2J.-C.W., National Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China.
FASEB J. 2013 Oct;27(10):4194-203. doi: 10.1096/fj.13-229070. Epub 2013 Jun 26.
Deregulation of promyelocytic leukemia zinc finger protein (PLZF), a tumor suppressor gene, was reported in different types of solid tumors. This study for the first time explored the reduced expression of PLZF and its effects in non-small-cell lung cancer (NSCLC) carcinogenesis. PLZF was found to be down-regulated by 62.8% in 87.1% of 154 paired NSCLC samples by quantitative real-time PCR, and its expression was found to be associated with the sex of the patient (P=0.02). Further analysis showed that down-regulation of PLZF in 35.6% NSCLC samples (31 out of 87) was triggered by hypermethylation in the promoter region. This was validated by demethylation analysis using the A549 cell line. Dual-luciferase reporter assay indicated that CTCF binding to the promoter region could activate PLZF transcription. Overexpression of PLZF in both A549 and LTEP lung cancer cell lines was found to inhibit proliferation and increase apoptosis. Therefore, reduced expression of PLZF was found to be common in NSCLC. PLZF down-regulation was partially correlated with hypermethylation in the promoter region. Decreased levels of PLZF expression may contribute to the pathogenesis of NSCLC by promoting cell survival. Therefore, the restoration of PLZF expression may serve as a new strategy for NSCLC therapy.
早幼粒细胞白血病锌指蛋白（PLZF）作为一种肿瘤抑制基因，其失调已在多种实体肿瘤中被报道。本研究首次探讨了 PLZF 在非小细胞肺癌（NSCLC）发生过程中的下调及其作用。通过实时定量 PCR 检测，发现 154 对 NSCLC 样本中 87.1%的样本中 PLZF 的表达下调了 62.8%，其表达与患者的性别有关（P=0.02）。进一步分析显示，在 35.6%（31/87）的 NSCLC 样本中，PLZF 的下调是由启动子区域的高甲基化触发的。这一发现通过 A549 细胞系的去甲基化分析得到了验证。双荧光素酶报告基因检测表明，CTCF 与启动子区域的结合可以激活 PLZF 的转录。在 A549 和 LTEP 肺癌细胞系中过表达 PLZF 后，发现细胞增殖受到抑制，凋亡增加。因此，PLZF 的下调在 NSCLC 中很常见。PLZF 下调与启动子区域的高甲基化部分相关。PLZF 表达水平的降低可能通过促进细胞存活而促进 NSCLC 的发病机制。因此，恢复 PLZF 的表达可能成为 NSCLC 治疗的一种新策略。
