Malignant transformation of immortalized HaCaT keratinocytes through deregulated nuclear factor kappaB signaling.
Publication/Presentation Date
5-15-2006
Abstract
Previous studies addressing functional aspects of nuclear factor kappaB (NF-kappaB) activation in normal and transformed keratinocytes revealed complex and seemingly contradictory roles of this transcription factor in this cell type. In normal skin, NF-kappaB signaling seems to inhibit squamous cell carcinoma development whereas, in squamous cell carcinoma themselves, deregulated NF-kappaB expression and/or signaling is frequently observed. To further investigate this paradox, we focused on NF-kappaB activation as it relates to the transformed phenotype of immortalized but nontumorigenic human keratinocytes (HaCaT cells). We observed that NF-kappaB activity contributed to survival and growth of cultured HaCaT keratinocytes as shown by use of pharmacologic NF-kappaB inhibitors, RNA interference, and inducible overexpression of a dominant interfering IkappaB construct. NF-kappaB activation was largely provided through interaction with extracellular matrix components because preventing cell attachment by forced suspension culture markedly reduced NFkappaB signaling associated with cell death (anoikis); conversely, anoikis was partially reversed by NF-kappaB activation induced either by tumor necrosis factor-alpha treatment or by overexpressing the NF-kappaB p65 subunit in HaCaT cells. Furthermore, overexpression of NF-kappaBp65 in HaCaT cells induced colony formation in soft agar and tumorigenicity in nude mice. In summary, as opposed to normal keratinocytes, immortalized HaCaT keratinocytes provide a cellular context in which deregulated NF-kappaB signaling supports multiple malignant traits in vitro and in vivo.
Volume
66
Issue
10
First Page
5209
Last Page
5215
ISSN
0008-5472
Published In/Presented At
Ren, Q., Kari, C., Quadros, M. R., Burd, R., McCue, P., Dicker, A. P., & Rodeck, U. (2006). Malignant transformation of immortalized HaCaT keratinocytes through deregulated nuclear factor kappaB signaling. Cancer research, 66(10), 5209–5215. https://doi.org/10.1158/0008-5472.CAN-05-4158
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
16707445
Department(s)
Administration and Leadership
Document Type
Article