Guo Jun, Zhu Peng, Ye Zhi, Wang Mengke, Yang Haijun, Huang Shiqiong, Shu Yan, Zhang Wei, Zhou Honghao, Li Qing
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China.
Front Pharmacol. 2021 Oct 1;12:744578. doi: 10.3389/fphar.2021.744578. eCollection 2021.
Lenvatinib is the latest and promising agent that has demonstrated a significant improvement of progression-free survival in advanced hepatocellular carcinoma (HCC). However, resistance emerges soon after initial treatment, limiting the clinical benefits of lenvatinib. Therefore, understanding the mechanism of resistance is necessary for improving lenvatinib efficacy. YRDC promotes the proliferation of hepatocarcinoma cells via regulating the activity of the RAS/RAF/MEK/ERK pathway, which was the primary pathway of the anticancer effect of lenvatinib. The purpose of this study is to investigate whether YRDC modulates the sensitivity of lenvatinib in hepatocarcinoma cells. Using the CCK-8 cell viability assay, wound-healing assay and clone formation assay in cell models, and xenograft assay in null mouse, we demonstrated that Huh7 cells with YRDC knockdown showed decreased susceptibility to lenvatinib than their control cells. Furthermore, we found that lenvatinib inhibited the expression of YRDC in a time-dependent manner. This effect may aggravate resistance to lenvatinib in hepatocarcinoma cells and may be an underlying cause of resistance, which emerges soon after lenvatinib initial treatment. To investigate how YRDC modulates the sensitivity of lenvatinib, we assessed the effect of tRNA with different tA levels on the translation of the KRAS gene by rabbit reticulocyte translation system and measured the expression levels of the KRAS gene by western blot together with qPCR. We found that YRDC regulates the protein translation of KRAS in cell models, and the tRNA with low tA modification level reduces the translation of the KRAS in the translation system. These results suggested that YRDC mediates the resistance of lenvatinib in hepatocarcinoma cells via modulating the translation of the KRAS. In this study, YRDC was confirmed to be a potential novel predictive biomarker of lenvatinib sensitivity in HCC.
乐伐替尼是一种最新且有前景的药物，已在晚期肝细胞癌（HCC）中显示出无进展生存期的显著改善。然而，初始治疗后很快就会出现耐药性，限制了乐伐替尼的临床益处。因此，了解耐药机制对于提高乐伐替尼疗效至关重要。YRDC通过调节RAS/RAF/MEK/ERK途径的活性促进肝癌细胞增殖，而该途径是乐伐替尼抗癌作用的主要途径。本研究的目的是探讨YRDC是否调节肝癌细胞对乐伐替尼的敏感性。通过细胞模型中的CCK-8细胞活力测定、伤口愈合测定和克隆形成测定以及裸鼠异种移植测定，我们证明敲低YRDC的Huh7细胞对乐伐替尼的敏感性低于其对照细胞。此外，我们发现乐伐替尼以时间依赖性方式抑制YRDC的表达。这种效应可能会加重肝癌细胞对乐伐替尼的耐药性，可能是乐伐替尼初始治疗后很快出现耐药的潜在原因。为了研究YRDC如何调节乐伐替尼的敏感性，我们通过兔网织红细胞翻译系统评估了不同tA水平的tRNA对KRAS基因翻译的影响，并通过蛋白质印迹和qPCR一起测量了KRAS基因的表达水平。我们发现YRDC在细胞模型中调节KRAS的蛋白质翻译，并且低tA修饰水平的tRNA在翻译系统中降低了KRAS的翻译。这些结果表明，YRDC通过调节KRAS的翻译介导肝癌细胞对乐伐替尼的耐药性。在本研究中，YRDC被证实是HCC中乐伐替尼敏感性的潜在新型预测生物标志物。
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