Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fujian, China.
Department of Pharmacology, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, The School of Pharmacy, Fujian Medical University, Fujian, China.
Mol Carcinog. 2021 Feb;60(2):151-163. doi: 10.1002/mc.23279. Epub 2021 Jan 11.
Regorafenib is approved for patients with unresectable hepatocellular carcinoma (HCC) following sorafenib. However, the effect of regorafenib on HCC metastasis and its mechanism are poorly understood. Here, our data showed that regorafenib significantly restrained the migration, invasion and vasculogenic mimicry (VM) of HCC cells, and downregulated the expression of epithelial-to-mesenchymal transition (EMT)/VM-related molecules. Using RNA-seq and cellular thermal shift assays, we found that inhibitor of differentiation 1 (ID1) was a key target of regorafenib. In HCC tissues, the protein expression of ID1 was positively correlated with EMT and VM formation (CD34 /PAS ). Functionally, ID1 knockdown inhibited HCC cell migration, invasion, metastasis, and VM formation in vitro and in vivo, with upregulation of E-cadherin and downregulation of Snail and VE-cadherin. Moreover, Snail overexpression promoted the migration, invasion, and VM formation of ID1 knockdown cells. Snail knockdown reduced the migration, invasion, and VM formation of ID1 overexpression cells. Finally, regorafenib suppressed VM formation and decreased the expression of ID1, VE-cadherin and Snail in HCC PDX model. In conclusion, we manifested that regorafenib distinctly inhibited EMT in HCC cells via targeting ID1, leading to the suppression of cell migration, invasion and VM formation. These findings suggest that regorafenib may be developed as a suitable therapeutic agent for HCC metastasis.
regorafenib 获批用于索拉非尼治疗后不可切除的肝细胞癌（HCC）患者。然而，regorafenib 对 HCC 转移的影响及其机制尚不清楚。在这里，我们的数据表明，regorafenib 可显著抑制 HCC 细胞的迁移、侵袭和血管生成拟态（VM），并下调上皮间质转化（EMT）/VM 相关分子的表达。通过 RNA-seq 和细胞热转移分析，我们发现分化抑制因子 1（ID1）是 regorafenib 的关键靶标。在 HCC 组织中，ID1 的蛋白表达与 EMT 和 VM 形成（CD34 / PAS ）呈正相关。功能上，ID1 敲低可抑制 HCC 细胞在体外和体内的迁移、侵袭、转移和 VM 形成，同时上调 E-钙粘蛋白，下调 Snail 和 VE-钙粘蛋白。此外，Snail 过表达促进 ID1 敲低细胞的迁移、侵袭和 VM 形成。Snail 敲低可降低 ID1 过表达细胞的迁移、侵袭和 VM 形成。最后，regorafenib 抑制 VM 形成并降低 HCC PDX 模型中 ID1、VE-钙粘蛋白和 Snail 的表达。总之，我们证实 regorafenib 通过靶向 ID1 明显抑制 HCC 细胞中的 EMT，从而抑制细胞迁移、侵袭和 VM 形成。这些发现表明，regorafenib 可能被开发为 HCC 转移的合适治疗药物。
