"We have shown that IKKα acts as a sentry, monitoring and, when necessary, halting proliferation of these important cells. In mice, we also found that deleting IKKα spontaneously induced squamous cell carcinomas," said senior author Yinling Hu.
Keratinocytes originate in the basal layer of the epidermis to replace skin cells at the surface. As keratinocytes gradually move up through the skin layers, they differentiate and finally form the top layer. In the terminal differentiation the cells lose their ability to reproduce and die.
Downregulation of IKKα has been noted in a variety of human squamous cell carcinomas. Hu’s group reported last year that a reduction in IKKα expression promotes the development of chemically induced papillomas and carcinomas. The researchers also demonstrated that an intact IKKα gene is required to suppress skin cancer development. But IKKα's role in maintaining skin homeostasis remained unclear because there was no mouse model. The researchers had to generate mice with IKKα deletions in their keratinocytes.
In a series of experiments, the group found evidence that IKKα functions as a sentry that monitors keratinocyte proliferation and then induces terminal differentiation. In one experiment, within a few days of birth, mutant mice had developed thickened skin and gradually showed retarded development. Even a low level of IKKα in the epidermis was sufficient to allow normal embryonic skin development.
The researchers examined the signaling pathways involved in overproliferation and reduced differentiation in IKKα -deficient cells. In one, they found that IKKα turns down a cellular signaling loop that activates EGFR and other growth factors previously found to regulate keratinocyte proliferation and differentiation.
Another experiment showed that IKKα deletions in keratinocytes cause skin carcinomas and that inactivating EGFR reverses this process in the mutant mice. Furthermore, either inactivation of EGFR or reintroduction of IKKα inhibited excessive cell division, induced terminal differentiation, and prevented skin cancer by repressing the EGFR-driven signaling loop.
MEDICA.de; Source: University of Texas M. D. Anderson Cancer Center