Nonmelanoma skin cancer (NMSC) represents the most common form of skin cancer, its incidence has been reported significantly increased up to 10% per annum, and currently 2-3 million new cases of NMSC are diagnosed worldwide every year. Despite mortality from NMSC is low, it is associated with significant morbidity and cost suggesting that knowledge of molecular basis underlying its formation are needed to improve prevention and clinical treatments.
Notch signaling is an important form of intracellular communication and plays a key role in cell fate determination and differentiation and its dysregulation gives rise various disease including cancer. However, in tumorigenesis its role remains unclear, indeed in skin cancer Notch1 may have dual role; specifically, in skin context, many reports supported a role of Notch1 as tumor suppressor or oncogene suggesting its ability to induce different responses dependent on crosstalk with other signaling pathways.
p21 is well-known cell cycle inhibitor and it is a Notch1 downstream target involved in induction of differentiation in mouse keratinocytes. Furthermore, p21 has a key function in tumor promotion because it can protect cells against apoptosis binding proteins involved in induction of this process and inhibiting their activity, among the others Ask1.
Because the transformation of epithelial cells depends on the deregulation of normal differentiation, the present proposal is aimed to investigate if the activity of Notch signaling, through the regulation of Ask1 by p21, can be modified to promote one response over another activating specific mechanism that in cancer cells may be selected as a strategy to enhance the malignant phenotype in keratinocyte cancerogenesis.
In this proposal, we will investigate the role of Notch1 and p21/Ask1 axis in initiation and progression of skin cancer of both mouse model and mouse primary keratinocytes under well-defined culture conditions. Mouse primary keratinocytes are easily grown in large numbers and provide an ideal experimental system to study the switch between epithelial cell growth and differentiation and tumoral development. Relative to established cell lines, use of a primary system eliminates the possibility of alterations in critical regulatory pathways which may occur in culture during prolonged propagation. Moreover, the use of keratinocytes derived from knockout mice (double Notch1/p21 KO or Notch1/Ask1 KO mice and triple Notch1/p21/Ask1 mice), make it possible to assess the specific contribution of individual genes to control of differentiation and transformation processes.
While our work is focused on in vivo and ex vivo mouse keratinocytes, using NMSCs as model system, we are confident it may be of great relevance because it may be translated into other diseases to better understand the etiopathogenesis of non keratinocyte-derived tumors also.
The proposed research is relevant to cancer research because it will open the way for the identification of the molecular mechanisms of field cancerization, which would be extremely useful for identifying clinically relevant targets for early-stage cancer diagnostics, prevention and therapies.