PTEN缺失诱导自分泌FGF信号传导以促进皮肤肿瘤发生。
Pten loss induces autocrine FGF signaling to promote skin tumorigenesis.
作者信息
Hertzler-Schaefer Kristina, Mathew Grinu, Somani Ally-Khan, Tholpady Sunil, Kadakia Madhavi P, Chen Yiping, Spandau Dan F, Zhang Xin
机构信息
Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
Departments of Ophthalmology, Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
出版信息
Cell Rep. 2014 Mar 13;6(5):818-26. doi: 10.1016/j.celrep.2014.01.045. Epub 2014 Feb 27.
Inactivation of the Pten tumor suppressor negatively regulates the PI3K-mTOR pathway. In a model of cutaneous squamous cell carcinoma (SCC), we demonstrate that deletion of Pten strongly elevates Fgf10 protein levels without increasing Fgf10 transcription in vitro and in vivo. The translational activation of Fgf10 by Pten deletion is reversed by genetic disruption of the mTORC1 complex, which also prevents skin tumorigenesis in Pten mutants. We further show that ectopic expression of Fgf10 causes skin papillomas, whereas Pten deletion-induced skin tumors are inhibited by epidermal deletion of Fgfr2. Collectively, our data identify autocrine activation of FGF signaling as an essential mechanism in promoting Pten-deficient skin tumors.
抑癌基因Pten的失活对PI3K-mTOR信号通路起负向调控作用。在皮肤鳞状细胞癌（SCC）模型中，我们证明，在体外和体内，Pten基因的缺失均能在不增加Fgf10转录的情况下显著提高Fgf10蛋白水平。mTORC1复合体的基因破坏可逆转因Pten缺失导致的Fgf10翻译激活，这也能预防Pten突变体中的皮肤肿瘤发生。我们进一步表明，Fgf10的异位表达会导致皮肤乳头状瘤，而Fgfr2的表皮缺失可抑制因Pten缺失诱导产生的皮肤肿瘤。总体而言，我们的数据表明FGF信号的自分泌激活是促进Pten缺陷型皮肤肿瘤的关键机制。
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