Therapeutic exosomes loaded with SERPINA5 attenuated endometrial cancer cell migration via the integrin β1/FAK signaling pathway
Therapeutic exosomes loaded with SERPINA5 attenuated endometrial cancer cell migration via the integrin β1/FAK signaling pathway
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DOI：
10.1007/s13402-022-00687-4
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发表时间：
2022-08
影响因子：
6.6
通讯作者：
Yunfeng Song;Lei Ye;Yuan Tan;Huan Tong;Zeheng Lv;X. Wan;Yiran Li
中科院分区：
文献类型：
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作者：
Yunfeng Song;Lei Ye;Yuan Tan;Huan Tong;Zeheng Lv;X. Wan;Yiran Li
背景转移仍然是子宫内膜癌（EC）相关死亡的主要原因。由于其生物学功能和再生特性，外泌体已被应用于治疗方案。SERPINA5在几种肿瘤中表达下调，并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。方法采用elisa法检测血浆外泌体SERPINA5水平。使用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试验研究SERPINA5过表达或外泌体SERPINA5对EC转移的影响。机制上，在EC细胞系中，SERPINA5的过表达或高外泌体SERPINA5水平介导了整合素β1/FAK信号通路的调节。采用异种移植模型测定外泌体SERPINA5的治疗效果。结果本研究发现EC患者循环血浆外泌体SERPINA5水平升高。此外，伴有远处转移的EC患者SERPINA5表达降低，SERPINA5低表达表明生存期较差。此外，SERPINA5在EC肿瘤附近的正常组织中升高。此外，SERPINA5的过表达抑制了体外EC细胞株的转移潜能。此外，装载在分泌外泌体上的SERPINA5降低了EC细胞的转移能力。值得注意的是，SERPINA5过表达或高外泌体SERPINA5水平通过抑制整合素β1/FAK信号通路的激活来抑制EC转移潜能。最后，在异种移植瘤模型中，外泌体SERPINA5阻碍肿瘤生长和转移。结论我们的研究结果表明，SERPINA5的低水平表达表明EC的生存预后较差，外源性SERPINA5装载外泌体可能是转移性EC的一种新的治疗策略。
BackgroundMetastasis 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.MethodsThe 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.ResultsThis 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.ConclusionsOur 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.