Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108; email:
Annu Rev Physiol. 2015;77:453-74. doi: 10.1146/annurev-physiol-021014-072018.
The reprogramming of the epigenome through silencing of genes and microRNAs by cytosine DNA methylation and chromatin remodeling is critical for the initiation and progression of lung cancer through affecting all major cell regulatory pathways. Importantly, the fact that epigenetic reprogramming is reversible by pharmacological agents has opened new avenues for clinical intervention. This review focuses on the tremendous progress made in elucidating genes and microRNAs that are epigenetically silenced in lung cancer and highlights how loss of function impacts cell phenotype and major signaling pathways. The article describes the utility of (a) an in vitro model using hTERT/Cdk4 immortalized human bronchial epithelial cell lines to identify genes and microRNAs silenced during premalignancy and (b) an in vivo orthotopic nude rat lung cancer model to evaluate response to epigenetic therapy. New insights regarding the advantage of aerosol delivery of demethylating agents and the concept of priming tumors for subsequent therapy are presented and discussed.
通过胞嘧啶 DNA 甲基化和染色质重塑沉默基因和 microRNAs，重新编程表观基因组，对于通过影响所有主要的细胞调控途径启动和促进肺癌的发生至关重要。重要的是，表观遗传重编程可以通过药理学药物逆转的事实为临床干预开辟了新的途径。本文重点介绍了在阐明肺癌中表观遗传沉默的基因和 microRNAs 方面所取得的巨大进展，并强调了功能丧失如何影响细胞表型和主要信号通路。本文描述了（a）使用 hTERT/Cdk4 永生化人支气管上皮细胞系的体外模型来鉴定在癌前病变期间沉默的基因和 microRNAs，以及（b）体内原位裸鼠肺癌模型来评估对表观遗传治疗的反应的应用。本文还提出并讨论了关于雾化递送去甲基化剂的优势的新见解，以及为后续治疗对肿瘤进行预处理的概念。
