EMBO Mol Med. 2014 Jan;6(1):80-98. doi: 10.1002/emmm.201302666.
Although non-melanoma skin cancer (NMSC) is the most common human cancer and its incidence continues to rise worldwide, the mechanisms underlying its development remain incompletely understood. Here, we unveil a cascade of events involving peroxisome proliferator-activated receptor (PPAR) β/δ and the oncogene Src, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPARβ/δ activity, which directly stimulated Src expression, increased Src kinase activity and enhanced the EGFR/Erk1/2 signalling pathway, resulting in increased epithelial-to-mesenchymal transition (EMT) marker expression. Consistent with these observations, PPARβ/δ-null mice developed fewer and smaller skin tumours, and a PPARβ/δ antagonist prevented UV-dependent Src stimulation. Furthermore, the expression of PPARβ/δ positively correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma (SCC), and critically, linear models applied to several human epithelial cancers revealed an interaction between PPARβ/δ and SRC and TGFβ1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARβ/δ modulators to attenuate the development of several epithelial cancers.
尽管非黑色素瘤皮肤癌（NMSC）是最常见的人类癌症，且其发病率在全球范围内持续上升，但它的发展机制仍不完全清楚。在这里，我们揭示了一系列事件，涉及过氧化物酶体增殖物激活受体（PPAR）β/δ 和原癌基因 Src，它们促进了小鼠中紫外线（UV）诱导的皮肤癌的发展。UV 诱导的 PPARβ/δ 活性直接刺激了 Src 的表达，增加了 Src 激酶活性，并增强了 EGFR/Erk1/2 信号通路，导致上皮间质转化（EMT）标志物的表达增加。与这些观察结果一致的是，PPARβ/δ 缺失小鼠皮肤肿瘤的数量更少、体积更小，PPARβ/δ 拮抗剂可预防 UV 依赖性 Src 刺激。此外，在人类皮肤鳞状细胞癌（SCC）中，PPARβ/δ 的表达与 SRC 和 EMT 标志物的表达呈正相关，而且重要的是，应用于几种人类上皮癌的线性模型揭示了 PPARβ/δ 和 SRC 以及 TGFβ1 转录水平之间的相互作用。综上所述，这些观察结果促使未来评估 PPARβ/δ 调节剂以减轻几种上皮癌的发展。
