Epidermal ROCK2-induces AKT1/GSK3β/β-catenin, NFκB and dermal tenascin-C; but enhanced differentiation and p53/p21 inhibit papilloma

Masre, S. F., Rath, N., Olson, M. F. and Greenhalgh, D. A. (2020) Epidermal ROCK2-induces AKT1/GSK3β/β-catenin, NFκB and dermal tenascin-C; but enhanced differentiation and p53/p21 inhibit papilloma. Carcinogenesis, 41(10), pp. 1409-1420. (doi: 10.1093/carcin/bgz205) (PMID:31907522) (PMCID:PMC7566339)

Abstract

ROCK2 roles in epidermal differentiation and carcinogenesis have been investigated in mice expressing an RU486-inducible, 4HT-activated ROCK2 transgene (K14.creP/lslROCKer). RU486/4HT-mediated ROCKer activation induced epidermal hyperplasia similar to cutaneous oncogenic rasHa (HK1.ras); however ROCKer did not elicit papillomas. Instead, anomalous basal-layer ROCKer expression corrupted normal ROCK2 roles underlying epidermal rigidity/stiffness and barrier maintanance, resulting in premature keratin K1, loricrin and filaggrin expression. Also, hyperproliferative/stress-associated keratin K6 was reduced; possibly reflecting altered ROCK2 roles in epidermal rigidity and keratinocyte flexibility/migration during wound healing. Consistent with increased proliferation, K14.creP/lslROCKer hyperplasia displayed supra-basal-to-basal increases in activated p-AKT1, inactivated p-GSK3β ser9 and membranous/nuclear β-catenin expression together with weak NFκB, which were absent in equivalent HK1.ras hyperplasia. Furthermore, ROCKer-mediated increases in epidermal rigidity via p-MypT1 inactivation/elevated MLC, coupled to anomalous β-catenin expression, induced tenascin C-positive dermal fibroblasts. Alongside an altered ECM, these latent tenascin C-positive dermal fibroblasts may become putative pre-cancer–associated fibroblasts (pre-CAFs) and establish a susceptibility that subsequently contributes to tumour progression. However, anomalous differentiation was also accompanied by an immediate increase in basal-layer p53/p21 expression; suggesting that while ROCK2/AKT1/β-catenin activation increased keratinocyte proliferation resulting in hyperplasia, compensatory p53/p21 and accelerated differentiation helped inhibit papillomatogenesis.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Greenhalgh, Dr David and Rath, Dr Nicola and Olson, Professor Michael
• Authors: Masre, S. F., Rath, N., Olson, M. F., and Greenhalgh, D. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Carcinogenesis
• Publisher: Oxford University Press
• ISSN: 0143-3334
• ISSN (Online): 1460-2180
• Published Online: 07 January 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Carcinogenesis 2020
• Publisher Policy: Reproduced in accordance with the publisher copyright policy