, Bronson RT, Tabin C, Sharpe A, Caput D, Crum C, McKeon F. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 1999; 398: 714–18.
- 12 Daniely Y, Liao G, Dixon D, Linnoila RI, Lori A, Randell SH, Oren M, Jetten AM Critical role of p63 in the development of a normal esophageal and tracheobronchial epithelium. Am J Physiol Cell Physiol 2004; 287: C171–81.
- 13 Carroll DK, Carroll JS, Leong Ch-O, Cheng F, Brown M, Mills AA, Brugge JS, Ellisen LW. P63 regulates an adhesion program and cell survival in epithelial cells. Nat Cell Biol 2006; 8: 551–61.
- 14 Ihrie R, Marques MR, Nguyen BT, Horner JS, Papazoglu C, Bronson RT, Mills AA, Attardi LD. Perp is a p63-regulated gene essential for epithelial integrity. Cell 2005; 120: 843–56.
- 15 Carroll DK, Brugge JS, Attardi LD. P63, cell adhesion and survival. Cell Cycle 2007; 6: e1–7.
- 16 Osada M, Nagakawa Y, Park HL, Yamashita K, Wu G, Kim MS, Fomenkov A, Trink B, Sidransky D. p63-specific activation of BPAG-1e promoter. J Invest Dermatol 2005; 125: 52–60.
- 17 Candi E, Rufini A, Terrinoni A, Dinsdale D, Ranalli M, Paradisi A, De Laurenzi V, Spagnoli LG, Catani MV, Ramadan S, Knight RA, Melino G. Differential roles of p63 isoforms in epidermal development: selective genetic complementation in p63 null mice. Cell Death Differ 2006; 13: 1037–47.
- 18 Niessen CM. Tight junctions/adherens junctions: basic structure and function. J Invest Dermatol 2007; 127: 2525–32.
- 19 Green KJ, Simpson CL. Desmosomes: new perspectives on a classic. J Invest Dermatol 2007; 127: 2499–515.
- 20 Schneerberger EE Lynch RD. The tight junction: a multifunctional complex. Am J Physiol Cell Physiol 2004; 286: C1213–28.
- 21 Sohl G, Willecke K. Gap junctions and the connexin protein family. Cardiovasc Res 2004; 62: 228–32.
- 22 Nishihira T, Hashimoto Y, Katayama M, Mori S, Kuroki T. Molecular and cellular features of esophageal cancer cells. J Cancer Res Clin Oncol 1993; 119: 441–9.
- 23 Krutovskikh V, Mazzoleni G, Mironov N, Omori Y, Aguelon AM, Mesnil M, Berger F, Partensky C, Yamasaki H. Altered homologous and heterologous gap-junctional intercellular communication in primary human liver tumors associated with aberrant protein localization but not gene mutation of connexin 32. Int J Cancer 1994; 56: 87–94.
- 24 Petitjean A, Ruptier C, Tribollet V, Hautefeuille A, Chardon F, Cavard C, Puisieux A, Hainaut P, Caron de Fromentel C. Properties of the six isoforms of p63: p53-like regulation in response to genotoxic stress and cross talk with ΔNp73. Carcinogenesis 2008; 29: 273–81.
- 25 Roman S, Pétré A, Thépot A, Hautefeuille A, Scoazec JY, Mion F, Hainaut P Downregulation of p63 upon exposure to bile salts and acid in normal and cancer esophageal cells in culture. Am J Physiol Gastrointest Liver Physiol 2007; 293: G45–53.
- 26 Shimomura Y, Wajid M, Shapiro L, Christiano AM. P-cadherin is a p63 target gene with a crucial role in the developing human limb bud and hair follicle. Development 2008; 135: 743–53.
- 27 Lopardo T, Lo Iacono N, Marinari B, Giustizieri ML, Cyr DG, Merlo G, Crosti F, Costanzo A, Guerrini L. Claudin-1 is a p63 target gene with a crucial role in epithelial development. PLoS One 2008; 3: e2715.
- 28 Candi E, Dinsdale D, Rufini A, Salomoni P, Knight RA, Mueller M, Krammer PH, Melino G. TAp63 and ΔNp63 in cancer and epidermal development. Cell Cycle 2007; 6: 274–85.
- 29 Troy TC, Arabzadeh A, Yerlikaya S, Turksen K. Claudin immunolocalization in neonatal mouse epithelial tissues. Cell Tissue Res 2007; 330: 381–8.
- 30 Pellegrini G, Dellambra E, Golisano O, Martinelli E, Fantozzi I, Bondanza S, Ponzin D, McKeon F, De Luca M. p63 identifies keratinocyte stem cells. Proc Natl Acad Sci USA 2001; 98: 3156–61.