Zhang Caiming, Chen Wenhui, Pan Si, Zhang Siyu, Xie Haijing, Zhang Zixiang, Lei Wei, Bao Lili, You Yiwen
Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, China.
Institute of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, China.
Cell Death Discov. 2023 Jan 6;9(1):2. doi: 10.1038/s41420-022-01262-4.
Reliable detection of circulating small extracellular vesicles (SEVs) and their miRNA cargo has been needed to develop potential specific non-invasive diagnostic and therapeutic marker for cancer metastasis. Here, we detected miR-6750, the precise molecular function of which was largely unknown, was significantly enriched in serum-SEVs from normal volunteers vs. patients with nasopharyngeal carcinoma (NPC). And we determined that miR-6750-SEVs attenuated NPC metastasis. Subsequently, miR-6750-SEVs was proven to inhibit angiogenesis and activate macrophage toward to M1 phenotype to inhibit pre-metastatic niche formation. After analyzing the expression level of miR-6750 in NPC cells, HUVECs and macrophage, we found that once miR-6750 level in NPC cells was close to or higher than normal nasopharyngeal epithelial cells (NP69), miR-6750-SEVs would be transferred from NPC cells to macrophage and then to HUVECs to modulate metastatic niche. Moreover, in vitro assays and BALB/c mouse tumor models revealed that miR-6750 directly targeted mannose 6-phosphate receptor (M6PR). Taken together, our findings revealed that miR-6750-M6PR axis can mediate NPC metastasis by remodeling tumor microenvironment (TME) via SEVs, which give novel sights to pathogenesis of NPC.
为了开发潜在的癌症转移特异性非侵入性诊断和治疗标志物，需要可靠地检测循环小细胞外囊泡（SEV）及其miRNA货物。在这里，我们检测到miR-6750，其精确的分子功能在很大程度上未知，在正常志愿者与鼻咽癌（NPC）患者的血清SEV中显著富集。并且我们确定miR-6750-SEV减弱了NPC转移。随后，miR-6750-SEV被证明可抑制血管生成并激活巨噬细胞向M1表型转化，以抑制转移前生态位的形成。在分析NPC细胞、人脐静脉内皮细胞（HUVEC）和巨噬细胞中miR-6750的表达水平后，我们发现一旦NPC细胞中的miR-6750水平接近或高于正常鼻咽上皮细胞（NP69），miR-6750-SEV就会从NPC细胞转移到巨噬细胞，然后再转移到HUVEC，以调节转移生态位。此外，体外试验和BALB/c小鼠肿瘤模型表明，miR-6750直接靶向甘露糖6-磷酸受体（M6PR）。综上所述，我们的研究结果表明，miR-6750-M6PR轴可通过SEV重塑肿瘤微环境（TME）来介导NPC转移，这为NPC的发病机制提供了新的见解。
