Traditional Chinese Medicine and Research Office, Suzhou Health College of Technology, Suzhou 215000, China.
Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine and Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Aging (Albany NY). 2023 Sep 14;15(17):9217-9229. doi: 10.18632/aging.205030.
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 . 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 by targeting DDR1-mediated immune infiltration.
大狼毒素 L1（EFL1）是一种来自大戟属植物大狼毒的裂环烯醚萜二萜类化合物，已被证明具有多种药理活性。然而，EFL1 对乳腺癌的作用尚不清楚。在这项研究中，我们探讨了 EFL1 对乳腺癌肝转移的作用及其机制。雌性 BALB/c 小鼠接受乳腺癌手术性肝植入（SHI）以建立乳腺癌肝转移模型。手术后 10 天，小鼠每天给予 EFL1 一次，共 2 周。通过测定血清天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）活性、腹围、腹腔积液、肿瘤重量和体积来评估乳腺癌的肝和肠系膜再转移。通过 H&E 染色观察肿瘤、肝脏和小肠组织的形态变化。通过 ELISA 观察炎症水平。通过 Western blot、免疫组化和流式细胞术方法测定肿瘤 DDR1 表达和免疫浸润。结果显示，EFL1 给药改善了 SHI 小鼠的肝功能（AST 和 ALT 活性）、腹水、肝转移和肠系膜再转移。此外，EFL1 治疗降低了 SHI 诱导的腹水炎症细胞浸润和白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）的产生。机制研究表明，EFL1 干预通过下调 SHI 小鼠肿瘤中的 DDR1，增强了 CD4+和 CD8+以及 CD49b+（NK）T 淋巴细胞的比例，并减少了 Treg 细胞。此外，DDR1 的过表达消除了 EFL1 在 SHI 小鼠中对肝转移的抑制作用和对免疫浸润的促进作用。总之，我们的研究结果表明，EFL1 通过靶向 DDR1 介导的免疫浸润来预防乳腺癌肝转移。
