Erbb2 up-regulation of ADAM12 expression accelerates skin cancer progression

Velidi H. Rao, Kristen Vogel, Jodi K. Yanagida, Nitin Marwaha, Amrit Kandel, Carol Trempus, Susan K. Repertinger, Laura A. Hansen

Research output: Contribution to journalArticle

6 Citations (Scopus)

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-rasHa 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.

Original languageEnglish
Pages (from-to)1026-1036
Number of pages11
JournalMolecular Carcinogenesis
Volume54
Issue number10
DOIs
StatePublished - Oct 1 2015

Fingerprint

Metalloproteases
Skin Neoplasms
Up-Regulation
Squamous Cell Carcinoma
Neoplasms
Skin
Tumor Burden
Small Interfering RNA
Radiation
Papilloma
DNA Damage
Cell Movement
Transfection
Cultured Cells
Reactive Oxygen Species
Proteins
Cell Line
Mutation

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Molecular Biology
  • Medicine(all)

Cite this

Rao, V. H., Vogel, K., Yanagida, J. K., Marwaha, N., Kandel, A., Trempus, C., ... Hansen, L. A. (2015). Erbb2 up-regulation of ADAM12 expression accelerates skin cancer progression. Molecular Carcinogenesis, 54(10), 1026-1036. https://doi.org/10.1002/mc.22171

Erbb2 up-regulation of ADAM12 expression accelerates skin cancer progression. / Rao, Velidi H.; Vogel, Kristen; Yanagida, Jodi K.; Marwaha, Nitin; Kandel, Amrit; Trempus, Carol; Repertinger, Susan K.; Hansen, Laura A.

In: Molecular Carcinogenesis, Vol. 54, No. 10, 01.10.2015, p. 1026-1036.

Research output: Contribution to journalArticle

Rao, VH, Vogel, K, Yanagida, JK, Marwaha, N, Kandel, A, Trempus, C, Repertinger, SK & Hansen, LA 2015, 'Erbb2 up-regulation of ADAM12 expression accelerates skin cancer progression', Molecular Carcinogenesis, vol. 54, no. 10, pp. 1026-1036. https://doi.org/10.1002/mc.22171
Rao VH, Vogel K, Yanagida JK, Marwaha N, Kandel A, Trempus C et al. Erbb2 up-regulation of ADAM12 expression accelerates skin cancer progression. Molecular Carcinogenesis. 2015 Oct 1;54(10):1026-1036. https://doi.org/10.1002/mc.22171
Rao, Velidi H. ; Vogel, Kristen ; Yanagida, Jodi K. ; Marwaha, Nitin ; Kandel, Amrit ; Trempus, Carol ; Repertinger, Susan K. ; Hansen, Laura A. / Erbb2 up-regulation of ADAM12 expression accelerates skin cancer progression. In: Molecular Carcinogenesis. 2015 ; Vol. 54, No. 10. pp. 1026-1036.
@article{7763cba79e094688a56f83e74cff1d01,
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-rasHa 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.",
author = "Rao, {Velidi H.} and Kristen Vogel and Yanagida, {Jodi K.} and Nitin Marwaha and Amrit Kandel and Carol Trempus and Repertinger, {Susan K.} and Hansen, {Laura A.}",
year = "2015",
month = "10",
day = "1",
doi = "10.1002/mc.22171",
language = "English",
volume = "54",
pages = "1026--1036",
journal = "Molecular Carcinogenesis",
issn = "0899-1987",
publisher = "Wiley-Liss Inc.",
number = "10",

}

TY - JOUR

T1 - Erbb2 up-regulation of ADAM12 expression accelerates skin cancer progression

AU - Rao, Velidi H.

AU - Vogel, Kristen

AU - Yanagida, Jodi K.

AU - Marwaha, Nitin

AU - Kandel, Amrit

AU - Trempus, Carol

AU - Repertinger, Susan K.

AU - Hansen, Laura A.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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-rasHa 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.

AB - 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-rasHa 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.

UR - http://www.scopus.com/inward/record.url?scp=84941659441&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84941659441&partnerID=8YFLogxK

U2 - 10.1002/mc.22171

DO - 10.1002/mc.22171

M3 - Article

VL - 54

SP - 1026

EP - 1036

JO - Molecular Carcinogenesis

JF - Molecular Carcinogenesis

SN - 0899-1987

IS - 10

ER -