Role of N-WASP in cell proliferation : implication for organ development and cancer

Abstract

N-WASP regulates actin cytoskeleton and plays key roles in many cellular processes such as cell-proliferation, cell-adhesion, cell-migration and endocytosis which are essential for normal cell physiology. Development of organs such as lungs and mammary glands requires elongation and branching of epithelial tissues which are critically depended on apical-basal polarity, cell adhesion, cell proliferation and interactions with the extracellular matrix proteins. N-WASP has also been shown to regulate cell invasion and EMT (Epithelial to Mesenchymal transition), which are often upregulated during cancer progression. Studies show that N-WASP expression is reduced in breast, colorectal and stage I lung cancer, however its role in lung cancer is not well characterized.It is known from developmental studies that majority of mammary gland development occurs during the adult stage in which extensive branching and duct elongation occurs.Ablation of N-WASP in mice using K5-Cre resulted in significantly decreased number of ducts and sub-ductal branches in the mammary gland. Immunohistochemistry showed significantly reduced number of PCNA positive cells in N-WASP KO mammary glands suggesting reduced proliferation. Moreover, N-WASP KO mammary glands also displayed significantly higher collagen content around the mammary ducts suggesting reduced invasion these ducts. In-vitro experiments with N-WASP knockdown, normal mammary epithelial cell line, MCF10A (MCF10A KD ) also showed reduced proliferation, migration, invasion and cell-cell adhesion. Re-expression of N-WASP in MCF10A KD rescued the proliferation defect suggesting N-WASP's direct role in cell proliferation.