afimoxifene and Carcinoma--Squamous-Cell

Raf is one of the downstream effectors of Ras GTPases, and plays a key role in regulating cell proliferation and differentiation through the activation of MAPK. We have previously demonstrated that temporal induction of Raf in the epidermis of K14-Raf:ER transgenic mice results in epidermal hyperplasia resembling squamous cell carcinoma and psoriasis. It has been demonstrated that epidermal Stat3 activation is required for psoriasis development, since keratinocyte-specific Stat3 activation in a mouse model elicits a psoriasis-like phenotype, which is reversed by inhibition of Stat3 signaling.. The aim of this study was whether Stat3 signaling is involved in Raf-MAPK-dependent epidermal hyperplasia.. K14-Raf:ER transgenic mice, in which the 4-hydroxytamoxifen (4OHT)-responsive mutant estrogen receptor ligand binding domain-Raf fusion gene is expressed under control of the keratin 14 promoter, were mated with epidermis-specific Stat3 null mice (K5-Cre.Stat3(flox/flox)). K5-Cre.Stat3(flox/flox) mice were used to define the impact of Stat3 deficiency on Raf-induced epidermal hyperplasia.. Over-expression of Raf by 4OHT treatment in K14-Raf:ER;K5-Cre.Stat3(flox/flox) mice greatly attenuated the epidermal hyperplasia and dermal cell infiltrates compared with K14-Raf:ER;K5-Cre.Stat3(flox/WT) mice. Also, up-regulation of psoriasis-associated cytokine profiles, including VEGF, was inhibited in the skin from K14-Raf:ER;K5-Cre.Stat3(flox/flox) mice following 4OHT treatment.. These results clearly indicate that Raf-MAPK-dependent psoriatic-like epidermal hyperplasia requires Stat3 signaling in keratinocytes.

Topics: Animals; Carcinoma, Squamous Cell; Cell Differentiation; Epidermis; Gene Expression Regulation; Humans; Hyperplasia; Keratinocytes; Ligands; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mutation; Phenotype; Psoriasis; raf Kinases; Receptors, Estrogen; Signal Transduction; STAT3 Transcription Factor; Tamoxifen

Mammalian epidermis is maintained by self-renewal of stem cells, but the underlying mechanisms are unknown. Deletion of Rac1, a Rho guanosine triphosphatase, in adult mouse epidermis stimulated stem cells to divide and undergo terminal differentiation, leading to failure to maintain the interfollicular epidermis, hair follicles, and sebaceous glands. Rac1 exerts its effects in the epidermis by negatively regulating c-Myc through p21-activated kinase 2 (PAK2) phosphorylation. We conclude that a pleiotropic regulator of cell adhesion and the cytoskeleton plays a critical role in controlling exit from the stem cell niche and propose that Rac and Myc represent a global stem cell regulatory axis.

Topics: Animals; Antigens, Differentiation; Apoptosis; Carcinoma, Squamous Cell; Cell Differentiation; Cells, Cultured; Epidermal Cells; Gene Deletion; Humans; Keratinocytes; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuropeptides; p21-Activated Kinases; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-myc; rac GTP-Binding Proteins; rac1 GTP-Binding Protein; Skin Neoplasms; Stem Cells; Tamoxifen

Growth of the human squamous cervical carcinoma cell line, HOG-I, was stimulated in response to oestradiol in serum-containing and chemically defined medium. The oestradiol-stimulated growth could be inhibited by 4-OH tamoxifen, progesterone and medroxyprogesterone acetate; the last 2 compounds also inhibited basal cell growth in serum-containing and chemically defined media. The data are consistent with the sensitivity of human squamous cervical cancer to sex-steroid hormones and suggest that endocrine therapies may be of benefit in this disease.

Topics: Adult; Carcinoma, Squamous Cell; Cell Division; Culture Media; Estradiol; Female; Humans; Medroxyprogesterone; Medroxyprogesterone Acetate; Tamoxifen; Tumor Cells, Cultured; Uterine Cervical Neoplasms