Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
FEBS Lett. 2013 Nov 1;587(21):3581-6. doi: 10.1016/j.febslet.2013.09.023. Epub 2013 Sep 23.
Cisplatin-induced and ATM-phosphorylated (p)-ΔNp63α regulates the expression of epidermal differentiation and skin barrier regulators (AQP3, CASP14, ALOX12B, and CLDN1) in squamous cell carcinoma (SCC) cells by dual transcriptional and post-transcriptional mechanisms. We found that p-ΔNp63α bound to target gene promoters, and regulated the activity of the tested promoters in vitro. P-ΔNp63α was shown to upregulate miR-185-5p and downregulate let7-5p, which subsequently modulated AQP3, CASP14, ALOX12B and CLDN1 through their respective 3'-untranslated regions. The introduction of miR-185-5p into resistant SCC-11M cells, which are unable to phosphorylate ΔNp63α, render these cells more sensitive to cisplatin treatment. Further studies of the AQP3, CASP14, ALOX12B, and CLDN1 contributions to chemoresistance may assist in developing novel microRNA-based therapies for human SCC.
顺铂诱导和 ATM 磷酸化（p）-ΔNp63α 通过双重转录和转录后机制调节鳞状细胞癌（SCC）细胞中表皮分化和皮肤屏障调节剂（AQP3、CASP14、ALOX12B 和 CLDN1）的表达。我们发现 p-ΔNp63α 结合到靶基因启动子上，并在体外调节测试启动子的活性。p-ΔNp63α 被证明可以上调 miR-185-5p 并下调 let7-5p，随后通过各自的 3'非翻译区调节 AQP3、CASP14、ALOX12B 和 CLDN1。将 miR-185-5p 引入无法磷酸化 ΔNp63α 的耐药 SCC-11M 细胞中，使这些细胞对顺铂治疗更敏感。对 AQP3、CASP14、ALOX12B 和 CLDN1 对化疗耐药性的贡献的进一步研究可能有助于开发针对人类 SCC 的新型基于 microRNA 的治疗方法。
