Chen Haiyan, Wang Xusheng, Chen Yu, Han Jimin, Kong Deqiang, Zhu Meizhong, Fu Xiaobing, Wu Yaojiong
Tsinghua-Berkeley Shenzhen Institute (TBSI), Tsinghua University, Guangdong, China.
State Key Laboratory of Chemical Oncogenomics, and the Shenzhen Key Laboratory of Health Sciences and Technology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong, China.
Theranostics. 2019 Oct 22;9(26):8321-8331. doi: 10.7150/thno.35467. eCollection 2019.
Accumulating data support that tissue stem cells give rise to cancer cells. Hair follicle stem cells (HFSCs) undergo cyclic quiescence and activation and may sever as the origin of cutaneous squamous cell carcinoma (SCC). is a tumor suppressor gene that is frequently mutated in hereditary cancer syndromes such as Cowden disease, which is featured with papillomatosis in cutaneous tissues and hyperkeratosis in the acral region of the skin. Additionally, mice with keratinocyte-specific deficiency ( mice) show epidermal hyperplasia and spontaneous tumor formation. However, the impact of mutation in HFSCs, such as in Lgr5 HFSCs, on SCC formation is unclear. : We established experiments with wildtype and mice, and used DMBA/TPA two-stage skin carcinogenesis model to explore the effect of loss in Lgr5 HFSCs of 3 weeks old mice in skin carcinogenesis. experiments (cell culture and protein expression analysis) are employed to investigate molecular mechanisms involved. : loss in Lgr5 HFSCs promoted SCC formation, which was attenuated in mice. Notably, β-catenin loss in Lgr5 HFSCs decreased the formation of SCC. In addition, loss in cultured epidermal stem cells upregulated the levels of both phospho-Akt and β-catenin. : loss in Lgr5 cells induced Akt/β-catenin signaling, and SCCs can subsequently be raised as progeny from these primed Lgr5 stem cells.
越来越多的数据支持组织干细胞会产生癌细胞。毛囊干细胞（HFSCs）经历周期性静止和激活，可能是皮肤鳞状细胞癌（SCC）的起源。是一种肿瘤抑制基因，在遗传性癌症综合征如考登病中经常发生突变，考登病的特征是皮肤组织出现乳头瘤病和皮肤远端区域出现角化过度。此外，角质形成细胞特异性缺陷小鼠表现出表皮增生和自发肿瘤形成。然而，HFSCs中的突变，如Lgr5 HFSCs中的突变，对SCC形成的影响尚不清楚。方法：我们建立了野生型和小鼠的实验，并使用二甲基苯并蒽/十四酰佛波醇乙酯两阶段皮肤致癌模型来探讨3周龄小鼠Lgr5 HFSCs中缺失在皮肤致癌中的作用。采用实验（细胞培养和蛋白质表达分析）来研究其中涉及的分子机制。结果：Lgr5 HFSCs中的缺失促进了SCC的形成，而在小鼠中这种促进作用减弱。值得注意的是，Lgr5 HFSCs中β-连环蛋白的缺失减少了SCC的形成。此外，培养的表皮干细胞中的缺失上调了磷酸化Akt和β-连环蛋白的水平。结论：Lgr5细胞中的缺失诱导了Akt/β-连环蛋白信号传导，随后这些被激活的Lgr5干细胞的后代可能会引发SCC。
