title: Erbb2 up-regulation of ADAM12 expression accelerates skin cancer progression.
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.
authors.affiliation: Department of Biomedical Sciences, Creighton University, Omaha, Nebraska.
authors.forename: Velidi H
authors.initials: VH
authors.lastname: Rao
authors.affiliation: Department of Biomedical Sciences, Creighton University, Omaha, Nebraska.
authors.forename: Kristen
authors.initials: K
authors.lastname: Vogel
authors.affiliation: Department of Biomedical Sciences, Creighton University, Omaha, Nebraska.
authors.forename: Jodi K
authors.initials: JK
authors.lastname: Yanagida
authors.affiliation: Department of Biomedical Sciences, Creighton University, Omaha, Nebraska.
authors.forename: Nitin
authors.initials: N
authors.lastname: Marwaha
authors.affiliation: Department of Biomedical Sciences, Creighton University, Omaha, Nebraska.
authors.forename: Amrit
authors.initials: A
authors.lastname: Kandel
authors.affiliation: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
authors.forename: Carol
authors.initials: C
authors.lastname: Trempus
authors.affiliation: Department of Pathology, Creighton University, Omaha, Nebraska.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Repertinger
authors.affiliation: Department of Biomedical Sciences, Creighton University, Omaha, Nebraska.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Hansen
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000072199:ADAM12 Protein; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D018450:Disease Progression; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*; D014466:Ultraviolet Rays / Q000009:adverse effects; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D051722:ADAM Proteins; D000072199:ADAM12 Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; C524056:Erbb2 protein, mouse; C096115:Adam12 protein, mouse
keywords: ADAM12; Erbb2/HER2; nonmelanoma skin cancer; tumor progression; ultraviolet irradiation