Keratin proteins and non-melanoma skin tumors

Johns Hopkins University, Baltimore MD

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Basal cell carcinoma (BCC) is the most frequent cancer in North America. It represents more than one-third of all cancers diagnosed in the U.S. every year, and its incidence is on the rise. Whereas it rarely metastasizes, BCC can be devastating in that tumors can be locally aggressive, leading to ulceration and disfigurement. There is relatively little known about the biochemical determinants of BCC tumor biology. The type I keratin 17 (K17) is consistently induced in BCC lesions, whether in human skin or in relevant transgenic mouse models, making it a reliable marker of this type of tumor in vivo. Molecularly, the association between K17 and BCC is the direct result of Gli-mediated transactivation of the K17 gene promoter. Gli family members are transcription factors and terminal effectors of sonic hedgehog (Shh) signaling. Genetically, most BCCs are associated with mutations at loci encoding key effectors of Shh signaling, resulting in its sustained activation, and creating a hyperproliferative state in hair follicles and epidermis that is conducive to the additional "genetic hits" required for neoplastic transformation. Recent work has shown that K17 serves multiple functions in skin epithelia. Like other keratins and all other intermediate filament proteins, K17 provides structural support. Examples of functions that are so far unique to K17 in skin epithelia are the protection of keratinocytes against TNFa-mediated apoptosis, which is manifested during the anagen (growth) phase in cycling hair follicles, and an ability to stimulate mTOR- dependent protein synthesis and cell growth in keratinocytes called upon to sustain rapid tissue growth, as occurs following tissue injury. Each of these three functions represents a key determinant of tumor biology. The overall objective of this project is to assess the functional contribution of K17 in the context of a well-established transgenic mouse model of BCC. We will do so by mating previously characterized K17 null mice, in which the K17 protein is completely missing, with transgenic mice that constitutively express Gli2 in progenitor keratinocytes of the skin, and which reproducibly develop BCC skin tumors as young adults. Mice carrying a null allele in K14 will provide a suitable reference for those studies. We have strong preliminary evidence indicating that loss of K17 (nut not K14) results in a delay in BCC tumor growth. In Aim 1, macroscopic, microscopic, molecular and biochemical outcomes will be used to assess tumor biology in the absence of either K17 or K14. In Aim 2, we will exploit keratinocyte primary to define the cellular and molecular basis for the apparent delay in tumor growth in vivo. A particular emphasis will be placed on the regulation of cell proliferation, programmed cell death, and protein synthesis. Altogether, the proposed studies will shed light on the role of keratins as determinants of the growth and aggressiveness of non-melanoma skin tumors. [unreadable] [unreadable] Project Narrative: Basal cell carcinoma (BCC) is the most frequent cancer in North America. It represents more than one-third of all cancers diagnosed in the U.S. every year, and its incidence is on the rise. Whereas it rarely metastasizes, BCC can be devastating in that tumors can be locally aggressive, leading to ulceration and disfigurement. There is relatively little known about the biochemical determinants of BCC tumor biology. A cytoskeletal protein named keratin 17 (K17) serves as a very useful marker for BCC lesions. Its potential contribution to the growth and fate of BCC lesions has not yet been examined. K17 normally functions to provide mechanical support, and participates in the regulation of programmed cell death as well as protein synthesis, in various types of skin epithelial cells. All of these roles represent key determinants of tumor biology. In this study, we will examine how BCC tumors fare in the complete absence of K17 protein in the context of an established experimental mouse model. We hope that our findings lead to new ideas for the therapeutic management of aggressive and recurring forms of these tumors. [unreadable] [unreadable] [unreadable]