EMP3抑制肝癌细胞异质性细胞叠套结构的形成

EMP3 inhibits the formation of heterotypic cell-in-cell structures in hepatocellular carcinoma

摘要:

异质性细胞叠套(heterotypic cell-in-cell, heCIC)结构是细胞间一种独特的相互作用方式，其中肿瘤细胞可内化免疫细胞形成heCIC结构，从而提升免疫细胞的杀伤效率。然而，调节heCIC结构形成的机制尚未阐明。本研究聚焦于上皮膜蛋白3 (epithelial membrane protein 3, EMP3)，一种在肝癌患者组织表达增加并伴随不良预后的PMP-22/EMP/MP20蛋白家族成员，探讨了其在调节自然杀伤细胞-肝癌细胞形成heCIC结构中的作用。通过分析课题组前期分选出的具有不同heCIC形成能力的单克隆肝癌细胞株，发现heCIC形成能力高的细胞株中EMP3表达较低，而heCIC形成能力低的细胞株中EMP3表达较高。利用基因编辑技术敲低EMP3表达可以促进heCIC结构的形成，而EMP3的过度表达则显著抑制了这一过程。通过检测与heCIC结构形成相关的分子表达水平发现，EMP3通过调节肿瘤细胞的黏附能力和细胞骨架来抑制肝癌细胞heCIC结构的形成。本研究为靶向EMP3促进肝癌细胞heCIC结构介导的肿瘤免疫增强提供了研究基础。

Abstract:

Heterotypic cell-in-cell (heCIC) structures represent a unique intercellular interaction where tumor cells internalize immune cells to enhance the killing efficiency of immune cells. However, the mechanism of heCIC structure formation remains to be fully elucidated. In this study, we explored the role of epithelial membrane protein 3 (EMP3), a PMP-22/EMP/MP20 protein family member highly expressed in the patients with hepatocellular carcinoma and poor prognosis, in the formation of the heCIC structure formed by natural killer cells and hepatocellular carcinoma cells. The analysis of monoclonal hepatocellular carcinoma cell lines revealed that EMP3 presented low expression in the cells with high capability to form heCIC structure and high expression in those with low capability. Knocking down the expression of EMP3 by gene editing promoted the formation of heCIC structures, while overexpression of EMP3 significantly inhibited this process. Additionally, the expression of factors involved in the heCIC structure formation suggested that EMP3 inhibited the formation of heCIC structures by modulating the adhesion ability and cytoskeleton of tumor cells. The findings lay a foundation for enhancing the heCIC-mediated tumor immunotherapy by targeting EMP3.