Abstract
BackgroundThe establishment and maintenance of polarity is vital for embryonic development and loss of polarity is a frequent characteristic of epithelial cancers, however the underlying molecular mechanisms remain unclear. Here, we identify a novel role for the polarity protein Scrib as a mediator of epidermal permeability barrier acquisition, skeletal morphogenesis, and as a potent tumor suppressor in cutaneous carcinogenesis.MethodsTo explore the role of Scrib during epidermal development, we compared the permeability of toluidine blue dye in wild-type, Scrib heterozygous and Scrib KO embryonic epidermis at E16.5, E17.5 and E18.5. Mouse embryos were stained with alcian blue and alizarin red for skeletal analysis. To establish whether Scrib plays a tumor suppressive role during skin tumorigenesis and/or progression, we evaluated an autochthonous mouse model of skin carcinogenesis in the context of Scrib loss. We utilised Cre-LoxP technology to conditionally deplete Scrib in adult epidermis, since Scrib KO embryos are neonatal lethal.ResultsWe establish that Scrib perturbs keratinocyte maturation during embryonic development, causing impaired epidermal barrier formation, and that Scrib is required for skeletal morphogenesis in mice. Analysis of conditional transgenic mice deficient for Scrib specifically within the epidermis revealed no skin pathologies, indicating that Scrib is dispensable for normal adult epidermal homeostasis. Nevertheless, bi-allelic loss of Scrib significantly enhanced tumor multiplicity and progression in an autochthonous model of epidermal carcinogenesis in vivo, demonstrating Scrib is an epidermal tumor suppressor. Mechanistically, we show that apoptosis is the critical effector of Scrib tumor suppressor activity during skin carcinogenesis and provide new insight into the function of polarity proteins during DNA damage repair.ConclusionsFor the first time, we provide genetic evidence of a unique link between skin carcinogenesis and loss of the epithelial polarity regulator Scrib, emphasizing that Scrib exerts a wide-spread tumor suppressive function in epithelia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0440-z) contains supplementary material, which is available to authorized users.
Highlights
SCRIB is a large scaffold protein containing 16 leucinerich repeats (LRRs) and 4 PDZ (PSD95-DLG1-ZO1) protein-interacting domains that interact with Discs large 1–4 (DLG1-4) and Lethal giant larvae (LGL1/2) to form the Scribble complex
To determine the role of Scrib during epidermal embryonic development, we initially examined the flank epidermis from viable wild-type (Wt) and Scrib+/− (Het) embryos compared to neonatal lethal Scrib-/- knockout (KO) embryos at E16.5, E17.5 and E18.5 (n = 8–29 per genotype and time point)
Quantitative real-time PCR analysis confirmed a significant reduction in Scrib mRNA transcript expression levels in Het and KO embryonic flank skin compared to Wt littermates at E16.5 (Fig. 1b)
Summary
SCRIB is a large scaffold protein containing 16 leucinerich repeats (LRRs) and 4 PDZ (PSD95-DLG1-ZO1) protein-interacting domains that interact with Discs large 1–4 (DLG1-4) and Lethal giant larvae (LGL1/2) to form the Scribble complex. Loss of epithelial organisation/ polarization causes aberrant embryonic morphogenesis [5–11], and is a common feature during epithelial cancer formation and progression [1–4, 7]. Scrib is required for lung morphogenesis [9] and cochlear sterociliary bundle organisation [12], underlining the possibility that Scrib universally mediates epithelial morphogenesis. The establishment and maintenance of polarity is vital for embryonic development and loss of polarity is a frequent characteristic of epithelial cancers, the underlying molecular mechanisms remain unclear. We identify a novel role for the polarity protein Scrib as a mediator of epidermal permeability barrier acquisition, skeletal morphogenesis, and as a potent tumor suppressor in cutaneous carcinogenesis
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