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The HPV 16 E6 oncoprotein and UVB irradiation inhibit the tumor suppressor TGF β pathway in the epidermis of the K 14E6 transgenic mouse
Author(s) -
PopocaCuaya Marco,
DiazChavez Jose,
HernandezMonge Jesus,
AlvarezRios Elizabeth,
Lambert Paul F.,
Gariglio Patricio
Publication year - 2015
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.12689
Subject(s) - epidermis (zoology) , carcinogenesis , cancer research , oncogene , apoptosis , biology , genetically modified mouse , signal transduction , transgene , cell cycle , keratinocyte , microbiology and biotechnology , cancer , cell culture , biochemistry , genetics , anatomy , gene
High‐risk human papillomaviruses (HR‐HPVs) are the causative agents of cervical cancer, and they are also associated with a subset of head and neck squamous cell carcinomas. In addition, HPVs have also been postulated in the development of non‐melanoma skin cancers (NMSC). In these cancers, the oncogene E6 is best known for its ability to inactivate the tumor suppressor p53 protein. Interestingly, in transgenic mice for HPV16 E6 (K14E6), it was reported that E6 alone induced epithelial hyperplasia and delay in differentiation in skin epidermis independently of p53 inactivation. Transforming growth factor β (TGFβ) is an important regulator of cell growth/differentiation and apoptosis, and this pathway is often lost during tumorigenesis. Ultraviolet radiation B (UVB) exposure activates diverse cellular responses, including DNA damage and apoptosis. In this study, we investigated whether the E6 oncogene alone or in combination with UVB dysregulate some components of the TGFβ pathway in the epidermis of K14E6 mice. We used 8‐day‐old K14E6 and non‐transgenic mice irradiated and unirradiated with a single dose of UVB. We found that the E6 oncogene and UVB irradiation impair the TGFβ pathway in epidermis of K14E6 mice by downregulation of the TGFβ type II receptor (TβRII). This loss of TβRII prevents downstream activation of Smad2 and target genes as p15, an important regulator of cell cycle progression. In summary, the TGFβ signalling in cells of the epidermis is downregulated in our mouse model by both the E6 oncoprotein and the UVB irradiation.