Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Department of Medicine/Division of Pulmonary Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Cancer Res. 2018 Sep 1;78(17):4971-4983. doi: 10.1158/0008-5472.CAN-17-3822. Epub 2018 Jul 11.
Persistent bronchial dysplasia is associated with increased risk of developing invasive squamous cell carcinoma (SCC) of the lung. In this study, we hypothesized that differences in gene expression profiles between persistent and regressive bronchial dysplasia would identify cellular processes that underlie progression to SCC. RNA expression arrays comparing baseline biopsies from 32 bronchial sites that persisted/progressed to 31 regressive sites showed 395 differentially expressed genes [ANOVA, FDR ≤ 0.05). Thirty-one pathways showed significantly altered activity between the two groups, many of which were associated with cell-cycle control and proliferation, inflammation, or epithelial differentiation/cell-cell adhesion. Cultured persistent bronchial dysplasia cells exhibited increased expression of Polo-like kinase 1 (PLK1), which was associated with multiple cell-cycle pathways. Treatment with PLK1 inhibitor induced apoptosis and G-M arrest and decreased proliferation compared with untreated cells; these effects were not seen in normal or regressive bronchial dysplasia cultures. Inflammatory pathway activity was decreased in persistent bronchial dysplasia, and the presence of an inflammatory infiltrate was more common in regressive bronchial dysplasia. Regressive bronchial dysplasia was also associated with trends toward overall increases in macrophages and T lymphocytes and altered polarization of these inflammatory cell subsets. Increased desmoglein 3 and plakoglobin expression was associated with higher grade and persistence of bronchial dysplasia. These results identify alterations in the persistent subset of bronchial dysplasia that are associated with high risk for progression to invasive SCC. These alterations may serve as strong markers of risk and as effective targets for lung cancer prevention. Gene expression profiling of high-risk persistent bronchial dysplasia reveals changes in cell-cycle control, inflammatory activity, and epithelial differentiation/cell-cell adhesion that may underlie progression to invasive SCC. .
持续性支气管发育不良与发生侵袭性鳞状细胞癌（SCC）的风险增加相关。在这项研究中，我们假设持续性和退行性支气管发育不良之间的基因表达谱差异将确定潜在进展为 SCC 的细胞过程。比较 32 个支气管部位的基线活检，这些部位持续/进展为 31 个退行性部位，RNA 表达谱显示 395 个差异表达基因[ANOVA，FDR ≤ 0.05）。两组之间有 31 个通路的活性明显改变，其中许多与细胞周期控制和增殖、炎症或上皮分化/细胞-细胞黏附有关。培养的持续性支气管发育不良细胞表现出 Polo 样激酶 1（PLK1）的表达增加，这与多个细胞周期途径有关。与未处理的细胞相比，用 PLK1 抑制剂处理可诱导细胞凋亡和 G-M 期阻滞，并降低增殖；在正常或退行性支气管发育不良培养物中未观察到这些作用。持续性支气管发育不良中的炎症途径活性降低，退行性支气管发育不良中炎症浸润更为常见。退行性支气管发育不良也与巨噬细胞和 T 淋巴细胞总数增加以及这些炎症细胞亚群的极化改变有关。桥粒芯糖蛋白 3 和桥粒斑蛋白表达增加与支气管发育不良的高等级和持续性相关。这些结果确定了与侵袭性 SCC 进展风险较高的持续性支气管发育不良的改变。这些改变可能是风险的有力标志物，并可作为肺癌预防的有效靶点。高危持续性支气管发育不良的基因表达谱分析揭示了细胞周期控制、炎症活性和上皮分化/细胞-细胞黏附的变化，这些变化可能是进展为侵袭性 SCC 的基础。
