Inducible 14-3-3 Sigma/Stratifin Ablation Cooperates with rasHa Activation to Accelerate Papillomatogenesis and Induce Malignant Conversion in Transgenic Mouse Skin Carcinogenesis

Hardman-Carter, R., Lefkati, R., McMenemy, C. and Greenhalgh, D. (2023) Inducible 14-3-3 Sigma/Stratifin Ablation Cooperates with rasHa Activation to Accelerate Papillomatogenesis and Induce Malignant Conversion in Transgenic Mouse Skin Carcinogenesis. British Journal of Dermatology 189(1):e17–e18. Meeting Abstract: British Society for Investigative Dermatology (BSID) Annual Meeting, Technology & Innovation Centre, University of Strathclyde, Glasgow, Scotland, 20–21 March 2023. (doi: 10.1093/bjd/ljad174.032)

Abstract

In carcinogenesis, the 14-3-3σ isoform (stratifin) is implicated by being downregulated in a mode of classic tumour suppression gene (TSG) loss and also via elevated oncogenic roles; with both scenarios appearing to be hallmarks of 14-3-3σ deregulation, depending on tumour stage or context. Mouse skin models highlight tumour-suppressive roles, as the Er/Er+/– repeated epilation stain possesses germline mutations that result in hyperplasia, failed follicular differentiation and susceptibility to squamous cell carcinoma (SCC). In transgenic models, 14-3-3σ knockout supports early roles, resulting in rapid papilloma formation in classic two-stage DMBA/TPA chemical carcinogenesis; however, our previous studies in this model demonstrated targeted overexpression of 14-3-3σ led to SCC of a follicular origin in collaboration with Fos and well-differentiated SCC in collaboration with rasHa. Therefore, to study mechanisms driving/inhibiting skin carcinogenesis, stage-specific expression of endogenous 14-3-3σ (stratifin) was analysed in early skin carcinogenesis driven by activated rasHa expression (HK1.ras) and subsequently via conditional RU486-inducible 14-3-3σ knockout (K14.creP-Δ14-3-3σ). Consistent with 14-3-3σ roles previously observed in epidermal differentiation, HK1.ras hyperplasia and early papillomas displayed elevated 14-3-3σ expression in suprabasal keratinocytes and in occasional K1-positive basal keratinocytes as they committed to differentiate. Older HK1.ras mice exhibited increasing 14-3-3σ positivity in papilloma basal layers, suggesting attempts to protect basal-layer p53 TSG function, given that 14-3-3σ acts as a chaperone protein to remove/relocate MDM2 for degradation, thus maintaining p53 levels. Indeed, such papillomas expressed activated p-MDM2166 confined to suprabasal layers, resulting in strong basal layer p53 expression and thus HK1.ras papillomas lacked malignant conversion. In mice where 14-3-3σ functions were ablated via an RU486-inducible Cre/loxP system expressed from a keratin 14 (K14) promoter (K14.creP-Δ14-3-3σ), treated HK1.ras-K14.Δ14-3-3σ mice exhibited a rapid papillomatogenesis and produced larger papillomas. These papillomas also exhibited rapid conversion to malignancy, associated with increased activated p-MDM2166 expression in basal layers and resultant p53 loss. These observations suggest that 14-3-3σ plays tumour suppressive roles involving p53 protection, where failure to regulate MDM2 activity led to p53 loss and susceptibility to malignant conversion.

• Item Type: Conference or Workshop Item
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Greenhalgh, Dr David and MCMENEMY, Carol
• Authors: Hardman-Carter, R., Lefkati, R., McMenemy, C., and Greenhalgh, D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• ISSN: 0007-0963