Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China; Shenzhen University General Hospital-Lishui Hospital Joint Research Center, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China.
Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, Key Laboratory of Precision Medicine of Lishui City, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui 323000, China.
Cell Signal. 2024 Dec;124:111467. doi: 10.1016/j.cellsig.2024.111467. Epub 2024 Oct 10.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Efforts have been focused on developing new anti-HCC agents and understanding their pharmacology. However, few agents have been able to effectively combat tumor growth and invasiveness due to the rapid progression of HCC. In this study, we discovered that fangchinoline (FAN), a bisbenzylisoquinoline alkaloid derived from Stephania tetrandra S. Moore, effectively inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells. FAN treatment also led to the suppression of IL6 and IL1β release, as well as the expression of inflammation-related proteins such as COX-2 and iNOS, and the activation of the NF-κB pathway, thereby reducing inflammation-related EMT. Additionally, FAN directly bound to forkhead box protein M1 (FOXM1), resulting in decreased levels of FOXM1 proteins and disruption of the FOXM1-ADAM17 axis. Our in vivo findings confirmed that FAN effectively hindered the growth and lung metastasis of HCCLM3-xenograft tumors. Importantly, the upregulation of FOXM1 in HCC tissue suggested that targeting FOXM1 inhibition with FAN or its inhibitors could be a promising therapeutic approach for HCC. Overall, this study elucidated the anti-tumor effects and potential pharmacological mechanisms of FAN, and proposed that targeting FOXM1 inhibition may be an effective therapeutic strategy for HCC with potential clinical applications.
肝细胞癌（HCC）是全球癌症相关死亡的主要原因。人们一直致力于开发新的抗 HCC 药物并了解其药理学。然而，由于 HCC 的快速进展，很少有药物能够有效地抑制肿瘤生长和侵袭。在这项研究中，我们发现来源于Stephania tetrandra S. Moore 的双苄基异喹啉生物碱 fangchinoline（FAN）能有效抑制 HCC 细胞的迁移、侵袭和上皮间质转化（EMT）。FAN 处理还导致 IL6 和 IL1β 的释放受到抑制，以及 COX-2 和 iNOS 等炎症相关蛋白的表达和 NF-κB 通路的激活，从而减少炎症相关的 EMT。此外，FAN 直接与叉头框蛋白 M1（FOXM1）结合，导致 FOXM1 蛋白水平降低，并破坏 FOXM1-ADAM17 轴。我们的体内研究结果证实 FAN 能有效抑制 HCCLM3 异种移植瘤的生长和肺转移。重要的是，FOXM1 在 HCC 组织中的上调表明，用 FAN 或其抑制剂靶向 FOXM1 抑制可能是 HCC 的一种有前途的治疗方法。总的来说，这项研究阐明了 FAN 的抗肿瘤作用和潜在的药理机制，并提出靶向 FOXM1 抑制可能是 HCC 的一种有效治疗策略，具有潜在的临床应用前景。
