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

ROCK2 roles in epidermal differentiation and carcinogenesis have been investigated in mice expressing an RU486-inducible, 4HT-activated ROCK2 transgene (K14.creP/lslROCK(er)). RU486/4HT-mediated ROCKer activation induced epidermal hyperplasia similar to cutaneous oncogenic ras(Ha) (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/lslROCK(er) hyperplasia displayed supra-basal-to-basal increases in activated p-AKT1, inactivated p-GSK3 beta(se)(r9) and membranous/nuclear beta-catenin expression together with weak NF kappa B, which were absent in equivalent HK1.ras hyperplasia. Furthermore, ROCKer-mediated increases in epidermal rigidity via p-MypT1 inactivation/elevated MLC, coupled to anomalous beta-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/beta-catenin activation increased keratinocyte proliferation resulting in hyperplasia, compensatory p53/p21 and accelerated differentiation helped inhibit papillomatogenesis.