| First Author | Masre SF | Year | 2020 |
| Journal | Carcinogenesis | Volume | 41 |
| Issue | 10 | Pages | 1409-1420 |
| PubMed ID | 31907522 | Mgi Jnum | J:299289 |
| Mgi Id | MGI:6478447 | Doi | 10.1093/carcin/bgz205 |
| Citation | Masre SF, et al. (2020) Epidermal ROCK2 induces AKT1/GSK3beta/beta-catenin, NFkappaB and dermal tenascin C; but enhanced differentiation and p53/p21 inhibit papilloma. Carcinogenesis 41(10):1409-1420 |
| abstractText | 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-GSK3beta ser9 and membranous/nuclear beta-catenin expression together with weak NFkappaB, 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. |
