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p21 suppresses inflammation and tumorigenesis on pRB-deficient stratified epithelia

Oncogene volume 33, pages 4599–4612 (2014)Cite this article

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Abstract

The retinoblastoma gene product (pRb) controls proliferation and differentiation processes in stratified epithelia. Importantly, and in contrast to other tissues, Rb deficiency does not lead to spontaneous skin tumor formation. As the cyclin-dependent kinase inhibitor p21 regulates proliferation and differentiation in the absence of pRb, we analyzed the consequences of deleting p21 in pRb-ablated stratified epithelia (hereafter pRbΔEpi;p21−/−). These mice display an enhancement of the phenotypic abnormalities observed in pRbΔEpi animals, indicating that p21 partially compensates pRb absence. Remarkably, pRbΔEpi;p21−/− mice show an acute skin inflammatory phenotype and develop spontaneous epithelial tumors, particularly affecting tongue and oral tissues. Biochemical analyses and transcriptome studies reveal changes affecting multiple pathways, including DNA damage and p53-dependent signaling responses. Comparative metagenomic analyses, together with the histopathological profiles, indicate that these mice constitute a faithful model for human head and neck squamous cell carcinomas. Collectively, our findings demonstrate that p21, in conjunction with pRb, has a central role in regulating multiple epithelial processes and orchestrating specific tumor suppressor functions.

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References

  1. Classon M, Harlow E . The retinoblastoma tumour suppressor in development and cancer. Nat Rev Cancer 2002; 2: 910–917.

    CAS  PubMed  Google Scholar 

  2. Sherr CJ, McCormick F . The RB and p53 pathways in cancer. Cancer Cell 2002; 2: 103–112.

    CAS  PubMed  Google Scholar 

  3. Weinberg RA . The retinoblastoma protein and cell cycle control. Cell 1995; 81: 323–330.

    CAS  PubMed  Google Scholar 

  4. Burkhart DL, Sage J . Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer 2008; 8: 671–682.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Dyson N . The regulation of E2F by pRB-family proteins. Genes Dev 1998; 12: 2245–2262.

    Article  CAS  PubMed  Google Scholar 

  6. Riley DJ, Nikitin AY, Lee WH . Adenovirus-mediated retinoblastoma gene therapy suppresses spontaneous pituitary melanotroph tumors in Rb+/- mice. Nat Med 1996; 2: 1316–1321.

    CAS  PubMed  Google Scholar 

  7. Sherr CJ, Roberts JM . CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999; 13: 1501–1512.

    CAS  PubMed  Google Scholar 

  8. Chu C, Qu K, Zhong FL, Artandi SE, Chang HY . Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions. Mol Cell 2011; 44: 667–678.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993; 75: 817–825.

    Article  CAS  PubMed  Google Scholar 

  10. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ . The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 1993; 75: 805–816.

    CAS  PubMed  Google Scholar 

  11. Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D . p21 is a universal inhibitor of cyclin kinases. Nature 1993; 366: 701–704.

    CAS  PubMed  Google Scholar 

  12. Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ . Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 1995; 377: 552–557.

    CAS  PubMed  Google Scholar 

  13. Deng C, Zhang P, Harper JW, Elledge SJ, Leder P . Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 1995; 82: 675–684.

    CAS  PubMed  Google Scholar 

  14. Weinberg WC, Denning MF . P21Waf1 control of epithelial cell cycle and cell fate. Crit Rev Oral Biol Med 2002; 13: 453–464.

    PubMed  Google Scholar 

  15. Philipp J, Vo K, Gurley KE, Seidel K, Kemp CJ . Tumor suppression by p27Kip1 and p21Cip1 during chemically induced skin carcinogenesis. Oncogene 1999; 18: 4689–4698.

    CAS  PubMed  Google Scholar 

  16. Topley GI, Okuyama R, Gonzales JG, Conti C, Dotto GP . p21(WAF1/Cip1) functions as a suppressor of malignant skin tumor formation and a determinant of keratinocyte stem-cell potential. Proc Natl Acad Sci USA 1999; 96: 9089–9094.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Weinberg WC, Fernandez-Salas E, Morgan DL, Shalizi A, Mirosh E, Stanulis E et al. Genetic deletion of p21WAF1 enhances papilloma formation but not malignant conversion in experimental mouse skin carcinogenesis. Cancer Res 1999; 59: 2050–2054.

    CAS  PubMed  Google Scholar 

  18. Missero C, Di Cunto F, Kiyokawa H, Koff A, Dotto GP . The absence of p21Cip1/WAF1 alters keratinocyte growth and differentiation and promotes ras-tumor progression. Genes Dev 1996; 10: 3065–3075.

    CAS  PubMed  Google Scholar 

  19. Martin-Caballero J, Flores JM, Garcia-Palencia P, Serrano M . Tumor susceptibility of p21(Waf1/Cip1)-deficient mice. Cancer Res 2001; 61: 6234–6238.

    CAS  PubMed  Google Scholar 

  20. Brugarolas J, Bronson RT, Jacks T . p21 is a critical CDK2 regulator essential for proliferation control in Rb-deficient cells. J Cell Biol 1998; 141: 503–514.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Brugarolas J, Moberg K, Boyd SD, Taya Y, Jacks T, Lees JA . Inhibition of cyclin-dependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1 arrest after gamma-irradiation. Proc Natl Acad Sci USA 1999; 96: 1002–1007.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Dimri GP, Nakanishi M, Desprez PY, Smith JR, Campisi J . Inhibition of E2F activity by the cyclin-dependent protein kinase inhibitor p21 in cells expressing or lacking a functional retinoblastoma protein. Mol Cell Biol 1996; 16: 2987–2997.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Poole AJ, Heap D, Carroll RE, Tyner AL . Tumor suppressor functions for the Cdk inhibitor p21 in the mouse colon. Oncogene 2004; 23: 8128–8134.

    CAS  PubMed  Google Scholar 

  24. Paramio JM, Segrelles C, Ruiz S, Martin-Caballero J, Page A, Martinez J et al. The ink4a/arf tumor suppressors cooperate with p21cip1/waf in the processes of mouse epidermal differentiation, senescence, and carcinogenesis. J Biol Chem 2001; 276: 44203–44211.

    CAS  PubMed  Google Scholar 

  25. Dotto GP . p21(WAF1/Cip1): more than a break to the cell cycle? Biochim Biophys Acta 2000; 1471: M43–M56.

    CAS  PubMed  Google Scholar 

  26. Devgan V, Bach-Cuc N, Oh H, Dotto DP . p21Waf1/Cip1 suppresses keratinocyte differentiation independently of the cell cycle through transcriptional upregulation of the IGF-1 gene. J Biol Chem 2006; 281: 30463–30470.

    CAS  PubMed  Google Scholar 

  27. Devgan V, Mammucari C, Millar SE, Brisken C, Dotto GP . p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation. Genes Dev 2005; 19: 1485–1495.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Di Cunto F, Topley G, Calautti E, Hsiao J, Ong L, Seth PK et al. Inhibitory function of p21Cip1/WAF1 in differentiation of primary mouse keratinocytes independent of cell cycle control. Science (New York, NY 1998; 280: 1069–1072.

    CAS  Google Scholar 

  29. Abbas T, Dutta A . p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 2009; 9: 400–414.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Marques-Torrejon MA, Porlan E, Banito A, Gomez-Ibarlucea E, Lopez-Contreras AJ, Fernandez-Capetillo O et al. Cyclin-dependent kinase inhibitor p21 controls adult neural stem cell expansion by regulating Sox2 gene expression. Cell Stem Cell 2013; 12: 88–100.

    CAS  PubMed  Google Scholar 

  31. Martinez LA, Chen Y, Fischer SM, Conti CJ . Coordinated changes in cell cycle machinery occur during keratinocyte terminal differentiation. Oncogene 1999; 18: 397–406.

    CAS  PubMed  Google Scholar 

  32. Paramio JM, Lain S, Segrelles C, Lane EB, Jorcano JL . Differential expression and functionally co-operative roles for the retinoblastoma family of proteins in epidermal differentiation. Oncogene 1998; 17: 949–957.

    CAS  PubMed  Google Scholar 

  33. D’Souza SJ, Pajak A, Balazsi K, Dagnino L . Ca2+ and BMP-6 signaling regulate E2F during epidermal keratinocyte differentiation. J Biol Chem 2001; 276: 23531–23538.

    PubMed  Google Scholar 

  34. D’Souza SJ, Vespa A, Murkherjee S, Maher A, Pajak A, Dagnino L . E2F-1 is essential for normal epidermal wound repair. J Biol Chem 2002; 277: 10626–10632.

    PubMed  Google Scholar 

  35. Paramio JM, Segrelles C, Casanova ML, Jorcano JL . Opposite functions for E2F1 and E2F4 in human epidermal keratinocyte differentiation. J Biol Chem 2000; 275: 41219–41226.

    CAS  PubMed  Google Scholar 

  36. Rodriguez-Puebla ML, de Marval PL, LaCava M, Moons DS, Kiyokawa H, Conti CJ . Cdk4 deficiency inhibits skin tumor development but does not affect normal keratinocyte proliferation. Am J Pathol 2002; 161: 405–411.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Miliani de Marval PL, Macias E, Conti CJ, Rodriguez-Puebla ML . Enhanced malignant tumorigenesis in Cdk4 transgenic mice. Oncogene 2004; 23: 1863–1873.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sotillo R, Garcia JF, Ortega S, Martin J, Dubus P, Barbacid M et al. Invasive melanoma in Cdk4-targeted mice. Proc Natl Acad Sci USA 2001; 98: 13312–13317.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang D, Russell J, Xu H, Johnson DG . Deregulated expression of DP1 induces epidermal proliferation and enhances skin carcinogenesis. Mol Carcinog 2001; 31: 90–100.

    CAS  PubMed  Google Scholar 

  40. Pierce AM, Schneider-Broussard R, Gimenez-Conti IB, Russell JL, Conti CJ, Johnson DG . E2F1 has both oncogenic and tumor-suppressive properties in a transgenic model. Mol Cell Biol 1999; 19: 6408–6414.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Lee EY, Chang CY, Hu N, Wang YC, Lai CC, Herrup K et al. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 1992; 359: 288–294.

    CAS  PubMed  Google Scholar 

  42. Clarke AR, Maandag ER, van Roon M, van der Lugt NM, van der Valk M, Hooper ML et al. Requirement for a functional Rb-1 gene in murine development. Nature 1992; 359: 328–330.

    CAS  PubMed  Google Scholar 

  43. Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA . Effects of an Rb mutation in the mouse. Nature 1992; 359: 295–300.

    CAS  PubMed  Google Scholar 

  44. Balsitis SJ, Sage J, Duensing S, Munger K, Jacks T, Lambert PF . Recapitulation of the effects of the human papillomavirus type 16 E7 oncogene on mouse epithelium by somatic Rb deletion and detection of pRb-independent effects of E7 in vivo. Mol Cell Biol 2003; 23: 9094–9103.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Ruiz S, Santos M, Segrelles C, Leis H, Jorcano JL, Berns A et al. Unique and overlapping functions of pRb and p107 in the control of proliferation and differentiation in epidermis. Development 2004; 131: 2737–2748.

    CAS  PubMed  Google Scholar 

  46. Lara MF, Santos M, Ruiz S, Segrelles C, Moral M, Martinez-Cruz AB et al. p107 acts as a tumor suppressor in pRb-deficient epidermis. Mol Carcinog 2008; 47: 105–113.

    CAS  PubMed  Google Scholar 

  47. Costa C, Santos M, Segrelles C, Duenas M, Lara MF, Agirre X et al. A novel tumor suppressor network in squamous malignancies. Scie Rep 2012; 2: 828.

    Google Scholar 

  48. Ruiz S, Santos M, Paramio JM . Is the loss of pRb essential for the mouse skin carcinogenesis? Cell Cycle 2006; 5: 625–629.

    CAS  PubMed  Google Scholar 

  49. Ruiz S, Santos M, Lara MF, Segrelles C, Ballestin C, Paramio JM . Unexpected roles for pRb in mouse skin carcinogenesis. Cancer Res 2005; 65: 9678–9686.

    CAS  PubMed  Google Scholar 

  50. Martinez-Cruz AB, Santos M, Lara MF, Segrelles C, Ruiz S, Moral M et al. Spontaneous squamous cell carcinoma induced by the somatic inactivation of retinoblastoma and Trp53 tumor suppressors. Cancer Res 2008; 68: 683–692.

    CAS  PubMed  Google Scholar 

  51. Bornachea O, Santos M, Martinez-Cruz AB, Garcia-Escudero R, Duenas M, Costa C et al. EMT and induction of miR-21 mediate metastasis development in Trp53-deficient tumours. Sci Rep 2012; 2: 434.

    PubMed  PubMed Central  Google Scholar 

  52. Martinez-Cruz AB, Santos M, Garcia-Escudero R, Moral M, Segrelles C, Lorz C et al. Spontaneous tumor formation in Trp53-deficient epidermis mediated by chromosomal instability and inflammation. Anticancer Res 2009; 29: 3035–3042.

    PubMed  Google Scholar 

  53. Garcia-Escudero R, Martinez-Cruz AB, Santos M, Lorz C, Segrelles C, Garaulet G et al. Gene expression profiling of mouse p53-deficient epidermal carcinoma defines molecular determinants of human cancer malignancy. Mol Cancer 2010; 9: 193.

    PubMed  PubMed Central  Google Scholar 

  54. Duenas M, Santos M, Aranda JF, Bielza C, Martinez-Cruz AB, Lorz C et al. Mouse p53-deficient cancer models as platforms for obtaining genomic predictors of human cancer clinical outcomes. PLoS One 2012; 7: e42494.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Lara MF, Garcia-Escudero R, Ruiz S, Santos M, Moral M, Martinez-Cruz AB et al. Gene profiling approaches help to define the specific functions of retinoblastoma family in epidermis. Mol Carcinog 2008; 47: 209–221.

    CAS  PubMed  Google Scholar 

  56. Santos M, Ruiz S, Lara MF, Segrelles C, Moral M, Martinez-Cruz AB et al. Susceptibility of pRb-deficient epidermis to chemical skin carcinogenesis is dependent on the p107 allele dosage. Mol Carcinog 2008; 47: 815–821.

    CAS  PubMed  Google Scholar 

  57. Mantovani A, Allavena P, Sica A, Balkwill F . Cancer-related inflammation. Nature 2008; 454: 436–444.

    CAS  PubMed  Google Scholar 

  58. Arwert EN, Hoste E, Watt FM . Epithelial stem cells, wound healing and cancer. Nat Rev Cancer 2012; 12: 170–180.

    CAS  PubMed  Google Scholar 

  59. Ford JW, McVicar DW . TREM and TREM-like receptors in inflammation and disease. Curr Opin Immunol 2009; 21: 38–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Srivastava MK, Zhu L, Harris-White M, Kar U, Huang M, Johnson MF et al. Myeloid suppressor cell depletion augments antitumor activity in lung cancer. PLoS One 2012; 7: e40677.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Dennis G Jr., Sherman BT, Hosack DA, Yang J, Gao W, Lane HC et al. DAVID: database for annotation, visualization, and integrated discovery. Genome Biol. 2003; 4: P3.

    PubMed  Google Scholar 

  62. Lachmann A, Xu H, Krishnan J, Berger SI, Mazloom AR, Ma’ayan A . ChEA: transcription factor regulation inferred from integrating genome-wide ChIP-X experiments. Bioinformatics 2010; 26: 2438–2444.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102: 15545–15550.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Toledo LI, Murga M, Zur R, Soria R, Rodriguez A, Martinez S et al. A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat Struct Mol Biol 2011; 18: 721–727.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Cimprich KA, Cortez DATR . an essential regulator of genome integrity. Nat Rev Mol Cell Biol 2008; 9: 616–627.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Lopez-Contreras AJ, Fernandez-Capetillo O . The ATR barrier to replication-born DNA damage. DNA Repair 2010; 9: 1249–1255.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Halazonetis TD, Gorgoulis VG, Bartek J . An oncogene-induced DNA damage model for cancer development. Science 2008; 319: 1352–1355.

    CAS  PubMed  Google Scholar 

  68. Chin D, Boyle GM, Porceddu S, Theile DR, Parsons PG, Coman WB . Head and neck cancer: past, present and future. Expert Rev Anticancer Ther 2006; 6: 1111–1118.

    PubMed  Google Scholar 

  69. Leeman RJ, Lui VW, Grandis JR . STAT3 as a therapeutic target in head and neck cancer. Expert Opin Biol Ther 2006; 6: 231–241.

    CAS  PubMed  Google Scholar 

  70. Moral M, Paramio JM . Akt pathway as a target for therapeutic intervention in HNSCC. Histol Histopathol 2008; 23: 1269–1278.

    CAS  PubMed  Google Scholar 

  71. Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs BB et al. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia 2007; 9: 166–180.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 2004; 6: 1–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Rickman DS, Millon R, De Reynies A, Thomas E, Wasylyk C, Muller D et al. Prediction of future metastasis and molecular characterization of head and neck squamous-cell carcinoma based on transcriptome and genome analysis by microarrays. Oncogene 2008; 27: 6607–6622.

    CAS  PubMed  Google Scholar 

  74. Serefoglou Z, Yapijakis C, Nkenke E, Vairaktaris E . Genetic association of cytokine DNA polymorphisms with head and neck cancer. Oral Oncol 2008; 44: 1093–1099.

    CAS  PubMed  Google Scholar 

  75. Haile LA, Greten TF, Korangy F . Immune suppression: the hallmark of myeloid derived suppressor cells. Immunol Invest 2012; 41: 581–594.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Pak AS, Wright MA, Matthews JP, Collins SL, Petruzzelli GJ, Young MR . Mechanisms of immune suppression in patients with head and neck cancer: presence of CD34(+) cells which suppress immune functions within cancers that secrete granulocyte-macrophage colony-stimulating factor. Clin Cancer Res 1995; 1: 95–103.

    CAS  PubMed  Google Scholar 

  77. Dannenberg JH, Schuijff L, Dekker M, van der Valk M, Riele HT . Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130. Genes Dev 2004; 18: 2952–2962.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Robanus-Maandag E, Dekker M, van der Valk M, Carrozza ML, Jeanny JC, Dannenberg JH et al. p107 is a suppressor of retinoblastoma development in pRb-deficient mice. Genes Dev 1998; 12: 1599–1609.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Costa C, Santos M, Martinez-Fernandez M, Duenas M, Lorz C, Garcia-Escudero R et al. E2F1 loss induces spontaneous tumour development in Rb-deficient epidermis. Oncogene 2012; 32: 2937–2951.

    PubMed  Google Scholar 

  80. Afshari CA, Nichols MA, Xiong Y, Mudryj M . A role for a p21-E2F interaction during senescence arrest of normal human fibroblasts. Cell Growth Differ 1996; 7: 979–988.

    CAS  PubMed  Google Scholar 

  81. De la Cueva E, Garcia-Cao I, Herranz M, Lopez P, Garcia-Palencia P, Flores JM et al. Tumorigenic activity of p21(Waf1/Cip1) in thymic lymphoma. Oncogene 2006; 25: 4128–4132.

    CAS  PubMed  Google Scholar 

  82. Martin-Caballero J, Flores JM, Garcia-Palencia P, Collado M, Serrano M . Different cooperating effect of p21 or p27 deficiency in combination with INK4a/ARF deletion in mice. Oncogene 2004; 23: 8231–8237.

    CAS  PubMed  Google Scholar 

  83. Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J, Morris PG et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 2012; 150: 165–178.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Woods KV, El-Naggar A, Clayman GL, Grimm EA . Variable expression of cytokines in human head and neck squamous cell carcinoma cell lines and consistent expression in surgical specimens. Cancer Res 1998; 58: 3132–3141.

    CAS  PubMed  Google Scholar 

  85. Chen Z, Malhotra PS, Thomas GR, Ondrey FG, Duffey DC, Smith CW et al. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin Cancer Res 1999; 5: 1369–1379.

    CAS  PubMed  Google Scholar 

  86. Jackson SP, Bartek J . The DNA-damage response in human biology and disease. Nature 2009; 461: 1071–1078.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A et al. The mutational landscape of head and neck squamous cell carcinoma. Science 2011; 333: 1157–1160.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 2011; 333: 1154–1157.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Pickering CR, Zhang J, Yoo SY, Bengtsson L, Moorthy S, Neskey DM et al. Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. Cancer Discov 2013; 3: 770–781.

    CAS  PubMed  Google Scholar 

  90. Lui VW, Hedberg ML, Li H, Vangara BS, Pendleton K, Zeng Y et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov 2013; 3: 761–769.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Chung CH, Gillison ML . Human papillomavirus in head and neck cancer: its role in pathogenesis and clinical implications. Clin Cancer Res 2009; 15: 6758–6762.

    CAS  PubMed  Google Scholar 

  92. Perez-Ordonez B, Beauchemin M, Jordan RC . Molecular biology of squamous cell carcinoma of the head and neck. J Clin Pathol 2006; 59: 445–453.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Pyeon D, Newton MA, Lambert PF, den Boon JA, Sengupta S, Marsit CJ et al. Fundamental differences in cell cycle deregulation in human papillomavirus-positive and human papillomavirus-negative head/neck and cervical cancers. Cancer Res 2007; 67: 4605–4619.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Leemans CR, Braakhuis BJ, Brakenhoff RH . The molecular biology of head and neck cancer. Nat Rev Cancer 2011; 11: 9–22.

    CAS  PubMed  Google Scholar 

  95. Shin MK, Balsitis S, Brake T, Lambert PF . Human papillomavirus E7 oncoprotein overrides the tumor suppressor activity of p21Cip1 in cervical carcinogenesis. Cancer Res 2009; 69: 5656–5663.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Buitrago-Perez A, Garaulet G, Vazquez-Carballo A, Paramio JM, Garcia-Escudero R . Molecular signature of HPV-induced carcinogenesis: pRb, p53 and gene expression profiling. Curr Genomics 2009; 10: 26–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Santos M, Perez P, Segrelles C, Ruiz S, Jorcano JL, Paramio JM . Impaired NF-kappa B activation and increased production of tumor necrosis factor alpha in transgenic mice expressing keratin K10 in the basal layer of the epidermis. J Biol Chem 2003; 278: 13422–13430.

    CAS  PubMed  Google Scholar 

  98. Ruiz S, Segrelles C, Bravo A, Santos M, Perez P, Leis H et al. Abnormal epidermal differentiation and impaired epithelial-mesenchymal tissue interactions in mice lacking the retinoblastoma relatives p107 and p130. Development 2003; 130: 2341–2353.

    CAS  PubMed  Google Scholar 

  99. Ruiz S, Segrelles C, Santos M, Lara MF, Paramio JM . Functional link between retinoblastoma family of proteins and the Wnt signaling pathway in mouse epidermis. Dev Dyn 2004; 230: 410–418.

    CAS  PubMed  Google Scholar 

  100. Martinez-Cruz AB, Costa C, Saiz C, Paramio JM, Santos M . In vivo transplantation of genetically modified mouse embryonic epidermis. Methods Mol Biol 2010; 585: 361–367.

    CAS  PubMed  Google Scholar 

  101. McMurray HR, Sampson ER, Compitello G, Kinsey C, Newman L, Smith B et al. Synergistic response to oncogenic mutations defines gene class critical to cancer phenotype. Nature 2008; 453: 1112–1116.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Brocke-Heidrich K, Kretzschmar AK, Pfeifer G, Henze C, Loffler D, Koczan D et al. Interleukin-6-dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family-independent survival pathway closely associated with Stat3 activation. Blood 2004; 103: 242–251.

    CAS  PubMed  Google Scholar 

  103. Dutta J, Fan Y, Gupta N, Fan G, Gelinas C . Current insights into the regulation of programmed cell death by NF-kappaB. Oncogene 2006; 25: 6800–6816.

    CAS  PubMed  Google Scholar 

  104. Inga A, Storici F, Darden TA, Resnick MA . Differential transactivation by the p53 transcription factor is highly dependent on p53 level and promoter target sequence. Mol Cell Biol 2002; 22: 8612–8625.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Kyng KJ, May A, Stevnsner T, Becker KG, Kolvra S, Bohr VA . Gene expression responses to DNA damage are altered in human aging and in Werner Syndrome. Oncogene 2005; 24: 5026–5042.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Pilar Hernández for her excellent technical support on histology preparations and sectioning. The technical support by the personnel of the CIEMAT Animal Facility is specially acknowledged. Grant support: MINECO grants SAF2011-26122-C02-01 and SAF2012-34378, CAM Oncocycle Program Grants S2010/BMD-2470, ISCIII-RETIC grants RD06/0020/0029 and RD12/0036/0009 to JMP. EU FP7-HEALTH-279174, REGENER-AR to MG. ISCIII grant PI12/01959 to MS. MMF is funded by a ‘Juan de la Cierva’ research fellowship (JCI-2010-06167) from MICINN. SR is funded by a ‘Ramón y Cajal’ research fellowship (11-866-25-04) from MICINN. Work in the laboratory of OF is supported by grants from the Spanish Ministry of Science (SAF2011-23753), the Association for International Cancer Research (12-0229), the Howard Hughes Medical Institute and the European Research Council (ERC-210520).

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Author notes

  1. C Saiz-Ladera and M F Lara: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Biomedicine, Molecular Oncology Unit (ed70A), Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain

    C Saiz-Ladera, M F Lara, M Santos, C Lorz, R García-Escudero, M Martínez-Fernández, C Segrelles & J M Paramio

  2. Division of Hematopoietic Innovative Therapies (HIT), Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid, Spain

    M Garín

  3. Genomic Instability Group, Spanish National Cancer Research Center, Madrid, Spain

    S Ruiz & O Fernández-Capetillo

  4. Department of Veterinary Clinical Sciences, University of Santiago de Compostela, Lugo, Spain

    A Bravo

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  1. C Saiz-Ladera
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  2. M F Lara
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  3. M Garín
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  4. S Ruiz
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  5. M Santos
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  6. C Lorz
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  7. R García-Escudero
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  8. M Martínez-Fernández
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  9. A Bravo
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  10. O Fernández-Capetillo
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  11. C Segrelles
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  12. J M Paramio
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Corresponding authors

Correspondence to C Segrelles or J M Paramio.

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The authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Oncogene website

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Saiz-Ladera, C., Lara, M., Garín, M. et al. p21 suppresses inflammation and tumorigenesis on pRB-deficient stratified epithelia. Oncogene 33, 4599–4612 (2014). https://doi.org/10.1038/onc.2013.417

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  • DOI: https://doi.org/10.1038/onc.2013.417

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