Zhu Meng, Zhang Ning, He Shuixiang, Lu Xinlan
Basic Medical College, Ningxia Medical University, Yinchuan, Ningxia, China.
Department of Pathology, General Hospital of Ningxia Medical University,Yinchuan, Ningxia, China.
Cell Cycle. 2020 May;19(10):1200-1221. doi: 10.1080/15384101.2020.1749467. Epub 2020 Apr 8.
Peritoneal metastasis develops in more than half of patients with gastric cancer but influencing factors are poorly characterized. Exosomes are increasingly recognized as a new mediator in cancer directional metastasis through the transfer of nucleic acids or proteins to neighboring or distant cells. The role of exosomes in peritoneal metastasis and whether it could establish pre-metastatic milieu are largely unknown. Here, we assessed the migration of gastric cancer (GC) cells and identified that PKH26-labeled exosomes from GC cells can be ingested by peritoneal mesothelial cells (MCs). Additionally, miRNA (miR-106a) that highly enriched in GC-derived exosomes (GC-exos) and essential for destroying the mesothelial barrier was demonstrated through the observation of the injury of the MCs including migratory enhancement and imbalance of apoptosis and proliferation. Moreover, either stimulating miR-106a or treatment with GC-exos could inhibit the expression of Smad7, accompanied by the concurrent elevated α-SMA and fibronectin in MCs. Silencing of miR-106a abolished GC-exos-induced gene expression in MCs. The MCs regain the viability, apoptosis reduction and Smad7 expression after rescue experiment conducted in miR-106a-enriched GC-exos. Xenograft model suggested that exosomal miR-106a had a potential to promote tumor growth through targeting Smad7. Collectively, we revealed that the delivery of miR-106a from GC-exos plays a crucial role in gastric cancer peritoneal metastasis. MiR-106a: microRNA-106a; Smad7: small mothers against decapentaplegic 7; GC: gastric cancer; MCs: mesothelial cells; Exos: exosomes; HG: high-differentiated gastric cancer cells; LG: low-differentiated gastric cancer cells.
超过半数的胃癌患者会发生腹膜转移，但影响因素尚不明确。外泌体作为一种新的介质，通过向邻近或远处细胞转移核酸或蛋白质，在癌症定向转移中日益受到关注。外泌体在腹膜转移中的作用以及它是否能够建立前转移微环境，目前尚不清楚。在此，我们评估了胃癌（GC）细胞的迁移情况，并发现PKH26标记的GC细胞外泌体可被腹膜间皮细胞（MCs）摄取。此外，通过观察MCs的损伤情况，包括迁移增强以及凋亡和增殖失衡，证实了在GC来源的外泌体（GC-exos）中高度富集且对破坏间皮屏障至关重要的miRNA（miR-106a）。此外，刺激miR-106a或用GC-exos处理均可抑制Smad7的表达，同时MCs中α-SMA和纤连蛋白的表达升高。miR-106a沉默消除了GC-exos诱导的MCs基因表达。在富含miR-106a的GC-exos中进行拯救实验后，MCs恢复了活力，凋亡减少且Smad7表达增加。异种移植模型表明，外泌体miR-106a可能通过靶向Smad7促进肿瘤生长。总的来说，我们揭示了GC-exos中miR-106a的传递在胃癌腹膜转移中起着关键作用。miR-106a：微小RNA-106a；Smad7：抗五聚体蛋白7小体；GC：胃癌；MCs：间皮细胞；Exos：外泌体；HG：高分化胃癌细胞；LG：低分化胃癌细胞。
