Dysregulation of microRNAs is a common mechanism in the development of lung cancer, but the relationship between microRNAs and expression subtypes in non-small-cell lung cancer (NSCLC) is poorly explored. Here, we analyzed microRNA expression from 241 NSCLC samples and correlated this with the expression subtypes of adenocarcinomas (AD) and squamous cell carcinomas (SCC) to identify microRNAs specific for each subtype. Gene set variation analysis and the hallmark gene set were utilized to calculate gene set scores specific for each sample, and these were further correlated with the expression of the subtype-specific microRNAs. In ADs, we identified nine aberrantly regulated microRNAs in the terminal respiratory unit (TRU), three in the proximal inflammatory (PI), and nine in the proximal proliferative subtype (PP). In SCCs, 1, 5, 5, and 9 microRNAs were significantly dysregulated in the basal, primitive, classical, and secretory subtypes, respectively. The subtype-specific microRNAs were highly correlated to specific gene sets, and a distinct pattern of biological processes with high immune activity for the AD PI and SCC secretory subtypes, and upregulation of cell cycle-related processes in AD PP, SCC primitive, and SCC classical subtypes were found. Several in silico predicted targets within the gene sets were identified for the subtype-specific microRNAs, underpinning the findings. The results were significantly validated in the LUAD (n = 492) and LUSC (n = 380) TCGA dataset (False discovery rates-corrected P-value < 0.05). Our study provides novel insight into how expression subtypes determined with discrete biological processes may be regulated by subtype-specific microRNAs. These results may have importance for the development of combinatory therapeutic strategies for lung cancer patients.

中文翻译：

---

鉴定参与表征NSCLC表达亚型的途径的microRNA。

microRNA的失调是肺癌发展中的常见机制，但在非小细胞肺癌（NSCLC）中，microRNA与表达亚型之间的关系却鲜为人知。在这里，我们分析了241个NSCLC样品中的microRNA表达，并将其与腺癌（AD）和鳞状细胞癌（SCC）的表达亚型相关联，以鉴定每种亚型特异的microRNA。利用基因组变异分析和标志性基因组计算每个样品特有的基因组评分，并将这些评分进一步与亚型特异性microRNA的表达相关。在AD中，我们在末端呼吸单元（TRU）中鉴定了9个异常调节的microRNA，在近端炎症（PI）中鉴定了3个，在近端增殖亚型（PP）中鉴定了9个。在SCC中，1、5、5 分别有9种microRNA在基础，原始，经典和分泌性亚型中失调。亚型特异性microRNA与特定基因组高度相关，并且具有独特的生物学过程模式，对AD PI和SCC分泌性亚型具有高免疫活性，并且在AD PP，SCC原始和SCC中细胞周期相关过程上调发现了经典亚型。基因组中的几个计算机模拟预测靶标被确定为亚型特异性microRNA，从而支持了这一发现。结果在LUAD（n = 492）和LUSC（n = 380）TCGA数据集中得到了有效验证（错误发现率校正的P值<0.05）。我们的研究提供了新的见解，以了解如何通过亚型特异性microRNA调节由离散的生物过程确定的表达亚型。这些结果可能对开发肺癌患者的联合治疗策略具有重要意义。