Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, 58# Zhongshan Road II, Guangzhou 510080, China.
Department of Otorhinolaryngology, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, No. 82, Qinglong Street, Qingyang District, Chengdu, Sichuan 610014, China.
Carcinogenesis. 2024 Sep 11;45(9):642-657. doi: 10.1093/carcin/bgae030.
Laryngeal cancer (LC) is the second most common head and neck cancer and has a decreasing 5-year survival rate worldwide. Circular RNAs (circRNAs) regulate cancer development in diverse ways based on their distinct biogenesis mechanisms and expansive regulatory roles. However, currently, there is little research on how exosomal circRNAs are involved in the development of LC. Here, we demonstrated that circPVT1, a circRNA derived from the well-studied long noncoding RNA PVT1, is correlated with disease progression in LC and promotes angiogenesis both in vivo and in vitro. Mechanistically, circPVT1 is loaded into LC cell-secreted exosomes and taken up by vascular epithelium cells. By sponging miR-30c-5p, exosomal circPVT1 promotes Rap1b expression, which dramatically enhances vascular endothelial growth factor receptor 2 and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation, ultimately resulting in the induction of angiogenesis. Furthermore, our xenograft models demonstrated that the combination of short hairpin RNA-circPVT1 and cetuximab showed high efficacy in inhibiting tumor growth and angiogenesis. Collectively, these findings uncover a novel mechanism of exosomal circRNA-mediated angiogenesis modulation and provide a preclinical rationale for testing this analogous combination in patients with LC.
喉癌(LC)是第二大常见的头颈部癌症,其全球 5 年生存率呈下降趋势。环状 RNA(circRNA)根据其不同的生物发生机制和广泛的调控作用,以多种方式调节癌症的发生发展。然而,目前关于外泌体 circRNA 如何参与 LC 发展的研究较少。在这里,我们证明了来源于研究充分的长链非编码 RNA PVT1 的 circPVT1 是与 LC 疾病进展相关的,并在体内和体外均促进血管生成。在机制上,circPVT1 被装载到 LC 细胞分泌的外泌体中,并被血管上皮细胞摄取。通过海绵吸附 miR-30c-5p,外泌体 circPVT1 促进 Rap1b 表达,从而显著增强血管内皮生长因子受体 2 和磷脂酰肌醇 3-激酶(PI3K)/AKT 通路的激活,最终诱导血管生成。此外,我们的异种移植模型表明,短发夹 RNA-circPVT1 和西妥昔单抗的联合使用在抑制肿瘤生长和血管生成方面具有很高的疗效。总之,这些发现揭示了外泌体 circRNA 介导的血管生成调节的新机制,并为在 LC 患者中测试这种类似组合提供了临床前依据。