载有 SERPINA5 的治疗性外泌体通过整合素 β1/FAK 信号通路抑制子宫内膜癌细胞迁移。

Therapeutic exosomes loaded with SERPINA5 attenuated endometrial cancer cell migration via the integrin β1/FAK signaling pathway.

机构信息

Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, No. 2699, West GaoKe Road, Pudong District, Shanghai, 201204, People's Republic of China.

Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.

出版信息

Cell Oncol (Dordr). 2022 Oct;45(5):861-872. doi: 10.1007/s13402-022-00687-4. Epub 2022 Aug 11.

DOI:10.1007/s13402-022-00687-4

PMID:35951287

Abstract

BACKGROUND

Metastasis is still the major cause of endometrial cancer (EC)-related death. Because of their biological function and regenerative properties, exosomes have been applied to therapeutic regimens. SERPINA5 expression is downregulated in several tumors and linked to tumor cell migration and invasion. However, the expression and biological functions of SERPINA5 in EC remain unclear.

METHODS

The levels of SERPINA5 in plasma exosomes were determined with ELISAs. SERPINA5 expression in EC and its relationship with survival outcomes were analyzed using the TCGA database and clinical EC tissue samples. The effect of SERPINA5 overexpression or exosomal SERPINA5 on EC metastasis was examined by cell migration and invasion assays in vitro. Mechanistically, overexpression of SERPINA5 or high exosomal SERPINA5 levels mediated the regulation of the integrin β1/FAK signaling pathway in EC cell lines. The therapeutic effect of exosomal SERPINA5 was determined with xenograft models.

RESULTS

This study revealed that the level of exosomal SERPINA5 was increased in the circulating plasma of EC patients. In addition, the expression of SERPINA5 was decreased in EC patients with distant metastasis, and low expression of SERPINA5 indicated worse survival. In addition, SERPINA5 was elevated in normal tissues adjacent to EC tumors. Moreover, overexpression of SERPINA5 inhibited metastatic potential of EC cell lines in vitro. Furthermore, SERPINA5 loaded on secreted exosomes reduced the metastatic ability of EC cells. Notably, overexpression of SERPINA5 or high exosomal SERPINA5 levels suppressed EC metastatic potential by suppressing integrin β1/FAK signaling pathway activation. Finally, exosomal SERPINA5 impeded tumor growth and metastasis in xenograft models.

CONCLUSIONS

Our findings revealed that a low level of SERPINA5 expression indicated poor survival outcomes in EC and that exogenous SERPINA5 loading of exosomes may be a novel therapeutic strategy for metastatic EC.

摘要

背景

转移仍然是子宫内膜癌（EC）相关死亡的主要原因。由于其生物功能和再生特性，外泌体已被应用于治疗方案。SERPINA5 在几种肿瘤中表达下调，与肿瘤细胞迁移和侵袭有关。然而，SERPINA5 在 EC 中的表达和生物学功能尚不清楚。

方法

通过 ELISA 测定血浆外泌体中的 SERPINA5 水平。利用 TCGA 数据库和临床 EC 组织样本分析 SERPINA5 在 EC 中的表达及其与生存结局的关系。通过体外细胞迁移和侵袭实验研究 SERPINA5 过表达或外泌体 SERPINA5 对 EC 转移的影响。机制上，SERPINA5 的过表达或高外泌体 SERPINA5 水平介导了 EC 细胞系中整合素β1/FAK 信号通路的调节。通过异种移植模型确定外泌体 SERPINA5 的治疗效果。

结果

本研究表明，EC 患者循环血浆中外泌体 SERPINA5 的水平增加。此外，SERPINA5 在有远处转移的 EC 患者中表达降低，SERPINA5 低表达预示着生存率较差。此外，SERPINA5 在 EC 肿瘤附近的正常组织中升高。此外，SERPINA5 的过表达抑制了 EC 细胞系在体外的转移潜力。此外，SERPINA5 加载到分泌的外泌体中降低了 EC 细胞的转移能力。值得注意的是，SERPINA5 的过表达或高外泌体 SERPINA5 水平通过抑制整合素β1/FAK 信号通路的激活抑制了 EC 的转移潜力。最后，外泌体 SERPINA5 抑制了异种移植模型中的肿瘤生长和转移。