Department of Hepatobiliary and Pancreatic Surgery, NHC Key Laboratory of Combined Multi-organ Transplantation, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China.
Signal Transduct Target Ther. 2024 Sep 19;9(1):249. doi: 10.1038/s41392-024-01963-5.
Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma (HCC). A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed. In this study, we aimed to dissect the underlying mechanism of lenvatinib resistance (LR) and provide effective treatment strategies. We established an HCC model of acquired LR. Cell counting, migration, self-renewal ability, chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells. Molecular and biochemical strategies such as RNA-sequencing, immunoprecipitation, mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms. Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance. We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α (HIF-1α) pathway activation is responsible for acquired LR in HCC. Phosphorylated non-muscle myosin heavy chain 9 (MYH9) at Ser1943, p-MYH9 (Ser1943), could recruit ubiquitin-specific protease 22 (USP22) to deubiquitinate and stabilize HIF-1α in lenvatinib-resistant HCC. Clinically, p-MYH9 (Ser1943) expression was upregulated in HCC samples, which predicted poor prognosis and LR. A casein kinase-2 (CK2) inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro. Therefore, the p-MYH9 (Ser1943)/USP22/HIF-1α axis is critical for LR and cancer stemness. For the diagnosis and treatment of LR in HCC, p-MYH9 (Ser1943), USP22, and HIF-1α might be valuable as novel biomarkers and targets.
仑伐替尼是一种用于肝细胞癌（HCC）一线治疗的靶向药物。深入了解 HCC 对仑伐替尼的耐药机制是当务之急。在这项研究中，我们旨在剖析仑伐替尼耐药（LR）的潜在机制，并提供有效的治疗策略。我们建立了 HCC 获得性 LR 模型。通过细胞计数、迁移、自我更新能力、化学耐药性和干细胞基因表达来检测 HCC 细胞的干性。利用 RNA 测序、免疫沉淀、质谱和泛素化测定等分子和生化策略来探索潜在机制。利用患者来源的 HCC 模型和患者 HCC 样本来证明其临床意义。我们发现，由缺氧诱导因子-1α（HIF-1α）通路激活驱动的癌症干性增加是 HCC 获得性 LR 的原因。磷酸化非肌球蛋白重链 9（MYH9）在丝氨酸 1943 位（p-MYH9（Ser1943））可以募集泛素特异性蛋白酶 22（USP22），使 HIF-1α去泛素化并稳定在仑伐替尼耐药的 HCC 中。临床上，HCC 样本中 p-MYH9（Ser1943）表达上调，预示着预后不良和 LR。酪蛋白激酶 2（CK2）抑制剂和 USP22 抑制剂在体内和体外均能有效逆转 LR。因此，p-MYH9（Ser1943）/USP22/HIF-1α 轴对于 LR 和癌症干性至关重要。对于 HCC 的 LR 诊断和治疗，p-MYH9（Ser1943）、USP22 和 HIF-1α 可能是有价值的新型生物标志物和靶点。
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