Akladios Bassem, Mendoza Reinoso Veronica, Cain Jason E, Wang Taopeng, Lambie Duncan L, Watkins D Neil, Beverdam Annemiek
School of Medical Sciences, UNSW Sydney, New South Wales, Sydney, Australia.
Hudson Institute of Medical Research, Clayton, Victoria, Australia.
PLoS One. 2017 Aug 18;12(8):e0183178. doi: 10.1371/journal.pone.0183178. eCollection 2017.
Skin is a highly plastic tissue that undergoes tissue turnover throughout life, but also in response to injury. YAP and Hedgehog signalling play a central role in the control of epidermal stem/progenitor cells in the skin during embryonic development, in postnatal tissue homeostasis and in skin carcinogenesis. However, the genetic contexts in which they act to control tissue homeostasis remain mostly unresolved. We provide compelling evidence that epidermal YAP and Hedgehog/GLI2 signalling undergo positive regulatory interactions in the control of normal epidermal homeostasis and in basal cell carcinoma (BCC) development, which in the large majority of cases is caused by aberrant Hedgehog signalling activity. We report increased nuclear YAP and GLI2 activity in the epidermis and BCCs of K14-CreER/Rosa-SmoM2 transgenic mouse skin, accompanied with increased ROCK signalling and ECM remodelling. Furthermore, we found that epidermal YAP activity drives GLI2 nuclear accumulation in the skin of YAP2-5SA-ΔC mice, which depends on epidermal β-catenin activation. Lastly, we found prominent nuclear activity of GLI2, YAP and β-catenin, concomitant with increased ROCK signalling and stromal fibrosis in human BCC. Our work provides novel insights into the molecular mechanisms underlying the interplay between cell signalling events and mechanical force in normal tissue homeostasis in vivo, that could potentially be perturbed in BCC development.
皮肤是一种高度可塑性的组织，其在整个生命过程中都会经历组织更新，在受到损伤时也是如此。YAP和Hedgehog信号通路在胚胎发育期间、出生后组织稳态维持以及皮肤癌发生过程中，对皮肤表皮干细胞/祖细胞的调控起着核心作用。然而，它们在控制组织稳态过程中发挥作用的遗传背景大多仍未明确。我们提供了令人信服的证据，表明表皮YAP和Hedgehog/GLI2信号通路在正常表皮稳态维持和基底细胞癌（BCC）发生过程中存在正向调节相互作用，而在大多数情况下，基底细胞癌是由异常的Hedgehog信号活性引起的。我们报告了在K14-CreER/Rosa-SmoM2转基因小鼠皮肤的表皮和基底细胞癌中，核YAP和GLI2活性增加，同时伴有ROCK信号通路增强和细胞外基质重塑。此外，我们发现表皮YAP活性在YAP2-5SA-ΔC小鼠皮肤中驱动GLI2核积累，这依赖于表皮β-连环蛋白的激活。最后，我们在人类基底细胞癌中发现了GLI2、YAP和β-连环蛋白的显著核活性，同时伴有ROCK信号通路增强和基质纤维化。我们的工作为体内正常组织稳态中细胞信号事件与机械力之间相互作用的分子机制提供了新的见解，而这种相互作用在基底细胞癌发生过程中可能会受到干扰。
