Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei, P. R. China.
Department of General Surgery, First People's Hospital Affiliated with Shanghai Jiao Tong University, Shanghai, P. R. China.
Am J Chin Med. 2022;50(1):313-332. doi: 10.1142/S0192415X22500124. Epub 2021 Dec 28.
18[Formula: see text]-glycyrrhetinic acid (GA) is the active ingredient of the traditional Chinese medicinal herb Glycyrrhizae radix et rhizoma. We previously demonstrated that GA inhibited tumor growth in hepatocellular carcinoma (HCC). However, the effect of GA on transforming growth factor-[Formula: see text] (TGF-[Formula: see text]-induced epithelial-mesenchymal transition (EMT) and metastasis were still unclear. In this study, transwell assays and immunofluorescence (IF) demonstrated that GA inhibited TGF-[Formula: see text]-induced migration, invasion and EMT of HCC cells. However, it had little effect on the inhibition of proliferation by TGF-[Formula: see text]. Moreover, we confirmed that GA suppressed the metastasis of HCC cells using an ectopic lung metastasis model. Furthermore, we found that GA inhibited TGF-[Formula: see text]-induced EMT mainly by reducing the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which played an essential role in TGF-[Formula: see text]-induced EMT and cell mobility. Mechanistically, GA inhibited the phosphorylation of STAT3 by increasing the expression of Src homology 2 domain-containing protein tyrosine phosphatases 1 and 2 (SHP1 and SHP2). Therefore, we concluded that GA inhibited TGF-[Formula: see text]-induced EMT and metastasis via the SHP1&SHP2/STAT3/Snail pathway. Our data provide an attractive therapeutic target for future multimodal management of HCC.
18β-甘草次酸（GA）是传统中药甘草根茎的活性成分。我们之前证明 GA 可抑制肝癌（HCC）中的肿瘤生长。然而，GA 对转化生长因子-β（TGF-β）诱导的上皮间质转化（EMT）和转移的影响仍不清楚。在这项研究中，Transwell 分析和免疫荧光（IF）表明 GA 抑制 TGF-β诱导的 HCC 细胞迁移、侵袭和 EMT。然而，它对 TGF-β抑制增殖的作用影响不大。此外，我们使用异位肺转移模型证实了 GA 抑制 HCC 细胞的转移。此外，我们发现 GA 通过降低信号转导子和转录激活子 3（STAT3）的磷酸化来抑制 TGF-β诱导的 EMT，STAT3 在 TGF-β诱导的 EMT 和细胞迁移中起关键作用。在机制上，GA 通过增加 SRC 同源 2 结构域蛋白酪氨酸磷酸酶 1 和 2（SHP1 和 SHP2）的表达来抑制 STAT3 的磷酸化。因此，我们得出结论，GA 通过 SHP1&SHP2/STAT3/Snail 通路抑制 TGF-β诱导的 EMT 和转移。我们的数据为 HCC 的未来多模式管理提供了一个有吸引力的治疗靶点。
