Role for EPS8 in squamous carcinogenesis

Huixin Wang, Vyomesh Patel, Hiroshi Miyazaki, J. Silvio Gutkind, William Andrew Yeudall

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

We have investigated the role of the signaling intermediate, EPS8, in tumor progression using a model system and in vivo. HN4 primary tumor cells express low levels of EPS8, similar to normal keratinocytes, and show minimal invasion in vitro in response to epidermal growth factor, whereas HN12 cells express high levels of EPS8 and are highly motile in vitro and tumorigenic in vivo. Additional independent tumor cell lines also showed elevated EPS8 expression compared with normal keratinocytes. Using retroviral transduction, we generated HN4 cell lines expressing EPS8 (HN4/EPS8) at levels equivalent to those present in HN12 cells. HN4/ EPS8 cells showed increased proliferation and migration compared with controls, together with elevated expression and activity of matrix metalloprotease (MMP)-9, which was dependent on protein kinase B (AKT) activity. Introduction of plasmids that direct synthesis of EPS8 short hairpin RNA (shRNA) into HN12 cells resulted in decreased EPS8 expression in these cells, which correlated with a decrease in their capacity to migrate and invade in vitro. In addition, shRNA-mediated knockdown of EPS8 reduced expression and activity of MMP-9 produced by these cells and reduced MMP-9 promoter activity. EPS8 knockdown cells showed decreased tumorigenicity in vivo compared with controls and lower MMP-9 expression. Conversely, overexpression of EPS8 in HN4 cells was sufficient to induce growth of these non-tumorigenic cells in orthotopic transplantation assays. Furthermore, EPS8 expression in clinical samples of squamous cell carcinoma showed variable expression levels and broadly paralleled expression of MMP-9. The data support a role for EPS8 in squamous carcinogenesis.

Original languageEnglish (US)
Pages (from-to)165-174
Number of pages10
JournalCarcinogenesis
Volume30
Issue number1
DOIs
StatePublished - Feb 3 2009
Externally publishedYes

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Carcinogenesis
Metalloproteases
Keratinocytes
Small Interfering RNA
Proto-Oncogene Proteins c-akt
Tumor Cell Line
Epidermal Growth Factor
Squamous Cell Carcinoma
Neoplasms
Plasmids
Transplantation
Cell Line
Growth
In Vitro Techniques

ASJC Scopus subject areas

  • Cancer Research

Cite this

Wang, H., Patel, V., Miyazaki, H., Gutkind, J. S., & Yeudall, W. A. (2009). Role for EPS8 in squamous carcinogenesis. Carcinogenesis, 30(1), 165-174. https://doi.org/10.1093/carcin/bgn252

Role for EPS8 in squamous carcinogenesis. / Wang, Huixin; Patel, Vyomesh; Miyazaki, Hiroshi; Gutkind, J. Silvio; Yeudall, William Andrew.

In: Carcinogenesis, Vol. 30, No. 1, 03.02.2009, p. 165-174.

Research output: Contribution to journalArticle

Wang, H, Patel, V, Miyazaki, H, Gutkind, JS & Yeudall, WA 2009, 'Role for EPS8 in squamous carcinogenesis', Carcinogenesis, vol. 30, no. 1, pp. 165-174. https://doi.org/10.1093/carcin/bgn252
Wang H, Patel V, Miyazaki H, Gutkind JS, Yeudall WA. Role for EPS8 in squamous carcinogenesis. Carcinogenesis. 2009 Feb 3;30(1):165-174. https://doi.org/10.1093/carcin/bgn252
Wang, Huixin ; Patel, Vyomesh ; Miyazaki, Hiroshi ; Gutkind, J. Silvio ; Yeudall, William Andrew. / Role for EPS8 in squamous carcinogenesis. In: Carcinogenesis. 2009 ; Vol. 30, No. 1. pp. 165-174.
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