Qingdao Medical College, Qingdao University, Qingdao 266071, China.
College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310014, China.
Biochim Biophys Acta Mol Cell Res. 2024 Jan;1871(1):119617. doi: 10.1016/j.bbamcr.2023.119617. Epub 2023 Oct 26.
Lenvatinib is the first-line treatment for patients with advanced HCC, however, drug resistance cannot be avoided during the treatment process, limiting the efficacy of Lenvatinib. We constructed drug-resistant HCC cells by gradually increasing the dose of Lenvatinib. The study found for the first time that USP22 and JMJD8 are upregulated in Lenvatinib resistant HCC cells. In addition, the expression level of stemness related proteins (CD133, C-MYC, BMI1, β-CATENIN) in drug-resistant cells was higher than that in wild-type HCC cells. Knockdown of USP22 in drug-resistant HCC cells could reduce the invasion, migration and stemness of cells. Next, we explored the mechanism of USP22 in Lenvatinib resistance of HCC cells. Under the treatment of Lenvatinib, USP22 knockdown inhibited the cell viability of drug-resistant HCC cells and promoted the apoptosis of drug-resistant cells. Animal experiments in nude mice further demonstrated the important role of USP22 in inducing the resistance of HCC to Lenvatinib in vivo. More importantly, we found that USP22 and JMJD8 constitute a functional axis regulating the drug resistance of Lenvatinib in HCC. In the rescue experiment, the overexpression of JMJD8 could reduce the apoptosis induced by USP22 knockdown. In general, this study shows that USP22-JMJD8 is a drug design target for the mechanism of Lenvatinib resistance in HCC, which may improve the long-term efficacy of Lenvatinib.
乐伐替尼是治疗晚期 HCC 患者的一线药物，但在治疗过程中不可避免会产生耐药性，从而限制了乐伐替尼的疗效。我们通过逐渐增加乐伐替尼的剂量来构建耐药 HCC 细胞。本研究首次发现，USP22 和 JMJD8 在耐药 HCC 细胞中上调。此外，耐药细胞中干性相关蛋白（CD133、C-MYC、BMI1、β-CATENIN）的表达水平高于野生型 HCC 细胞。在耐药 HCC 细胞中敲低 USP22 可降低细胞的侵袭、迁移和干性。接下来，我们探讨了 USP22 在 HCC 细胞对乐伐替尼耐药中的作用机制。在乐伐替尼的处理下，USP22 敲低抑制耐药 HCC 细胞的细胞活力并促进耐药细胞的凋亡。裸鼠动物实验进一步证明了 USP22 在体内诱导 HCC 对乐伐替尼耐药中的重要作用。更重要的是，我们发现 USP22 和 JMJD8 构成了调节 HCC 中乐伐替尼耐药的功能轴。在挽救实验中，JMJD8 的过表达可以降低 USP22 敲低诱导的细胞凋亡。总之，这项研究表明，USP22-JMJD8 是 HCC 中乐伐替尼耐药机制的药物设计靶点，可能提高乐伐替尼的长期疗效。
