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Aberrant expression of β-catenin and its association with ΔNp63, Notch-1, and clinicopathological factors in oral squamous cell carcinoma

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Abstract

The present study focuses on the correlation between the expression pattern of β-catenin (component of Wnt signaling), ΔNp63 (proliferation marker), and Notch 1 (transmembrane receptor) in oral squamous cell carcinoma. The study also aims to investigate the interaction between β-catenin and ΔNp63 in oral cancer. Furthermore, we also analyzed the prognostic significance of β-catenin, ΔNp63, and Notch 1 in oral squamous cell carcinoma. Immunohistochemical analysis of β-catenin, ΔNp63, and Notch 1 were done in 62 cases of oral squamous cell carcinoma. Co-immunoprecipitation analysis was done to study the possible interaction between β-catenin and ΔNp63 in oral cancer. Kaplan–Meier method was used to estimate overall and disease-free survival, and the Log-rank test was used to compare the resulting curves. Statistically significant positive correlation was found between the localization of β-catenin and the expression of ΔNp63 (p = 0.001**, r s = 0.427), whereas, no significant association was found between the expression pattern of β-catenin and Notch 1. Interestingly, interaction between β-catenin and ΔNp63 was observed in oral carcinoma. Moreover, β-catenin and ΔNp63 may be related to worst survival in oral carcinoma. Statistically significant positive association between localization of β-catenin and expression of ΔNp63 suggests that they might have dependent roles in maintaining the proliferation of oral carcinoma cells. In addition, the downregulated expression of Notch 1 was related to invasion and differentiation status of oral carcinoma cells. Furthermore, β-catenin and ΔNp63 may be used as independent prognostic markers of oral carcinoma. On the other hand, interaction of β-catenin with ΔNp63 may be a key event in maintaining the proliferation of oral carcinoma cells. The present study indicates that β-catenin and ΔNp63 may be used as independent prognostic markers of oral carcinoma and the interaction of β-catenin with ΔNp63 may be a crucial event in regulating proliferation and differentiation of oral carcinoma cells, which may be used as a target for therapeutic implications.

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References

  1. Warnakulasuriya S (2009) Global epidemiology of oral and oropharyngeal cancer. Oral Oncol 45:309–316

    Article  PubMed  Google Scholar 

  2. Ishida K, Ito S, Wada N, Deguchi H, Hata T, Hosoda M, Nohno T (2007) Nuclear localization of beta-catenin involved in precancerous change in oral leukoplakia. Mol Cancer 6:62

    Article  PubMed  Google Scholar 

  3. He TC, Sparks AB, Rago C, Hermeking H, Zawel L, Da Costa LT, Morin PJ, Vogelstein B, Kinzler KW (1998) Identification of c-MYC as a target of the APC pathway. Science 281:1509–1512

    Article  PubMed  Google Scholar 

  4. Barker N, Clevers H (2000) Catenins, Wnt signaling and cancer. Bioessays 22:961–965

    Article  PubMed  Google Scholar 

  5. Kobayashi M, Honma T, Matsuda Y, Suzuki Y, Narisawa R, Ajioka Y, Asakura H (2000) Nuclear translocation of beta-catenin in colorectal cancer. Br J Cancer 82:1689–1693

    Article  PubMed  Google Scholar 

  6. Udhayakumar G, Jayanthi V, Devaraj N, Devaraj H (2007) Interaction of MUC1 with beta-catenin modulates the Wnt target gene cyclinD1 in H. pylori-induced gastric cancer. Mol Carcino 46:807–817

    Article  Google Scholar 

  7. Behbod F, Rosen JM (2005) Will cancer stem cells provide new therapeutic targets? Carcinogenesis 26:703–711

    Article  PubMed  Google Scholar 

  8. Pellegrini G, Dellambra E, Golisano O, Martinelli E, Fantozzi I, Bondanza S, Ponzin D, McKeon F, De Luca M (2001) p63 identifies keratinocyte stem cells. Proc Natl Acad Sci 98:3156–3161

    Article  PubMed  Google Scholar 

  9. Moll UM (2003) The role of p63 and p73 in tumour formation and progression: coming of age toward clinical usefulness. Clin Cancer Res 9:5437–5441

    PubMed  Google Scholar 

  10. Parsa R, Yang A, McKeon F, Green H (1999) Association of p63 with proliferative potential in normal and neoplastic human keratinocytes. J Invest Dermatol 113:1099–1105

    Article  PubMed  Google Scholar 

  11. Di Como CJ, Urist MJ, Babayan I, Drobnjak M, Hedvat CV, Teruya-Feldstein J, Pohar K, Hoos A, Cordon-Cardo C (2002) p63 expression profiles in human normal and tumor tissues. Clin Cancer Res 8:494–501

    PubMed  Google Scholar 

  12. Chen YK, Hsue SS, Lin LM (2005) Expression of p63 protein and mRNA in oral epithelial dysplasia. J Oral Pathol Med 34:232–239

    Article  PubMed  Google Scholar 

  13. Nylander K, Coates PJ, Hall PA (2000) Characterization of the expression pattern of p63 alpha and delta Np63 alpha in benign and malignant oral epithelial lesions. Int J Cancer 87:368–372

    Article  PubMed  Google Scholar 

  14. Allenspach EJ, Maillard I, Aster JC, Pear WS (2002) Notch signaling in cancer. Cancer Biol Ther 1:466–476

    Article  PubMed  Google Scholar 

  15. Brennan K, Brown AM (2003) Is there a role for Notch signaling in human breast cancer? Breast Cancer Res 5:69–75

    Article  PubMed  Google Scholar 

  16. Nguyen BC, Lefort K, Mandinova A, Antonini D, Devgan V, Della Gatta G, Koster MI, Zhang Z, Wang J, Tommasi di Vignano A, Kitajewski J, Chiorino G, Roop DR, Missero C, Dotto GP (2006) Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev 20:1028–1042

    Article  PubMed  Google Scholar 

  17. Su L, Morgan PR, Lane EB (1996) Keratin 14 and 19 expression in normal, dysplastic and malignant oral epithelia. A study using in situ hybridization and immunohistochemistry. J Oral Pathol Med 25:293–301

    Article  PubMed  Google Scholar 

  18. Presland RB, Dale BA (2000) Epithelial structural proteins of the skin and oral cavity: function in health and disease. Crit Rev Oral Biol Med 11:383–408

    Article  PubMed  Google Scholar 

  19. Fillies T, Jogschies M, Kleinheinz J, Brandt B, Joos U, Buerger H (2007) Cytokeratin alteration in oral leukoplakia and oral squamous cell carcinoma. Oncol Rep 18:639–643

    PubMed  Google Scholar 

  20. Byrne C, Tainsky M, Fuchs E (1994) Programming gene expression in developing epidermis. Development 120:2369–2383

    PubMed  Google Scholar 

  21. Pindborg JJ, Reichart PA, Smith CJ, der waal Van I (1997) Histological typing of cancer and precancer of the oral mucosa, 2nd edn. Heidelberg, Springer

    Book  Google Scholar 

  22. Minter HA, Eveson JW, Huntley S, Elder DJE, Hague A (2003) The cyclooxygenase 2-selective inhibitor NS398 inhibits proliferation of oral carcinoma cell lines by mechanisms dependent and independent of reduced prostaglandin E2 synthesis. Clin Cancer Res 9:1885

    PubMed  Google Scholar 

  23. Li H, Cherukuri P, Li N, Cowling V, Spinella M, Cole M, Godwin AK, Wells W, DiRenzo J (2007) Nestin is expressed in the basal/myoepithelial layer of the mammary gland and is a selective marker of basal epithelial breast tumors. Cancer Res 67:501–510

    Article  PubMed  Google Scholar 

  24. Pinilla MR, Peralto JLR, Hitt R, Sanchez JJ, Verde LS, Alameda F, Ballestin C, Cespedes MS (2005) β-Catenin, Nf-kB and FAS protein expression are independent events in head and neck cancer: study of their association with clinical parameters. Cancer Lett 230:141–148

    Article  Google Scholar 

  25. Ratovitski EA, Patturajan M, Hibi K, Trink B, Yamaguchi K, Sidransky D (2001) p53 associates with and targets ΔNp63 into a protein degradation pathway. Proc National Acad Sci 98:1817–1822

    Article  Google Scholar 

  26. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    PubMed  Google Scholar 

  27. Patturajan M, Nomoto S, Sommer M, Fomenkov A, Hibi K, Zangen R, Poliak N, Califano J, Trink B, Ratovitski E, Sidransky D (2002) ΔNp63 induces β-catenin nuclear accumulation and signaling. Cancer Cell 1:369–379

    Article  PubMed  Google Scholar 

  28. Tysnes BB, Bjerkvig R (2007) Cancer initiation and progression: involvement of stem cells and the microenvironment. Biochim Biophys Acta 1775:283–297

    PubMed  Google Scholar 

  29. Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111

    Article  PubMed  Google Scholar 

  30. Pelengaris S, Littlewood T, Khan M, Elia G, Evan G (1999) Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. Mol Cell 3:565–577

    Article  PubMed  Google Scholar 

  31. Cai Z-G, Shi X-J, Gao Y, Wei M-J, Wang C-Y, Yu G-Y (2008) β-catenin expression pattern in primary oral squamous cell Carcinoma. Chin Med J 121:1866–1870

    PubMed  Google Scholar 

  32. Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, Oh H, Aster JC, Krishna S, Metzger D, Chambon P, Miele L, Aguet M, Radtke F, Dotto GP (2001) Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J 20:3427–3436

    Article  PubMed  Google Scholar 

  33. Proweller A, Tu L, Lepore JJ, Cheng L, Lu MM, Seykora J, Millar SE, Pear WS, Parmacek MS (2006) Impaired notch signaling promotes de novo squamous cell carcinoma formation. Cancer Res 66:7438–7444

    Article  PubMed  Google Scholar 

  34. Odajima T, Sasaki Y, Tanaka N, Kato-Mori Y, Asanuma H, Ikeda T, Satoh M, Hiratsuka H, Tokino T, Sawada N (2005) Abnormal β-catenin expression in oral cancer with no gene mutation: correlation with expression of cyclin D1 and epidermal growth factor receptor, ki-67 labeling index, and clinicopathological feature. Hum Pathol 36:234–241

    Article  PubMed  Google Scholar 

  35. Lo Muzio L, Santarelli A, Caltabiano R, Rubini C, Pieramici T, Trevisiol L, Carinci F, Leonardi R, De Lillo A, Lanzafame S, Bufo P, Piattelli A (2005) P63 overexpression associates with poor prognosis in head and neck squamous cell carcinoma. Hum Pathol 36:187–194

    Article  PubMed  Google Scholar 

  36. Moergel M, Abt E, Stockinger M, Kunkel M (2010) Overexpression of p63 is associated with radiation resistance and prognosis in oral squamous cell carcinoma. Oral Oncol 46:667–671

    Article  PubMed  Google Scholar 

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Acknowledgments

We acknowledge “UGC-Meritorious Research Fellowship Programme” for financial assistance. We are also grateful to Dr. Birgitte Lane (Institute of Medical Biology, Singapore) and Dr. James Direnzo (Dartmouth Medical School, USA) for providing anti-CK14 and anti-ΔNp63 antibodies, respectively. We would like to thank Dr. Angela Hague (Department of Oral and Dental Science, University of Bristol, UK) for providing H314 cell line used in this study. We also thank Dr. Mary Lilly (Professor of Pathology, Royapettah Government Hospital, Chennai, India) for her support throughout this study. Finally, we would like to acknowledge Dr. R. Ravanan (Associate Professor, Department of Statistics, Presidency College, Chennai, India) for his kind help in reviewing and revising the statistical analysis.

Conflict of interest

We have no conflict of interest.

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Authors and Affiliations

  1. Unit of Biochemistry, Department of Zoology, University of Madras, Guindy Campus, Chennai, Tamil Nadu, India

    Gokulan Ravindran & Halagowder Devaraj

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  1. Gokulan Ravindran
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  2. Halagowder Devaraj
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Correspondence to Halagowder Devaraj.

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Supplement Fig. 1

Overall survival of patients with oral squamous cell carcinoma according to stage (a) and beta catenin localization (c); disease-free survival of patients with oral squamous cell carcinoma according to stage (b) and beta catenin localization (d) calculated by the Kaplan–Meier method. Intra. intracellular. (JPEG 127 KB)

High resolution image (JPEG 127 kb)

Supplement Table 1

Correlation of β-catenin, ΔNp63, and Notch 1 expression with clinical parameters (DOC 27 kb)

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Ravindran, G., Devaraj, H. Aberrant expression of β-catenin and its association with ΔNp63, Notch-1, and clinicopathological factors in oral squamous cell carcinoma. Clin Oral Invest 16, 1275–1288 (2012). https://doi.org/10.1007/s00784-011-0605-0

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