YRDC Mediates the Resistance of Lenvatinib in Hepatocarcinoma Cells via Modulating the Translation of KRAS

Abstract

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.

RNA structural dynamics modulate EGFR-TKIs resistance through controllingYRDCtranslation in NSCLC cells

“…Previous studies have reported that YRDC regulates RNA translation via involvement in tRNA’s N6-threonyl carbamoyl adenosine (t 6 A) synthesis(El Yacoubi et al, 2009; Lescrinier et al, 2006; Murphy et al, 2004), and it has been reported that can regulate HCC cell resistance to lenvatinib by regulating KRAS translation(Guo et al, 2021). In our study, we found that YRDC has a higher translation efficiency in EGFR-TKI resistant cells than sensitive cells (Figure 3A).…”

“…YRDC is involved primarily in adenosine 37 N 6 -threonyl-carbamoylation in tRNA’s ANN-type tRNAs (t 6 A) synthesis for recognizing ANN codons(El Yacoubi et al, 2009). t 6 A represents the widely distributed modification necessary to maintain the accurate and efficient translation(Lescrinier et al, 2006; Murphy et al, 2004), and YRDC regulates HCC cell resistance to lenvatinib by regulating KRAS translation(Guo et al, 2021). The present work found that YRDC facilitates EGFR-TKIs resistance in NSCLC cells, and the RNA structure in 3’ UTR of YRDC mRNA can modulate translation efficiency, which only exists in PC9 cell that is sensitive to EGFR-TKIs.…”

Methylation-mediated silencing of EDN3 promotes cervical cancer proliferation, migration and invasion

“…All the primers were produced by Shanghai Sangon Biotech Co., Ltd, Shanghai, China. The qPCR was performed as described ( 32 ). Data were analyzed using the -ΔCt method and the expression of β-actin was used as normalization control.…”

Evaluation and Application of Drug Resistance by Biomarkers in the Clinical Treatment of Liver Cancer

“…It also promotes the proliferation of HCC cells by regulating the activity of the RAS pathway—the primary pathway impacted by the anticancer effects of lenvatinib. Notably, YRDC was found to mediate the resistance of lenvatinib in HCC cells by modulating translation of the proto-oncogene K-Ras [ 158 ]. Consistent with this, YRDC has been confirmed as a potential predictive biomarker of lenvatinib sensitivity in HCC.…”