Inducible ROCK 2 activation increases primary keratinocyte differentiation but co-operates with rasHa activation in transgenic mouse skin carcinogenesis

Masre, S.F., Olson, M.F. and Greenhalgh, D.A. (2013) Inducible ROCK 2 activation increases primary keratinocyte differentiation but co-operates with rasHa activation in transgenic mouse skin carcinogenesis. Journal of Investigative Dermatology, 133(S1), S57-S57. (doi:10.1038/jid.2013.96)

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To investigate ROCK 2 signalling in epidermal differentiation and co-operation with rasHa activation in squamous cell carcinogenesis [SCCs], transgenic mice expressing a conditionally active, 4-hydroxytamoxifen (4HT)-regulated, human ROCK2 transgene from a keratin 14 promoter K14.ROCK<sup>er</sup> were crossed with mice expressing activated ras<sup>Ha</sup> exclusively in epidermal transit amplifying keratinocytes [HK1.ras]. 4HT-treatment of K14.ROCK<sup>er</sup> alone for 12 weeks induced epidermal and follicular hyperplasia but no papillomas. Western analysis of primary K14.ROCK<sup>er</sup>keratinocyte differentiation showed elevated K1 expression following calcium challenge in vitro, consistent with a role in differentiation, whereas little K6 expression was detectable in 4-HT treated K14.ROCK<sup>er</sup> hyperplasia in vivo, an unusual result for epidermal hyperplasia. In addition hyperplastic anagen follicles expressed elevated collagen deposits in the hair bulb/IRS regions, a result also observed in bi-genic K14.ROCK<sup>er</sup>/HK1.ras papillomas. Here, 4-HT treatment for 12-14 weeks had little apparent effect on HK1.ras papillomatogenesis, with tumours appearing by approx 8-10 wks in treated and untreated cohorts. However K14.ROCK<sup>er</sup>/HK1.ras histotype was quite different, with increased collagen deposits appearing in the connective tissue of papillomas, which now expressed K6 but at lower levels and in an atypical, supra-basal fashion compared to untreated, bi-genic controls. Further, the basal layer architecture was also disturbed whilst 4-HT treated K14.ROCK<sup>er</sup>/HK1.ras papillomas taken at 12-14 weeks displayed areas of malignant conversion with both carcinoma in situ and overt SCC. These interesting data demonstrate significant roles for ROCK 2 in epidermal differentiation and identify unique epidermal responses to its deregulated signalling and novel early-stage co-operation with HK1.ras in skin carcinogenesis.

Item Type:Articles
Additional Information:Conference paper abstract
Glasgow Author(s) Enlighten ID:Greenhalgh, Dr David and Olson, Professor Michael
Authors: Masre, S.F., Olson, M.F., and Greenhalgh, D.A.
Subjects:R Medicine > RB Pathology
R Medicine > RL Dermatology
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Research Group:Dermatology
Journal Name:Journal of Investigative Dermatology
Journal Abbr.:JID
ISSN (Online):1523-1747

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