Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary London University, London, UK.
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary London University, London, UK.
J Invest Dermatol. 2019 Aug;139(8):1658-1671.e8. doi: 10.1016/j.jid.2019.01.020. Epub 2019 Jan 30.
Keratinocyte skin cancer, comprising cutaneous squamous (cSCC) and basal cell carcinoma, is the most common malignancy in the United Kingdom. P53 is frequently mutated in cSCC. iASPP is a key inhibitor of p53 and NF-κB signaling pathways and has been documented as highly expressed in several types of human cancer. We have previously identified an autoregulatory feedback loop between iASPP and p63, which is critical in epidermal homeostasis. We hypothesized a potential role for dysregulation of this axis in the pathogenesis of keratinocyte malignancies. Immunostaining of 116 cSCC clinical samples revealed increased iASPP and ΔNp63 expression, but also highlighted a significant alteration of iASPP cellular localization, with consequent deregulation of its function. Expression patterns, functionality, and gene and microRNA expression analysis were further investigated in 10 cSCC cell lines. Our data suggest that while direct effects of iASPP and p63 upon each other's expression are maintained in cSCC, epigenetic dysregulation of the feedback loop occurs at the microRNA level by a previously unreported mechanism controlling p63 expression. We demonstrate that this autoregulatory feedback loop controls cell migration in cSCC by blocking epithelial-mesenchymal transition and promoting proliferation, and provides future directions for clinical biomarker and therapeutic target discovery in cutaneous SCC.
角朊细胞皮肤癌包括皮肤鳞状细胞癌 (cSCC) 和基底细胞癌，是英国最常见的恶性肿瘤。p53 在 cSCC 中经常发生突变。iASPP 是 p53 和 NF-κB 信号通路的关键抑制剂，已在多种人类癌症中被证实高表达。我们之前已经确定了 iASPP 和 p63 之间的自动反馈回路，这对表皮稳态至关重要。我们假设该轴的失调在角朊细胞恶性肿瘤的发病机制中可能起作用。对 116 例 cSCC 临床样本的免疫染色显示 iASPP 和 ΔNp63 表达增加，但也突出了 iASPP 细胞定位的显著改变，从而导致其功能失调。在 10 种 cSCC 细胞系中进一步研究了表达模式、功能以及基因和 microRNA 表达分析。我们的数据表明，尽管 iASPP 和 p63 对彼此表达的直接影响在 cSCC 中得以维持，但通过以前未报道的机制，在 microRNA 水平上发生了反馈回路的表观遗传失调，从而控制 p63 的表达。我们证明，这个自动反馈回路通过阻断上皮-间充质转化并促进增殖来控制 cSCC 中的细胞迁移，并为皮肤 SCC 的临床生物标志物和治疗靶标发现提供了未来的方向。
