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Elevated ΔNp63α levels facilitate epidermal and biliary oncogenic transformation

Michael Devos (UGent) , Barbara Gilbert (UGent) , Geertrui Denecker (UGent) , Kirsten Leurs (UGent) , Conor Mc Guire (UGent) , Kelly Lemeire (UGent) , Tino Hochepied (UGent) , Marnik Vuylsteke, Jo Lambert (UGent) , Caroline Van den Broecke (UGent) , et al.
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Abstract
Unlike its family member p53, TP63 is rarely mutated in human cancer. However, Delta Np63 alpha protein levels are often elevated in tumors of epithelial origin, such as squamous cell carcinoma and cholangiocarcinoma. To study the oncogenic properties of Delta Np63 alpha in vivo, we generated transgenic mice overexpressing Delta Np63 alpha from the Rosa26 locus promoter controlled by keratin 5-Cre. We found that these mice spontaneously develop epidermal cysts and ectopic Delta Np63 alpha expression in the bile duct epithelium that leads to dilatation of the intrahepatic biliary ducts, to hepatic cyst formation and bile duct adenoma. Moreover, when subjected to models of 7,12-dimethylbenz[a]anthracene-based carcinogenesis, tumor initiation was increased in Delta Np63 alpha transgenic mice in a gene dosage-dependent manner although Delta Np63 alpha overexpression did not alter the sensitivity to 7,12-dimethylbenz[a] anthracene-induced cytotoxicity in vivo. However, keratinocytes isolated from Delta Np63 alpha transgenic mice displayed increased survival and delayed cellular senescence compared with wild-type keratinocytes, marked by decreased p16 Ink4a and p19 Arf expression. Taken together, we show that increased Delta Np63 alpha protein levels facilitate oncogenic transformation in the epidermis as well as in the bile duct.
Keywords
SQUAMOUS-CELL CARCINOMA, ENDOTHELIAL GROWTH-FACTOR, POOR-PROGNOSIS, EPITHELIAL DEVELOPMENT, BREAST CARCINOMAS, PROGENITOR CELLS, UP-REGULATION, P53 HOMOLOG, STEM-CELLS, P63

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Chicago
Devos, Michael, Barbara Gilbert, Geertrui Denecker, Kirsten Leurs, Conor Mc Guire, Kelly Lemeire, Tino Hochepied, et al. 2017. “Elevated ΔNp63α Levels Facilitate Epidermal and Biliary Oncogenic Transformation.” Journal of Investigative Dermatology 137 (2): 494–505.
APA
Devos, Michael, Gilbert, B., Denecker, G., Leurs, K., Mc Guire, C., Lemeire, K., Hochepied, T., et al. (2017). Elevated ΔNp63α levels facilitate epidermal and biliary oncogenic transformation. JOURNAL OF INVESTIGATIVE DERMATOLOGY, 137(2), 494–505.
Vancouver
1.
Devos M, Gilbert B, Denecker G, Leurs K, Mc Guire C, Lemeire K, et al. Elevated ΔNp63α levels facilitate epidermal and biliary oncogenic transformation. JOURNAL OF INVESTIGATIVE DERMATOLOGY. 2017;137(2):494–505.
MLA
Devos, Michael, Barbara Gilbert, Geertrui Denecker, et al. “Elevated ΔNp63α Levels Facilitate Epidermal and Biliary Oncogenic Transformation.” JOURNAL OF INVESTIGATIVE DERMATOLOGY 137.2 (2017): 494–505. Print.
@article{8510062,
  abstract     = {Unlike its family member p53, TP63 is rarely mutated in human cancer. However, Delta Np63 alpha protein levels are often elevated in tumors of epithelial origin, such as squamous cell carcinoma and cholangiocarcinoma. To study the oncogenic properties of Delta Np63 alpha in vivo, we generated transgenic mice overexpressing Delta Np63 alpha from the Rosa26 locus promoter controlled by keratin 5-Cre. We found that these mice spontaneously develop epidermal cysts and ectopic Delta Np63 alpha expression in the bile duct epithelium that leads to dilatation of the intrahepatic biliary ducts, to hepatic cyst formation and bile duct adenoma. Moreover, when subjected to models of 7,12-dimethylbenz[a]anthracene-based carcinogenesis, tumor initiation was increased in Delta Np63 alpha transgenic mice in a gene dosage-dependent manner although Delta Np63 alpha overexpression did not alter the sensitivity to 7,12-dimethylbenz[a] anthracene-induced cytotoxicity in vivo. However, keratinocytes isolated from Delta Np63 alpha transgenic mice displayed increased survival and delayed cellular senescence compared with wild-type keratinocytes, marked by decreased p16 Ink4a and p19 Arf expression. Taken together, we show that increased Delta Np63 alpha protein levels facilitate oncogenic transformation in the epidermis as well as in the bile duct.},
  author       = {Devos, Michael and Gilbert, Barbara and Denecker, Geertrui and Leurs, Kirsten and Mc Guire, Conor and Lemeire, Kelly and Hochepied, Tino and Vuylsteke, Marnik and Lambert, Jo and Van den Broecke, Caroline and Libbrecht, Louis and Haigh, Jody and Berx, Geert and Lippens, Saskia and Vandenabeele, Peter and Declercq, Wim},
  issn         = {0022-202X},
  journal      = {JOURNAL OF INVESTIGATIVE DERMATOLOGY},
  language     = {eng},
  number       = {2},
  pages        = {494--505},
  title        = {Elevated \ensuremath{\Delta}Np63\ensuremath{\alpha} levels facilitate epidermal and biliary oncogenic transformation},
  url          = {http://dx.doi.org/10.1016/j.jid.2016.09.026},
  volume       = {137},
  year         = {2017},
}

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