Inducible 14-3-3 Sigma/Stratifin Ablation Accelerates Malignant Progression in HK1.ras/fos-Δ5PTENflx Transgenic Mouse Skin Carcinogenesis

Rawlinson, I., McMenemy, C. and Greenhalgh, D. (2023) Inducible 14-3-3 Sigma/Stratifin Ablation Accelerates Malignant Progression in HK1.ras/fos-Δ5PTENflx Transgenic Mouse Skin Carcinogenesis. British Journal of Dermatology 189(1):e21. 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/ljad174.040)

Abstract

In human carcinogenesis, given the plethora of pathways associated with 14-3-3σ and their complex interactions, the causality of 14-3-3σ deregulation remains elusive, with both tumour suppressive and oncogenic roles. To study mechanisms driving/inhibiting skin carcinogenesis, stage-specific expression of endogenous 14-3-3σ (stratifin) was analysed in skin carcinogenesis driven by activated rasHa/fos expression (HK1.ras/fos) and ablation of phosphatase and tensin homolog (PTEN)-mediated Akt regulation (K14.creP/Δ5PTENflx) and via conditional RU486-inducible 14-3-3σ knockout (K14.creP-Δ14-3-3). Consistent with 14-3-3σ roles in the commitment of keratinocytes to differentiate, bigenic HK1.fos/Δ5PTENflx hyperplasia expressed 14-3-3σ in basal layers and paralleled keratin K1 expression which appeared alongside elevated p53/p21 to increase keratinocyte differentiation leading to a keratoacanthoma (KA) aetiology. Trigenic HK1.ras/fos-Δ5PTENflx hyperplasia/papillomas also displayed increased basal-layer 14-3-3σ, suggesting attempts to protect basal layer p53 tumour suppressor gene function, given that 14-3-3σ acts as a chaperone protein to remove/relocate MDM2 for degradation, thus maintaining p53 levels. With time, HK1.ras/fos-Δ5PTENflx papillomas exhibited reduced p53 and increased p-MDM2166 activity in basal layers, which coincided with malignant conversion. Surprisingly, despite this p53 loss, 14-3-3σ expression persisted in well-differentiated squamous cell carcinomas (wdSCC) and, alongside elevated p21, appeared to limit further malignant progression via inhibiting p-Akt1473 expression. To further assess causality, 14-3-3σ functions were ablated in this model via an RU486-inducible cre/loxP system expressed from a keratin 14 (K14) promoter (K14.creP-Δ14-3-3σ). In bigenic HK1.fos-Δ14-3-3σ, preliminary data suggest loss of 14-3-3σ functions resulted in increased hyperplasia and keratosis similar to that observed in bigenic HK1.fos/Δ5PTENflx hyperplasia. Functional 14-3-3σ ablation in HK1.ras.fos/Δ5PTENflx/Δ14-3-3σflx genotypes apparently failed to accelerate papillomatogenesis, suggesting elements of redundancy in terms of tumour promotion; however, loss of 14-3-3σ facilitated increased p-MDM2166 and p53 loss, resulting in malignant conversion with progression to aggressive SCC. Collectively, these data suggest that 14-3-3σ/stratifin exerts suppressive roles in papillomatogenesis via MDM2/p53-dependent mechanisms, while persistent expression in wdSCCs suggests p53-independent scenarios that may involve p21-mediated Akt1 inhibition. However, if ablated, this limit of early-stage malignant progression is lost and 14-3-3σ loss leads to rapid progression to aggressive, p21-negative SCCs exhibiting uniform p-Akt1473activation.

• Item Type: Conference or Workshop Item
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Greenhalgh, Dr David and MCMENEMY, Carol
• Authors: Rawlinson, I., McMenemy, C., and Greenhalgh, D.
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• ISSN: 0007-0963