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PAD2 overexpression in transgenic mice augments malignancy and tumor-associated inflammation in chemically initiated skin tumors

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We previously found that transgenic mice overexpressing MMTV-FLAG-hPAD2 (PAD2OE) developed spontaneous skin lesions, with a subset of these lesions progressing to invasive squamous cell carcinoma (SCC). The goal of this report was to better understand the potential mechanisms by which PAD2 overexpression promotes skin cancer. Here, PAD2OE mice were treated with the carcinogen, 9,10-dimethyl-1,2-benzanthracene and with O-tetradecanoylphorbol-13-acetate and then scored for papilloma formation. Additionally, tumor sections were evaluated for evidence of tumor cell invasion and inflammation. We found that the total number of papillomas was significantly increased in PAD2OE mice compared to controls. Histopathologic analysis of the lesions found that in PAD2OE skin tumors progressed to invasive SCC more frequently than controls. Additionally, we found that PAD2OE lesions were highly inflamed, with a dense inflammatory cell infiltrate and an associated increase in nuclear phospho-STAT3 (signal transducer and activator of transcription 3) in the transgenic tumors. These data suggest that overexpression of the hPAD2 transgene in the epidermis increases the malignant conversion rate of benign tumors by promoting an inflammatory microenvironment.

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Correspondence to Scott A. Coonrod.

Electronic supplementary material

Supplementary Fig. 1

DMBA-TPA treated WT and PAD2 overexpressing (PAD2OE) tumor samples carry an activating mutation in codon 61 of Hras. Xbal digestion product indicates presence of activating mutation in tested (n = 3) WT and PAD2OE tumors. Untreated tissue from WT and PAD2OE lines did not contain the mutation. (GIF 46 kb)

Supplementary Fig. 2

High-magnification images showing range of histotypes seen in WT and PAD2OE tumors following DMBA-TPA treatment. Representative images of hyperplasia (a), dysplasia (b), and anaplasia (c). (GIF 205 kb)

High resolution image (TIFF 3625 kb)

High resolution image (TIFF 11567 kb)

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Mohanan, S., Horibata, S., Anguish, L.J. et al. PAD2 overexpression in transgenic mice augments malignancy and tumor-associated inflammation in chemically initiated skin tumors. Cell Tissue Res 370, 275–283 (2017). https://doi.org/10.1007/s00441-017-2669-x

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  • DMBA-TPA carcinogenesis model
  • Peptidylarginine deiminase 2 (PAD2)
  • PAD2 overexpression
  • Tumor associated inflammation
  • Squamous cell carcinoma