State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, China.
Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.
EMBO Rep. 2021 Aug 4;22(8):e50922. doi: 10.15252/embr.202050922. Epub 2021 May 31.
Several studies have examined the functions of nucleic acids in small extracellular vesicles (sEVs). However, much less is known about the protein cargos of sEVs and their functions in recipient cells. This study demonstrates the presence of lysine-specific demethylase 1 (LSD1), which is the first identified histone demethylase, in the culture medium of gastric cancer cells. We show that sEVs derived from gastric cancer cells and the plasma of patients with gastric cancer harbor LSD1. The shuttling of LSD1-containing sEVs from donor cells to recipient gastric cancer cells promotes cancer cell stemness by positively regulating the expression of Nanog, OCT4, SOX2, and CD44. Additionally, sEV-delivered LSD1 suppresses oxaliplatin response of recipient cells in vitro and in vivo, whereas LSD1-depleted sEVs do not. Taken together, we demonstrate that LSD1-loaded sEVs can promote stemness and chemoresistance to oxaliplatin. These findings suggest that the LSD1 content of sEV could serve as a biomarker to predict oxaliplatin response in gastric cancer patients.
已有多项研究探讨了核酸在小型细胞外囊泡（sEV）中的功能。然而，人们对 sEV 的蛋白质货物及其在靶细胞中的功能知之甚少。本研究证明赖氨酸特异性去甲基化酶 1（LSD1）存在于胃癌细胞的培养基中。我们发现，源自胃癌细胞的 sEV 以及胃癌患者的血浆中均存在 LSD1。来自供体细胞的含有 LSD1 的 sEV 转移到受体胃癌细胞中，通过正向调节 Nanog、OCT4、SOX2 和 CD44 的表达促进癌细胞干性。此外，sEV 传递的 LSD1 在体外和体内抑制了受体细胞对奥沙利铂的反应，而 LSD1 耗尽的 sEV 则没有。综上所述，我们证明了 LSD1 负载的 sEV 可促进干性和对奥沙利铂的化学耐药性。这些发现表明，sEV 中的 LSD1 含量可以作为预测胃癌患者对奥沙利铂反应的生物标志物。
