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1.
Mol Carcinog ; 54(10): 1026-36, 2015 Oct.
Article in English | MEDLINE | ID: mdl-24798404

ABSTRACT

Solar ultraviolet (UV) radiation can cause severe damage to the skin and is the primary cause of most skin cancer. UV radiation causes DNA damage leading to mutations and also activates the Erbb2/HER2 receptor through indirect mechanisms involving reactive oxygen species. We hypothesized that Erbb2 activation accelerates the malignant progression of UV-induced skin cancer. Following the induction of benign squamous papillomas by UV exposure of v-ras(Ha) transgenic Tg.AC mice, mice were treated topically with the Erbb2 inhibitor AG825 and tumor progression monitored. AG825 treatment reduced tumor volume, increased tumor regression, and delayed the development of malignant squamous cell carcinoma (SCC). Progression to malignancy was associated with increased Erbb2 and ADAM12 (A Disintegin And Metalloproteinase 12) transcripts and protein, while inhibition of Erbb2 blocked the increase in ADAM12 message upon malignant progression. Similarly, human SCC and SCC cell lines had increased ADAM12 protein and transcripts when compared to normal controls. To determine whether Erbb2 up-regulation of ADAM12 contributed to malignant progression of skin cancer, Erbb2 expression was modulated in cultured SCC cells using forced over-expression or siRNA targeting, demonstrating up-regulation of ADAM12 by Erbb2. Furthermore, ADAM12 transfection or siRNA targeting revealed that ADAM12 increased both the migration and invasion of cutaneous SCC cells. Collectively, these results suggest Erbb2 up-regulation of ADAM12 as a novel mechanism contributing to the malignant progression of UV-induced skin cancer. Inhibition of Erbb2/HER2 reduced tumor burden, increased tumor regression, and delayed the progression of benign skin tumors to malignant SCC in UV-exposed mice. Inhibition of Erbb2 suppressed the increase in metalloproteinase ADAM12 expression in skin tumors, which in turn increased migration and tumor cell invasiveness.


Subject(s)
ADAM Proteins/genetics , Gene Expression/genetics , Receptor, ErbB-2/genetics , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Up-Regulation/genetics , ADAM12 Protein , Animals , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Cell Line , Cell Line, Tumor , DNA Damage/genetics , Disease Progression , Humans , Mice , Mice, Transgenic , Skin/pathology , Ultraviolet Rays/adverse effects
2.
Carcinogenesis ; 35(5): 1084-91, 2014 May.
Article in English | MEDLINE | ID: mdl-24464785

ABSTRACT

Ras is frequently activated in cutaneous squamous cell carcinoma, a prevalent form of skin cancer. However, the pathways that contribute to Ras-induced transformation have not been entirely elucidated. We have previously demonstrated that in transgenic mice, overexpression of the Ras activator RasGRP1 promotes the formation of spontaneous skin tumors and enhances malignant progression in the multistage carcinogenesis skin model that relies on the oncogenic activation of H-Ras. Utilizing a RasGRP1 knockout mouse model (RasGRP1 KO), we now show that lack of RasGRP1 reduced the susceptibility to skin tumorigenesis. The dependency on RasGRP1 was associated with a diminished response to the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Specifically, we found impairment of epidermal hyperplasia induced by TPA through keratinocyte proliferation. Using a keratinocyte cell line that carries a ras oncogenic mutation, we also demonstrated that RasGRP1 could further activate Ras in response to TPA. Thus, we propose that RasGRP1 upregulates signaling from Ras and contributes to epidermal tumorigenesis by increasing the total dosage of active Ras.


Subject(s)
Cell Transformation, Neoplastic/genetics , Gene Deletion , Guanine Nucleotide Exchange Factors/genetics , Skin Neoplasms/genetics , Skin/metabolism , Animals , Cell Transformation, Neoplastic/metabolism , Codon , Gene Targeting , Genes, ras , Hyperplasia/drug therapy , Hyperplasia/genetics , Mice , Mice, Knockout , Mutation , Skin/pathology , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Tetradecanoylphorbol Acetate/adverse effects , Transcriptional Activation/drug effects
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