Qiao Guan'en, Li Changjuan, Wang Meng, Zhang Wenjuan, Shi Junjie, Meng Bing, Zhang Lixia, Zhang Ruiqing, Qi Huihui, Xin Shuanli
Department of Digestive, Handan First Hospital, Handan City, Hebei Province, 056002, China.
Department of Thoracic Surgery, Handan First Hospital, Handan, Hebei Province, 056002, China.
BMC Gastroenterol. 2025 Aug 20;25(1):605. doi: 10.1186/s12876-025-03978-w.
Esophageal squamous cell carcinoma (ESCC) is characterized by a complex tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) play a crucial role in the TME that facilitate tumor progression via interactions with cancer cells. However, the mechanisms underlying the activation of CAFs in TME remain largely unknown. Here, we characterized the exosomes derived from normoxic and hypoxic ESCC cells using electron microscopy and western blot. The impact of exosomes on CAF activation and the motility of ESCC cells was examined in vitro. The molecular complex involving circNRIP1 was explored using RNA pull-down. We demonstrated that exosomes derived from ESCC cells, including KYSE-150 and TE-10 cells, exhibited a significantly increase in secretion under hypoxic conditions. These hypoxic exosomes were internalized by fibroblasts and further promoted the transformation of normal fibroblasts into CAFs, as evidenced by enhanced migration and secretion of pro-inflammatory cytokines. circNRIP1 was enriched in hypoxic exosomes, and its absence abolished the effect of hypoxic exosomes to activate CAFs. Furthermore, the CAFs activated by exosomal circNRIP1 further promoted the migration and invasion of ESCC cells. Mechanistically, circNRIP1 bound to the N1-methyladenosine (m1A) methyltransferase TRMT6 and activated CAFs in a TRMT6-dependent manner. This study revealed the role of hypoxia-induced exosomal circNRIP1 in the activation of CAFs, which contributes to ESCC development. These findings shed light on the mechanisms of the CAF activation in ESCC, positioning hypoxia-induced exosomal circNRIP1 as a potential molecular target for ESCC.
食管鳞状细胞癌（ESCC）的特征是具有复杂的肿瘤微环境（TME）。癌症相关成纤维细胞（CAFs）在TME中起着关键作用，通过与癌细胞相互作用促进肿瘤进展。然而，TME中CAFs激活的潜在机制在很大程度上仍不清楚。在这里，我们使用电子显微镜和蛋白质免疫印迹对常氧和缺氧ESCC细胞来源的外泌体进行了表征。体外研究了外泌体对CAF激活和ESCC细胞迁移能力的影响。使用RNA下拉技术探索了涉及circNRIP1的分子复合物。我们证明，包括KYSE-150和TE-10细胞在内的ESCC细胞来源的外泌体在缺氧条件下分泌显著增加。这些缺氧外泌体被成纤维细胞内化，并进一步促进正常成纤维细胞向CAFs的转化，促炎细胞因子迁移和分泌增强证明了这一点。circNRIP1在缺氧外泌体中富集，其缺失消除了缺氧外泌体激活CAFs的作用。此外，外泌体circNRIP1激活的CAFs进一步促进了ESCC细胞的迁移和侵袭。机制上，circNRIP1与N1-甲基腺苷（m1A）甲基转移酶TRMT6结合，并以TRMT6依赖的方式激活CAFs。这项研究揭示了缺氧诱导的外泌体circNRIP1在CAFs激活中的作用，这有助于ESCC的发展。这些发现揭示了ESCC中CAF激活的机制，将缺氧诱导的外泌体circNRIP1定位为ESCC的潜在分子靶点。
