Background: MicroRNAs (miRNAs) modulate the expression of oncogenes and tumor suppressor genes, functioning as significant epigenetic regulators in cancer. IsomiRs are miRNA molecules that have undergone small modifications during miRNA processing. These modifications can alter an isomiR’s binding stability with mRNA targets, and certain isomiRs have been implicated in the development of specific cancers. Still, the isomiRomes of many tissues, including the lung, have not been characterized; Methods: In this study, we analyzed small RNA sequencing data for three cohorts of lung adenocarcinoma (LUAD) and adult non-malignant lung (ANL) samples. Results: We quantified isomiR expression and found 16 A-to-I edited isomiRs expressed in multiple cohorts, as well as 213 5′ isomiRs, 128 3′ adenylated isomiRs, and 100 3′ uridylated isomiRs. Rates of A-to-I editing at editing hotspots correlated with mRNA expression of the editing enzymes ADAR and ADARB1, which were both observed to be deregulated in LUAD. LUAD samples displayed lower overall rates of A-to-I editing and 3′ adenylation than ANL samples. Support vector machines and random forest models were trained on one cohort to distinguish ANL and stage I/II LUAD samples using reads per million (RPM) and frequency data for different types of isomiRs. Models trained on A-to-I editing rates at editing hotspots displayed high accuracy when tested on the other two cohorts and compared favorably to classifiers trained on miRNA expression alone; Conclusions: We have identified isomiRs in the human lung and found that their expression differs between non-malignant and tumor tissues, suggesting they hold potential as cancer biomarkers.
背景：微小RNA（miRNA）通过调控癌基因和抑癌基因的表达，在癌症中发挥重要的表观遗传调控作用。同源异构miRNA（isomiR）是在miRNA加工过程中发生微小修饰的miRNA分子。这些修饰可能改变isomiR与mRNA靶标的结合稳定性，某些isomiR已被证实与特定癌症的发生发展相关。然而，包括肺组织在内的多种组织的isomiR组尚未得到系统解析。方法：本研究分析了三组肺腺癌（LUAD）和成人非恶性肺组织（ANL）样本的小RNA测序数据。结果：我们定量检测了isomiR表达水平，发现16个A-to-I编辑型isomiR在多个队列中表达，同时鉴定出213个5′端异构型isomiR、128个3′端腺苷酸化isomiR和100个3′端尿苷酸化isomiR。编辑热点区域的A-to-I编辑率与编辑酶ADAR和ADARB1的mRNA表达水平呈正相关，这两种酶在LUAD中均呈现表达失调。与ANL样本相比，LUAD样本的总体A-to-I编辑率和3′端腺苷酸化水平显著降低。基于一个队列样本，我们采用支持向量机和随机森林模型，利用不同类型isomiR的每百万读数（RPM）和频率数据来区分ANL与I/II期LUAD样本。以编辑热点区域A-to-I编辑率构建的模型在另外两个队列测试中表现出高准确度，其分类性能优于仅基于miRNA表达构建的分类器。结论：本研究首次系统鉴定了人肺组织中的isomiR，并发现其在非恶性与肿瘤组织间存在差异表达，提示其具有作为癌症生物标志物的潜力。
肿瘤(癌症)患者之家