Abstract B18: Expression of CTIP2/Bcl11b is linked to disease progression in head and neck cancer and is a critical mediator of epithelial cell migration and motility during wound healing processes
Authors: Bajaj Gaurav , Hyo-Sang Jang , Savage Talicia , Liang Xiaobo , Leid Mark , Indra Arup , Ganguli-Indra Gitali 
Published: June 2012

We have previously shown that transcriptional regulator Ctip2 controls epidermal homeostasis during skin morphogenesis and plays a crucial role in epidermal permeability barrier (EPB) formation (1,2). In a recent study we have shown that CTIP2 expression is upregulated in human head and neck tumors and in atopic dermatitis (3,4). It is known that “cancers are wounds that do not heal” and genes implicated in wound healing are known to influence cancer progression.

Interestingly, Ctip2 expression was also induced in mouse skin following tape stripping (mild injury by abrasion) and in cutaneous full thickness wounds. We therefore investigated function of Ctip2 during cutaneous wound healing using both in vitro scratch assay and in vivo full thickness wound healing assay. In the present study we looked at the Ctip2 expression levels by immunohistochemical (IHC) and western blot on wild-type mice skin after inducing mild abrasion injury by tape stripping and in full thickness wounds by punch biopsy. We have also analyzed the effect of Ctip2 deletion in the epidermis of mice skin using Ctip2ep-/- mice in these two processes using histology, immunohistochemistry (IHC), and Western blotting. Our data on in vitro scratch migration assay demonstrated a delay in keratinocyte migration and wound closure in mutant keratinocytes. Similarly, healing of cutaneous wounds was significantly delayed by 2-3 days in Ctip2ep-/- mice (selectively lacking the gene for Ctip2 in epidermal keratinocytes) in comparison to wild-type control (Ctip2L2/L2) mice where wounds closed much faster. Histological analyses of skin wounds revealed that the distance between the two migratory tongues of epithelial cells was larger in the mutant mice [1.2 fold (p&lt;0.001)] compared to the wild-type controls (Ctip2L2/L2) suggesting a possible role of Ctip2 in re-epithelialization process probably effecting the keratinocyte migration similar to what was seen in our in vitro data on scratch migration assay. Immunohistochemistry (IHC) and western blotting confirmed a persistant expression of PCNA and the delayed induction of both K16 and K6 (markers of activated keratinocytes) in the epidermal keratinocytes from the mutant wounds compared to control mice wounds suggesting a possible delay in the onset of restoration of differentiation in the newly formed epidermis of Ctip2ep-/- mutant mice. Altogether, we showed for the first time that keratinocytic Ctip2 modulated cutaneous wound healing by affecting the re- epithelialization and differentiation processes. Identification of genes regulated by Ctip2 during wound healing which are also involved in epithelial cancer progression is expected to improve diagnosis and treatment of human epithelial cancers.

References

1. Golonzhka O, Leid M, Indra G, Indra AK. Expression of COUP-TF- interacting protein 2 (CTIP2) in mouse skin during development and in adulthood. Gene Expr Patterns. 2007;7:754-60.

2. Golonzhka O, Liang X, Messaddeq N, Bornert JM, Campbell AL, Metzger D, Chambon P, Ganguli-Indra G, Leid M, Indra AK. Dual role of COUP-TF-interacting protein 2 in epidermal homeostasis and permeability barrier formation. J Invest Dermatol. 2009;129:1459-70.

3. Ganguli-Indra G, Liang X, Hyter S, Leid M, Hanifin J, Indra AK. Expression of COUP-TF-interacting protein 2 (CTIP2) in human atopic dermatitis and allergic contact dermatitis skin. Exp Dermatol. 2009;18:994-6.

4. Ganguli-Indra G, Wasylyk C, Liang X, Millon R, Leid M, Wasylyk B, Abecassis J, Indra A. CTIP2 expression in human head and neck squamous cell carcinoma is linked to poorly differentiated tumor status. PLoS ONE. 2009;4:e5367.

Citation Information: Clin Cancer Res 2010;16(14 Suppl):B18.