Department of Pathology, Microbiology & Immunology, University of South Carolina School of Medicine at Columbia, Columbia, SC 29208, USA.
Department of Pathology, Microbiology & Immunology, University of South Carolina School of Medicine at Columbia, Columbia, SC 29208, USA; Inner Mongolia Agricultural University, Hohhot, Inner Mongolia, China.
Virology. 2019 Nov;537:20-30. doi: 10.1016/j.virol.2019.08.009. Epub 2019 Aug 13.
The homeodomain transcription factor SIX1 plays a critical role in embryogenesis, is not expressed in normal adult tissue, but is expressed in many malignancies, including cervical cancer. SIX1 drives the progression of HPV16-immortalized human keratinocytes (HKc/HPV16) toward malignancy: HKc/HPV16 express high levels of SIX1 mRNA and protein; overexpression of SIX1 in HKc/HPV16 produces pre-malignant, differentiation-resistant lines (HKc/DR); SIX1 overexpression in HKc/DR induces tumorigenicity. In this paper, we explore the consequences of inhibition of SIX1 expression in premalignant HKc/DR. Only partial inhibition of SIX1 expression could be obtained in HKc/DR by RNA interference. Decreased SIX1 expression (up to 80%) in HKc/DR resulted in slower proliferation, decreased HPV16-E6/E7 mRNA levels, and increased p53 protein levels. Gene expression changes induced in HKc/DR by anti-SIX1 shRNA were indicative of mesenchymal-epithelial transition (MET) and changes in TGF-beta signaling. We conclude that HPV16-transformed cells depend on SIX1 for survival, HPV16 E6/E7 gene expression and epithelial-mesenchymal transition.
同源盒转录因子 SIX1 在胚胎发生中发挥关键作用，在正常成人组织中不表达，但在许多恶性肿瘤中表达，包括宫颈癌。SIX1 驱动 HPV16 永生化人角质细胞（HKc/HPV16）向恶性肿瘤的进展：HKc/HPV16 表达高水平的 SIX1 mRNA 和蛋白；SIX1 在 HKc/HPV16 中的过表达产生了具有潜在恶性、分化抵抗的细胞系（HKc/DR）；SIX1 在 HKc/DR 中的过表达诱导了致瘤性。在本文中，我们探讨了抑制潜在恶性 HKc/DR 中 SIX1 表达的后果。通过 RNA 干扰，只能在 HKc/DR 中部分抑制 SIX1 的表达。在 HKc/DR 中，SIX1 表达的减少（高达 80%）导致增殖减慢、HPV16-E6/E7 mRNA 水平降低和 p53 蛋白水平升高。抗 SIX1 shRNA 诱导的 HKc/DR 中的基因表达变化表明间充质上皮转化（MET）和 TGF-β信号通路的变化。我们得出结论，HPV16 转化的细胞依赖于 SIX1 存活、HPV16 E6/E7 基因表达和上皮间质转化。
