Chen Wen-Ju, Dai Ying-Jie, Gu Wan-Hong, Zhang Chun-Ling, Wang Yi-Chao
Department of Clinical Laboratory Medicine, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China.
J Biochem Mol Toxicol. 2025 Mar;39(3):e70148. doi: 10.1002/jbt.70148.
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Unfortunately, the effective targeted therapies for HCC are lacking at present. While the regulation of microRNA-1246 (miR-1246) has been identified in HCC, its specific mechanism in exosomes derived from HCC remains elusive. This study aimed to explore the regulation of tumor-derived exosome miR-1246 in HCC cell invasion, migration, proliferation, and epithelial-mesenchymal transition (EMT).
Exosomes secreted by HepG2 cells were characterized via Western blotting, nanoparticle tracking analysis, and transmission electron microscopy, followed by transfection with a miR-1246 inhibitor. RT-qPCR was employed for measuring the miR-1246 levels. Also, the impacts of the exosome miR-1246 inhibitor on HepG2 cell migration, invasion, proliferation, and EMT were evaluated.
The findings revealed elevated miR-1246 levels in HCC tissues relative to adjacent non-cancerous tissues, with a greater enrichment of miR-1246 in HepG2-derived exosomes than in HepG2 cells. HCC cell invasion, migration, proliferation, and EMT were significantly enhanced by HCC-derived exosomes, while exosomes loaded with miR-1246 inhibitor inhibited these biological functions. Further mechanistic studies illustrated an association of the regulatory role of miR-1246 with FSTL5 and ERK/p38 MAPK signaling.
In conclusion, tumor-derived miR-1246 enters hepatocellular carcinoma cells in the form of exosomes and promotes cancer cell invasion, EMT, and migration. The potential mechanism of miR-1246 is potentially relevant to the targeted gene FSTL5 as well as the ERK/p38 signaling.
肝细胞癌（HCC）是全球最常见的恶性肿瘤之一。不幸的是，目前缺乏针对HCC的有效靶向治疗方法。虽然已在HCC中鉴定出微小RNA-1246（miR-1246）的调控作用，但其在HCC来源的外泌体中的具体机制仍不清楚。本研究旨在探讨肿瘤来源的外泌体miR-1246对HCC细胞侵袭、迁移、增殖和上皮-间质转化（EMT）的调控作用。
通过蛋白质免疫印迹、纳米颗粒跟踪分析和透射电子显微镜对HepG2细胞分泌的外泌体进行表征，然后用miR-1246抑制剂进行转染。采用逆转录-定量聚合酶链反应（RT-qPCR）检测miR-1246水平。此外，评估外泌体miR-1246抑制剂对HepG2细胞迁移、侵袭、增殖和EMT的影响。
研究结果显示，与相邻的非癌组织相比，HCC组织中miR-1246水平升高，且HepG2来源的外泌体中miR-1246的富集程度高于HepG2细胞。HCC来源的外泌体显著增强了HCC细胞的侵袭、迁移、增殖和EMT，而装载有miR-1246抑制剂的外泌体则抑制了这些生物学功能。进一步的机制研究表明，miR-1246的调控作用与FSTL5以及ERK/p38丝裂原活化蛋白激酶（MAPK）信号通路有关。
总之，肿瘤来源的miR-1246以外泌体的形式进入肝细胞癌细胞，并促进癌细胞的侵袭、EMT和迁移。miR-1246的潜在机制可能与靶向基因FSTL5以及ERK/p38信号通路有关。
