研究动态
Articles below are published ahead of final publication in an issue. Please cite articles in the following format: authors, (year), title, journal, DOI.

通过DDR1介导的免疫浸润,大戟因子L1抑制乳腺癌肝转移。

Euphorbia factor L1 suppresses breast cancer liver metastasis via DDR1-mediated immune infiltration.

发表日期:2023 Sep 14
作者: Dongjing Jiang, XiaoQin Gao, RuLan Tan, Xun Liu, Ye Zhu, Li Zhang
来源: Cellular & Molecular Immunology

摘要:

来自药用植物刺花大戟(Euphorbia lathyris L.)的乳母酮类二萜Euphorbia factor L1 (EFL1) 已被证实具有多种药理活性。然而,EFL1对于乳腺癌的作用尚不明确。本研究旨在探讨EFL1对乳腺癌肝转移的影响和机制。我们在雌性BALB/c小鼠上进行了乳腺癌-手术性肝移植(SHI)来建立体内乳腺癌肝转移模型。术后10天,小鼠每天一次给予EFL1治疗,共治疗2周。通过测定血清转氨酶(AST和ALT)活性、腹围、腹水、肿瘤重量和体积来评估乳腺癌肝转移和肠系膜再转移。使用H&E染色观察肿瘤、肝脏和小肠组织的形态学变化。采用ELISA检测炎症水平。通过西方印迹、免疫组织化学和流式细胞仪方法来确定肿瘤DDR1表达和免疫浸润。我们的结果显示,EFL1治疗可改善SHI小鼠的肝功能(AST和ALT活性)、腹水积聚、肝转移和肠系膜再转移。此外,EFL1治疗降低了SHI诱导的炎性细胞浸润和腹水中IL-1β、IL-6和TNF-α的产生。机制研究揭示,EFL1干预能通过下调肿瘤DDR1来增强CD4+、CD8+和CD49b+(NK)T淋巴细胞的比例,并减少Treg细胞在SHI小鼠肿瘤中的水平。此外,DDR1的过表达消除了EFL1对SHI小鼠肝转移抑制和促进免疫浸润的作用。综上,我们的研究结果表明,EFL1通过靶向DDR1介导的免疫浸润来保护体内乳腺癌肝转移。
Euphorbia factor L1 (EFL1), a lathyrane-type diterpenoid from the medicinal herb Euphorbia lathyris L., has been documented to possess various pharmacologic actives. However, the function of EFL1 on breast cancer is not clear. In this study, we explored the effect and mechanism of EFL1 on breast cancer liver metastasis. Female BALB/c mice were subjected to breast cancer-surgical hepatic implantation (SHI) to establish breast cancer liver metastasis model in vivo. At 10 days post-surgery, mice were administrated with EFL1 once daily for a total of 2 weeks. Serum AST and ALT activities, abdominal circumference, peritoneal fluid, tumor weight and volume were determined to assess liver and mesenteric re-metastasis of breast cancer. H&E staining was used to observe morphology changes in tumor, liver and small intestine tissues. ELISA was applied to observe inflammatory levels. Tumor DDR1 expression and immune infiltration were determined using western blotting, immunohistochemistry and flow cytometer methods. Our results showed that EFL1 administration improved liver function (AST and ALT activities), ascites, liver metastasis and mesenteric re-metastasis in SHI mice. Also, SHI-induced inflammatory cell infiltration and IL-1β, IL-6, TNF-α generation in ascites were decreased by EFL1 treatment. Mechanism study revealed that EFL1 intervention enhanced the ratios of CD4+ and CD8+ and CD49b+(NK) T lymphocytes and decreased Treg cells through downregulating DDR1 in the tumor of SHI mice. Furthermore, overexpression of DDR1 abolished the anti-liver metastasis effect and pro-immune infiltration action of EFL1 in SHI mice. Together, our findings suggested that EFL1 protects against breast cancer liver metastasis in vivo by targeting DDR1-mediated immune infiltration.