Institute of Biochemistry and Molecular Biology, Collaborative Innovation Center for antitumor active substance research and development, Guangdong Medical University, Zhanjiang, China.
Center for Laboratory Medicine, Department of Blood Transfusion, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Cancer Biol Ther. 2022 Dec 31;23(1):1-13. doi: 10.1080/15384047.2022.2133332.
Our previous studies have demonstrated that human papillomavirus (HPV)-16 E7 oncoprotein promoted epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC) cells. Moreover, recent studies have found that exosomes can mediate EMT of NSCLC cells and epidermal growth factor receptor (EGFR) is related to the progression of NSCLC. Here, we further investigated the role of exosomal EGFR in HPV-16 E7-induced EMT of NSCLC cells. Our results showed that the exosomes derived from the stable HPV-16 E7-overexpressing A549 and NCI-H460 NSCLC cells (E7 Exo) significantly increased migration, invasion, and proliferation abilities of NSCLC cells as compared with the exosomes derived from empty vector-infected NSCLC cells (ev Exo). Moreover, both and results demonstrated that E7 Exo dramatically enhanced EMT of NSCLC cells and promoted the growth of subcutaneous NSCLC xenografts. Additionally, HPV-16 E7 enhanced the expression of EGFR and p-EGFR in both NSCLC cells and exosomes. Furthermore, the inhibition of EGFR activation or exosome secretion suppressed E7 Exo-induced migration, invasion, and EMT of NSCLC. Moreover, 12 kinds of differentially expressed miRNAs between E7 Exo and ev Exo (fold change≥2, ≤ .05) were screened out, of which 7 miRNAs were up-regulated while 5 miRNAs were down-regulated in A549 E7 Exo. Taken together, our findings suggest that exosomal EGFR is involved in HPV-16 E7-induced EMT of NSCLC cells, which may play a key role in the progression of HPV-related NSCLC.
我们之前的研究表明，人乳头瘤病毒（HPV）-16 E7 癌蛋白促进非小细胞肺癌（NSCLC）细胞发生上皮-间充质转化（EMT）。此外，最近的研究发现外泌体可以介导 NSCLC 细胞的 EMT，表皮生长因子受体（EGFR）与 NSCLC 的进展有关。在这里，我们进一步研究了外泌体 EGFR 在 HPV-16 E7 诱导的 NSCLC 细胞 EMT 中的作用。我们的结果表明，与空载体感染的 NSCLC 细胞来源的外泌体（ev Exo）相比，稳定过表达 HPV-16 E7 的 A549 和 NCI-H460 NSCLC 细胞来源的外泌体（E7 Exo）显著增加了 NSCLC 细胞的迁移、侵袭和增殖能力。此外，和结果均表明，E7 Exo 显著增强了 NSCLC 细胞的 EMT，并促进了皮下 NSCLC 异种移植物的生长。此外，HPV-16 E7 增强了 NSCLC 细胞及其外泌体中 EGFR 和 p-EGFR 的表达。此外，EGFR 激活或外泌体分泌的抑制抑制了 E7 Exo 诱导的 NSCLC 迁移、侵袭和 EMT。此外，筛选出 E7 Exo 和 ev Exo 之间有 12 种差异表达的 miRNA（倍数变化≥2，P≤0.05），其中 A549 E7 Exo 中有 7 个 miRNA 上调，5 个 miRNA 下调。总之，我们的研究结果表明，外泌体 EGFR 参与 HPV-16 E7 诱导的 NSCLC 细胞 EMT，这可能在 HPV 相关 NSCLC 的进展中起关键作用。
