YRDC Mediates the Resistance of Lenvatinib in Hepatocarcinoma Cells via Modulating the Translation of KRAS.
YRDC Mediates the Resistance of Lenvatinib in Hepatocarcinoma Cells via Modulating the Translation of KRAS.
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DOI：
10.3389/fphar.2021.744578
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发表时间：
2021
影响因子：
5.6
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Guo J;Zhu P;Ye Z;Wang M;Yang H;Huang S;Shu Y;Zhang W;Zhou H;Li Q
仑伐替尼是最新且有前途的药物，已证明可显着改善晚期肝细胞癌（HCC）的无进展生存期。然而，初始治疗后不久就出现了耐药性，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通路活性促进肝癌细胞增殖，这是乐伐替尼抗癌作用的主要通路。本研究的目的是探讨 YRDC 是否调节肝癌细胞中乐伐替尼的敏感性。使用CCK-8细胞活力测定、细胞模型中的伤口愈合测定和克隆形成测定以及裸鼠的异种移植测定，我们证明YRDC敲低的Huh7细胞比对照细胞对乐伐替尼的敏感性降低。此外，我们发现乐伐替尼以时间依赖性方式抑制 YRDC 的表达。这种效应可能会加剧肝癌细胞对乐伐替尼的耐药性，并且可能是耐药性的根本原因，这种耐药性在乐伐替尼初始治疗后不久就出现。为了研究YRDC如何调节乐伐替尼的敏感性，我们通过体外兔网织红细胞翻译系统评估了不同t6A水平的tRNA对KRAS基因翻译的影响，并通过蛋白质印迹和qPCR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的蛋白翻译，并且低t6A修饰水平的tRNA在体外翻译系统中降低KRAS的翻译。这些结果表明，YRDC 通过调节 KRAS 的翻译来介导肝癌细胞对乐伐替尼的耐药性。在这项研究中，YRDC 被证实是 HCC 乐伐替尼敏感性的潜在新型预测生物标志物。
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 t6A levels on the translation of the KRAS gene by in vitro 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 t6A modification level reduces the translation of the KRAS in the in vitro 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.
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