The polarity protein Scrib mediates epidermal development and exerts a tumor suppressive function during skin carcinogenesis

Molecular Cancer

Research

Edwina McGlinn¹  Anuratha Srikumar²  Christina B. Woelwer²  Nathan J. Gödde²  Holger Schlüter³  Helen B. Pearson⁴  Pritinder Kaur⁴  Patrick Humbert⁵  Wayne A. Phillips⁶  Andrew Ryan⁷  Toby J. Phesse⁸  Matthias Ernst⁸ 

[1] EMBL Australia, Australian Regenerative Medicine Institute, Monash University, 3800, Clayton, VIC, Australia;Peter MacCallum Cancer Centre, St Andrew’s Place, 3002, East Melbourne, VIC, Australia;Peter MacCallum Cancer Centre, St Andrew’s Place, 3002, East Melbourne, VIC, Australia;Present address: National Center for Tumor Diseases Heidelberg (NCT), German Cancer Research Centre (DKFZ), 69120, Heidelberg, Germany;Peter MacCallum Cancer Centre, St Andrew’s Place, 3002, East Melbourne, VIC, Australia;Sir Peter MacCallum Department of Oncology, The University of Melbourne, 3010, Parkville, VIC, Australia;Peter MacCallum Cancer Centre, St Andrew’s Place, 3002, East Melbourne, VIC, Australia;Sir Peter MacCallum Department of Oncology, The University of Melbourne, 3010, Parkville, VIC, Australia;Department of Pathology, The University of Melbourne, 3010, Parkville, VIC, Australia;Department of Biochemistry and Molecular Biology, The University of Melbourne, 3010, Parkville, VIC, Australia;Peter MacCallum Cancer Centre, St Andrew’s Place, 3002, East Melbourne, VIC, Australia;Sir Peter MacCallum Department of Oncology, The University of Melbourne, 3010, Parkville, VIC, Australia;Department of Surgery (St. Vincent’s Hospital), The University of Melbourne, 3010, Parkville, VIC, Australia;TissuPath Laboratories, 3149, Mount Waverley, VIC, Australia;Walter and Eliza Hall Institute of Medical Research, 3052, Melbourne, VIC, Australia;Present address: Olivia Newton-John Cancer Research Institute and School of Cancer Medicine at La Trobe University, 3084, Heidelberg, VIC, Australia;

关键词: Polarity;    Scrib;    Skin;    Carcinogenesis;    Permeability barrier;   

DOI  :  10.1186/s12943-015-0440-z

 received in 2015-05-15, accepted in 2015-08-31,  发布年份 2015

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© Pearson et al. 2015