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Protein "Switch" Suppresses Skin Cancer Development

When IKKa fails to keep cell replacement cycle in balance, cancer follows

M. D. Anderson News Release 09/09/08

The protein IKKalpha (IKKa) regulates the cell cycle of keratinocytes and plays a key role in keeping these specialized skin cells from becoming malignant, researchers at The University of Texas M. D. Anderson Cancer Center report in the Sept. 9 issue of Cancer Cell.

"We have shown that IKKa acts as a sentry, monitoring and, when necessary, halting proliferation of these important cells. In the first mouse model of its kind, we also found that deleting IKKa spontaneously induced squamous cell carcinomas by activating the epidermal growth factor receptor pathway," said senior author Yinling Hu, Ph.D., assistant professor in M. D. Anderson's Department of Carcinogenesis at the Science Park - Research Division in Smithville, Texas. "These results provide new therapeutic targets for prevention of skin cancer."

Keratinocytes originate in the basal layer of the epidermis to replace skin cells at the surface that have been shed. As keratinocytes gradually move up through the skin layers, they differentiate and eventually form the top layer of the skin, which is composed of squamous cells. The cycle ends through terminal differentiation, in which cells lose their ability to reproduce by dividing in two. They eventually die.

Hu and colleagues reported in research last year that a reduction in IKKa expression promotes the development of chemically induced papillomas and carcinomas, which are benign and malignant tumors of the epithelium respectively. Epithelial cells make up the outer layers of skin and the inner linings of many organs, including the lungs and the gastrointestinal, reproductive and urinary tracts.  Most cancers originate in organ epithelial cells. The researchers also demonstrated that an intact IKKa gene is required to suppress skin cancer development.
      
Downregulation of IKKa has been noted in a variety of human squamous cell carcinomas, including those of the skin, esophagus, lungs, and head and neck.
      
IKKa's role in maintaining skin homeostasis, or stability, had remained unclear because an appropriate mouse model was not available. To solve this problem, Bigang Liu, the first author, and colleagues generated mice with IKKa deletions in their keratinocytes.
      
In a series of experiments, Hu's group found evidence that IKKa 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 and wrinkled skin and gradually showed retarded development. The researchers also found that even a low level of IKKa in the epidermis was sufficient to allow normal embryonic skin development.
      
The researchers examined the signaling pathways involved in overproliferation and reduced differentiation in IKKa -deficient cells. In one, they found that IKKa turns down a cellular signaling loop that activates EGFR and other growth factors previously found to regulate keratinocyte proliferation and differentiation.
      
Another experiment demonstrated that IKKa 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 IKKa inhibited excessive cell division, induced terminal differentiation, and prevented skin cancer by repressing the EGFR-driven signaling loop.
      
Hu's group concluded that IKKa is a switch for proliferation and differentiation and is essential to maintaining skin homeostasis, or stability, and preventing skin cancer.
      
"This study has revealed the importance of IKKa in maintaining skin homeostasis and in preventing skin cancer, as well as the mechanism of how IKKa acts in these processes," Hu said. "We will further investigate how IKKa deletion targets a single cancer initiation cell, which will provide new avenues to treat cancer."
      
Co-authors with  Hu and Liu are Xiaojun Xia, Ph.D., Feng Zhu, Ph.D., Eunmi Park, Ph.D., Steve Carbajal, Kaoru Kiguchi, M.D., Ph.D., John DiGiovanni, Ph.D., and Susan Fischer, Ph.D., all of M. D. Anderson's Science Park - Research Division.
      
Research was funded by grants from the National Cancer Institute. Hu moved this month to the Cancer and Inflammation Program, Center for Cancer Research at the National Cancer Institute. 09/08/08


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