Sun Yufeng, He Xiaoqian, Han Jiayi, Yin Wenxuan, Wang Haichen, Li Jing, Liu Weiqi, Kuai Xingwang, Lv Jiaying, Ji Juling
Department of Pathology, Medical School of Nantong University, Nantong, China.
Key Laboratory of Microenvironment and Translational Cancer Research, Nantong, China.
Front Immunol. 2024 Dec 17;15:1489679. doi: 10.3389/fimmu.2024.1489679. eCollection 2024.
The progression of hepatoma is heavily influenced by the microenvironment. Tumor-associated macrophages (TAMs) are considered to play a critical role in the tumor microenvironment (TME) and increase the aggressiveness of hepatoma. The activation of hepatic stellate cells (HSCs) is involved in hepatoma progression, and accumulating evidence demonstrates a change in microRNA (miRNA) expression during HSC activation. Therefore, the potential roles of HSCs-related miRNAs in macrophage differentiation and hepatoma progression deserve to be explored. The present study aimed to investigate the effects of miRNAs carried by small extracellular vesicles (sEVs) released by activated HSCs on hepatoma progression. The results indicated that miR-27a-3p was significantly upregulated in cells and corresponding sEVs during the activation of primary rat HSCs and human HSC line-LX2 cells. Furthermore, miR-27a-3p contributed to the proliferation and migration of hepatoma cells and promoted M2 polarization of macrophage. HSC-sEVs overexpressing miR-27a-3p can directly facilitate tumor progression and modulate macrophage polarization, indirectly contributing to hepatoma progression. Finally, Sprouty2 (SPRY2) was verified to be the target gene of miR-27a-3p. In conclusion, activated HSC-derived sEVs with high levels of miR-27a-3p might induce M2 macrophage polarization and promote hepatoma progression, providing new insights into the mechanism of hepatoma progression.
肝癌的进展受到微环境的严重影响。肿瘤相关巨噬细胞（TAMs）被认为在肿瘤微环境（TME）中起关键作用，并增加肝癌的侵袭性。肝星状细胞（HSCs）的激活参与肝癌进展，越来越多的证据表明在HSC激活过程中微小RNA（miRNA）表达发生变化。因此，与HSCs相关的miRNA在巨噬细胞分化和肝癌进展中的潜在作用值得探索。本研究旨在探讨活化的HSCs释放的小细胞外囊泡（sEVs）携带的miRNA对肝癌进展的影响。结果表明，在原代大鼠HSCs和人HSC系-LX2细胞激活过程中，miR-27a-3p在细胞和相应的sEVs中显著上调。此外，miR-27a-3p促进肝癌细胞的增殖和迁移，并促进巨噬细胞的M2极化。过表达miR-27a-3p的HSC-sEVs可直接促进肿瘤进展并调节巨噬细胞极化，间接促进肝癌进展。最后，Sprouty2（SPRY2）被证实为miR-27a-3p的靶基因。总之，含有高水平miR-27a-3p的活化HSC来源的sEVs可能诱导M2巨噬细胞极化并促进肝癌进展，为肝癌进展机制提供了新的见解。
