Center for Genomic and Precision Medicine, Texas Medical Center, Texas A&M Institute of Biosciences and Technology, Houston, TX 77030, USA.
Department of Animal Wealth Development, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt.
Int J Mol Sci. 2024 Oct 3;25(19):10674. doi: 10.3390/ijms251910674.
Several microRNAs (miRNAs), including miR-221-5p, Let-7b-5p, miR-21-5p, miR-9-5p, miR-126-3p, and miR-222-3p, were recently found to be enriched in circulating exosomes of patients with non-small cell lung cancers (NSCLCs). These miRNAs distinguished cancer cases from controls with high precision and were predicted to modulate the expression of genes within the oncogenic LINE-1 regulatory network. To test this hypothesis, plasma exosomes from controls, early, and late-stage NSCLC patients were co-cultured with non-tumorigenic lung epithelial cells for 72 h and processed for measurements of gene expression. Exosomes from late-stage NSCLC patients markedly increased the mRNA levels of LINE-1 ORF1 and ORF2, as well as the levels of target miRNAs in naïve recipient cells compared to saline or control exosomes. Late-stage exosomes also modulated the expression of oncogenic targets within the LINE-1 regulatory network, namely, ICAM1, AGL, RGS3, RGS13, VCAM1, and TGFβ1. In sharp contrast, exosomes from controls or early-stage NSCLC patients inhibited LINE-1 expression, along with many of the genetic targets within the LINE-1 regulatory network. Thus, late-stage NSCLC exosomes activate LINE-1 and miRNA-regulated oncogenic signaling in non-tumorigenic, recipient lung bronchial epithelial cells. These findings raise important questions regarding lung cancer progression and metastasis and open the door for the exploration of new therapeutic interventions.
几种 microRNAs（miRNAs），包括 miR-221-5p、Let-7b-5p、miR-21-5p、miR-9-5p、miR-126-3p 和 miR-222-3p，最近被发现在非小细胞肺癌（NSCLC）患者的循环外泌体中富集。这些 miRNAs 以高精度区分癌症病例和对照病例，并且被预测调节致癌 LINE-1 调节网络内的基因表达。为了验证这一假设，将对照、早期和晚期 NSCLC 患者的血浆外泌体与非肿瘤性肺上皮细胞共培养 72 小时，并进行基因表达测量。与生理盐水或对照外泌体相比，晚期 NSCLC 患者的外泌体显着增加了 LINE-1 ORF1 和 ORF2 的 mRNA 水平，以及幼稚受体细胞中靶 miRNAs 的水平。晚期外泌体还调节了 LINE-1 调节网络内的致癌靶标表达，即 ICAM1、AGL、RGS3、RGS13、VCAM1 和 TGFβ1。相比之下，对照或早期 NSCLC 患者的外泌体抑制 LINE-1 表达，以及 LINE-1 调节网络内的许多遗传靶标。因此，晚期 NSCLC 外泌体激活非肿瘤性、受体肺支气管上皮细胞中的 LINE-1 和 miRNA 调节的致癌信号。这些发现提出了有关肺癌进展和转移的重要问题，并为探索新的治疗干预措施开辟了道路。
