Pearson Helen B, McGlinn Edwina, Phesse Toby J, Schlüter Holger, Srikumar Anuratha, Gödde Nathan J, Woelwer Christina B, Ryan Andrew, Phillips Wayne A, Ernst Matthias, Kaur Pritinder, Humbert Patrick
Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC, 3002, Australia.
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia.
Mol Cancer. 2015 Sep 17;14:169. doi: 10.1186/s12943-015-0440-z.
The 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.
To 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.
We 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.
For 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.
极性的建立和维持对胚胎发育至关重要，而极性丧失是上皮癌的常见特征，但其潜在的分子机制仍不清楚。在此，我们确定了极性蛋白Scrib的新作用，它是表皮通透性屏障形成、骨骼形态发生的介导因子，也是皮肤癌发生过程中的一种强效肿瘤抑制因子。
为了探究Scrib在表皮发育过程中的作用，我们比较了野生型、Scrib杂合子和Scrib基因敲除（KO）胚胎在E16.5、E17.5和E18.5时表皮对甲苯胺蓝染料的通透性。用阿尔新蓝和茜素红对小鼠胚胎进行染色以进行骨骼分析。为了确定Scrib在皮肤肿瘤发生和/或进展过程中是否发挥肿瘤抑制作用，我们在Scrib缺失的情况下评估了一种皮肤癌发生的原位小鼠模型。由于Scrib基因敲除胚胎在新生儿期致死，我们利用Cre-LoxP技术在成年表皮中条件性地耗尽Scrib。
我们证实Scrib在胚胎发育过程中扰乱角质形成细胞成熟，导致表皮屏障形成受损，并且Scrib是小鼠骨骼形态发生所必需的。对表皮特异性缺失Scrib的条件性转基因小鼠的分析显示没有皮肤病变，表明Scrib对正常成年表皮稳态是可有可无的。然而，在体内表皮癌发生的原位模型中，Scrib的双等位基因缺失显著增强了肿瘤的多发性和进展，证明Scrib是一种表皮肿瘤抑制因子。从机制上讲，我们表明凋亡是皮肤癌发生过程中Scrib肿瘤抑制活性的关键效应器，并为极性蛋白在DNA损伤修复过程中的功能提供了新的见解。
我们首次提供了皮肤癌发生与上皮极性调节因子Scrib缺失之间独特联系的遗传学证据，强调Scrib在上皮中发挥广泛的肿瘤抑制功能。
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