Cutaneous squamous cell carcinoma (cSCC) is the most common UV-induced keratinocyte-derived cancer, and its progression is characterized by the epithelial–mesenchymal transition (EMT) process. We previously demonstrated that PPARγ activation by 2,4,6-octatrienoic acid (Octa) prevents cutaneous UV damage. We investigated the possible role of the PPARγ activators Octa and the new compound (2Z,4E,6E)-2-methoxyocta-2,4,6-trienoic acid (A02) in targeting keratinocyte-derived skin cancer. Like Octa, A02 exerted a protective effect against UVB-induced oxidative stress and DNA damage in NHKs. In the squamous cell carcinoma A431 cells, A02 inhibited cell proliferation and increased differentiation markers’ expression. Moreover, Octa and even more A02 counteracted the TGF-β1-dependent increase in mesenchymal markers, intracellular ROS, the activation of EMT-related signal transduction pathways, and cells’ migratory capacity. Both compounds, especially A02, counterbalanced the TGF-β1-induced cell membrane lipid remodeling and the release of bioactive lipids involved in EMT. In vivo experiments on a murine model useful to study cell proliferation in adult animals showed the reduction of areas characterized by active cell proliferation in response to A02 topical treatment. In conclusion, targeting PPARγ may be useful for the prevention and treatment of keratinocyte-derived skin cancer.

中文翻译：

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(2Z,4E,6E)-2-methoxyocta-2,4,6-trienoic Acid 激活 PPARγ 抵消皮肤癌变过程中的上皮-间质转化过程

皮肤鳞状细胞癌 (cSCC) 是最常见的紫外线诱导的角质形成细胞来源的癌症，其进展的特点是上皮-间质转化 (EMT) 过程。我们之前证明，2,4,6-辛三烯酸 (Octa) 激活 PPARγ 可防止皮肤紫外线损伤。我们研究了 PPARγ 激活剂 Octa 和新化合物 (2Z,4E,6E)-2-methoxyocta-2,4,6-trienoic acid (A02) 在靶向角质形成细胞衍生的皮肤癌中的可能作用。与 Octa 一样，A02 对 NHK 中 UVB 诱导的氧化应激和 DNA 损伤具有保护作用。在鳞状细胞癌A431细胞中，A02抑制细胞增殖并增加分化标志物的表达。此外，Octa 甚至更多 A02 抵消了间充质标记物、细胞内 ROS、EMT 相关信号转导通路的激活和细胞迁移能力。这两种化合物，尤其是 A02，都能抵消 TGF-β1 诱导的细胞膜脂质重塑和 EMT 中涉及的生物活性脂质的释放。用于研究成年动物细胞增殖的小鼠模型的体内实验显示，响应于 A02 局部治疗，以活跃细胞增殖为特征的区域减少。总之，靶向 PPARγ 可能有助于预防和治疗角质形成细胞源性皮肤癌。用于研究成年动物细胞增殖的小鼠模型的体内实验显示，响应于 A02 局部治疗，以活跃细胞增殖为特征的区域减少。总之，靶向 PPARγ 可能有助于预防和治疗角质形成细胞源性皮肤癌。用于研究成年动物细胞增殖的小鼠模型的体内实验显示，响应于 A02 局部治疗，以活跃细胞增殖为特征的区域减少。总之，靶向 PPARγ 可能有助于预防和治疗角质形成细胞源性皮肤癌。