DeltaNp63 isoform-mediated beta-defensin family up-regulation is associated with (lymph)angiogenesis and poor prognosis in patients with squamous cell carcinoma.
[en] Beside a role in normal development/differentiation, high p63 immunoreactivity is also frequently observed in squamous cell carcinoma (SCC). Due to the complexity of the gene, the role of each p63 isotype in tumorigenesis is still confusing. Constitutively produced or induced in inflammatory conditions, human beta-defensins (HbetaDs) are cationic peptides involved in host defenses against bacteria, viruses and fungi. Here, we investigated both the role of p63 proteins in the regulation of HbetaDs and the implication of these antimicrobial peptides in tumor (lymph)angiogenesis. Thus, in contrast to TAp63 isotypes, we observed that DeltaNp63 proteins (alpha, beta, gamma) induce HbetaD1, 2 and 4 expression. Similar results were observed in cancer tissues and cell lines. We next demonstrated that DeltaNp63-overexpressing SCC are associated with both a poor prognosis and a high tumor vascularisation and lymphangiogenesis. Moreover, we showed that HbetaDs exert a chemotactic activity for (lymphatic) endothelial cells in a CCR6-dependent manner. The ability of HbetaDs to enhance (lymph)angiogenesis in vivo was also evaluated. We observed that HbetaDs increase the vessel number and induce a significant increase in relative vascular area compared to negative control. Taken together, the results of this study suggest that DeltaNp63-regulated HbetaD could promote tumor (lymph)angiogenesis in SCC microenvironment.
RONCARATI, Patrick ; Centre Hospitalier Universitaire de Liège - CHU > Anatomie pathologique
Erpicum, Charlotte ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Boniver, Jacques ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Castronovo, Vincenzo ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire
Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Saussez, Sven
Peulen, Olivier ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Delvenne, Philippe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Herfs, Michael ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
DeltaNp63 isoform-mediated beta-defensin family up-regulation is associated with (lymph)angiogenesis and poor prognosis in patients with squamous cell carcinoma.
Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dötsch V, Andrews NC, Caput D, and McKeon F. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell. 1998; 2: 305-316.
Koster MI, Kim S, Mills AA, DeMayo FJ, and Roop DR. p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev. 2004; 18: 126-131.
Truong AB, Kretz M, Ridky TW, Kimmel R, and Khavari PA. p63 regulates proliferation and differentiation of developmentally mature keratinocytes. Genes Dev. 2006; 20: 3185-3197.
Senoo M, Pinto F, Crum CP, and McKeon F. p63 Is essential for the proliferative potential of stem cells in stratified epithelia. Cell. 2007; 129: 523-536.
Di Como CJ, Urist MJ, Babayan I, Drobnjak M, Hedvat CV, Teruya-Feldstein J, Pohar K, Hoos A, and Cordon- Cardo C. p63 expression profiles in human normal and tumor tissues. Clin Cancer Res. 2002; 8: 494-501.
Su X, Chakravarti D, and Flores ER. p63 steps into the limelight: crucial roles in the suppression of tumorigenesis and metastasis. Nat Rev Cancer. 2013; 13: 136-143.
Gallant-Behm CL, Ramsey MR, Bensard CL, Nojek I, Tran J, Liu M, Ellisen LW, and Espinosa JM. DeltaNp63alpha represses anti-proliferative genes via H2A.Z deposition. Genes Dev. 2012; 26: 2325-2336.
Leonard MK, Kommagani R, Payal V, Mayo LD, Shamma HN, and Kadakia MP. DeltaNp63alpha regulates keratinocyte proliferation by controlling PTEN expression and localization. Cell Death Differ. 2011; 18: 1924-1933.
Wu G, Osada M, Guo Z, Fomenkov A, Begum S, Zhao M, Upadhyay S, Xing M, Wu F, Moon C, Westra WH, Koch WM, Mantovani R, Califano JA, Ratovitski E, Sidransky D, and Trink B. DeltaNp63alpha up-regulates the Hsp70 gene in human cancer. Cancer Res. 2005; 65: 758-766.
Celardo I, Antonov A, Amelio I, Annicchiarico-Petruzzelli M, and Melino G. p63 transcriptionally regulates the expression of matrix metallopeptidase 13. Oncotarget. 2014; accepted.
Guo X, Keyes WM, Papazoglu C, Zuber J, Li W, Lowe SW, Vogel H, and Mills AA. TAp63 induces senescence and suppresses tumorigenesis in vivo. Nat Cell Biol. 2009; 11: 1451-1457.
Su X, Chakravarti D, Cho MS, Liu L, Gi YJ, Lin YL, Leung ML, El-Naggar A, Creighton CJ, Suraokar MB, Wistuba I, and Flores ER. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature. 2010; 467: 986-990.
Mattiske S, Ho K, Noll JE, Neilsen PM, Callen DF, and Suetani RJ. TAp63 regulates oncogenic miR-155 to mediate migration and tumor growth. Oncotarget. 2013; 4: 1894- 1903.
Chen H, Xu Z, Peng L, Fang X, Yin X, Xu N, and Cen P. Recent advances in the research and development of human defensins. Peptides. 2006; 27: 931-940.
Ganz T. Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol. 2003; 3: 710-720.
Klotman ME and Chang TL. Defensins in innate antiviral immunity. Nat Rev Immunol. 2006; 6: 447-456.
Hubert P, Herman L, Maillard C, Caberg JH, Nikkels A, Pierard G, Foidart JM, Noel A, Boniver J, and Delvenne P. Defensins induce the recruitment of dendritic cells in cervical human papillomavirus-associated (pre)neoplastic lesions formed in vitro and transplanted in vivo. FASEB J. 2007; 21: 2765-2775.
Yang D, Chen Q, Chertov O and Oppenheim JJ. Human neutrophil defensins selectively chemoattract naive T and immature dendritic cells. J Leukoc Biol. 2000; 68: 9-14.
Yang D, Chertov O, Bykovskaia SN, Chen Q, Buffo MJ, Shogan J, Anderson M, Schröder JM, Wang JM, Howard OM, and Oppenheim JJ. Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science. 1999; 286: 525-528.
Weinberg A, Jin G, Sieg S, and McCormick TS. The yin and yang of human Beta-defensins in health and disease. Front Immunol. 2012; 3: 294.
Jin G, Kawsar HI, Hirsch SA, Zeng C, Jia X, Feng Z, Ghosh SK, Zheng QY, Zhou A, McIntyre TM, and Weinberg A. An antimicrobial peptide regulates tumor-associated macrophage trafficking via the chemokine receptor CCR2, a model for tumorigenesis. PLoS One. 2010; 5: e10993.
Baroni A, Donnarumma G, Paoletti I, Longanesi-Cattani I, Bifulco K, Tufano MA, and Carriero MV. Antimicrobial human beta-defensin 2 stimulates migration, proliferation and tube formation of human umbilical vein endothelial cells. Peptides. 2009; 30: 267-272.
Barbieri CE, Tang LJ, Brown KA, and Pietenpol JA. Loss of p63 leads to increased cell migration and up-regulation of genes involved in invasion and metastasis. Cancer Res. 2006; 66: 7589-7597.
Dallas NA, Samuel S, Xia L, Fan F, Gray MJ, Lim SJ, and Ellis LM. Endoglin (CD105): a marker of tumor vasculature and potential target for therapy. Clin Cancer Res. 2008; 14: 1931-1937.
Foubert P, and Varner JA. Integrins in tumor angiogenesis and lymphangiogenesis. Methods Mol Biol. 2012; 757: 471-486.
Duong T, Koopman P, and Francois M. Tumor lymphangiogenesis as a potential therapeutic target. J Oncol 2012; 2012: 204946.
Mizukawa N, Sawaki K, Yamachika E, Fukunaga J, Ueno T, Takagi S, and Sugahara T. Presence of human betadefensin-in oral squamous cell carcinoma. Anticancer Res. 2000; 20: 2005-2007.
Herfs M, Hubert P, Suarez-Carmona M, Reschner A, Saussez S, Berx G, Savagner P, Boniver J, and Delvenne P. Regulation of p63 isoforms by snail and slug transcription factors in human squamous cell carcinoma. Am J Pathol. 2010; 176: 1941-1949.
Higashikawa K, Yoneda S, Tobiume K, Taki M, Shigeishi H, and Kamata N. Snail-induced down-regulation of DeltaNp63alpha acquires invasive phenotype of human squamous cell carcinoma. Cancer Res. 2007; 67: 9207- 9213.
Moergel M, Abt E, Stockinger M, and Kunkel M. Overexpression of p63 is associated with radiation resistance and prognosis in oral squamous cell carcinoma. Oral Oncol. 2010; 46: 667-671.
Lo Muzio L, Santarelli Santarelli A, Caltabiano R, Rubini C, Pieramici T, Trevisiol L, Carinci F, Leonardi R, De Lillo A, Lanzafame S, Bufo P, and Piattelli A. p63 overexpression associates with poor prognosis in head and neck squamous cell carcinoma. Hum Pathol 2005; 36: 187- 194.
Matin RN, Chikh A, Chong Chong SL, Mesher D, Graf M, Sanza' P, Senatore V, Scatolini M, Moretti F, Leigh IM, Proby CM, Costanzo A, Chiorino G, Cerio R, Harwood CA, and Bergamaschi D. p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis. J Exp Med. 2013; 210: 581-603.
Senoo M, Matsumura Y, and Habu S. TAp63gamma (p51A) and dNp63alpha (p73L), two major isoforms of the p63 gene, exert opposite effects on the vascular endothelial growth factor (VEGF) gene expression. Oncogene. 2002; 21: 2455-2465.
Bid HK, Roberts RD, Cam M, Audino A, Kurmasheva RT, Lin J, Houghton PJ, and Cam H. δNp63 Promotes Pediatric Neuroblastoma and Osteosarcoma by Regulating Tumor Angiogenesis. Cancer Res. 2014; 74: 320-329.
Rohrl J, Huber B, Koehl GE, Geissler EK, and Hehlgans T. Mouse beta-defensin 14 (Defb14) promotes tumor growth by inducing angiogenesis in a CCR6-dependent manner. J Immunol. 2012; 188: 4931-4939.
Herfs M, Hubert P, Poirrier AL, Vandevenne P, Renoux V, Habraken Y, Cataldo D, Boniver J, and Delvenne P. Proinflammatory cytokines induce bronchial hyperplasia and squamous metaplasia in smokers: implications for chronic obstructive pulmonary disease therapy. Am J Respir Cell Mol Biol. 2012; 47: 67-79.
Herfs M, Vargas SO, Yamamoto Y, Howitt BE, Nucci MR, Hornick JL, McKeon FD, Xian W, and Crum CP. A novel blueprint for 'top down' differentiation defines the cervical squamocolumnar junction during development, reproductive life, and neoplasia. J Pathol. 2013; 229: 460- 468.
Herfs M, Hubert P, Kholod N, Caberg JH, Gilles C, Berx G, Savagner P, Boniver J, and Delvenne P. Transforming growth factor-beta1-mediated slug and snail transcription factor up-regulation reduces the density of Langerhans cells in epithelial metaplasia by affecting E-cadherin expression. Am J Pathol. 2008; 172: 1391-1402.
