YRDC Mediates the Resistance of Lenvatinib in Hepatocarcinoma Cells via Modulating the Translation of KRAS
Author
Guo, JunZhu, Peng
Ye, Zhi
Wang, Mengke
Yang, Haijun
Huang, Shiqiong
Shu, Yan
Zhang, Wei
Zhou, Honghao
Li, Qing
Date
2021-10-01Journal
Frontiers in PharmacologyPublisher
Frontiers Media SAType
Article
Metadata
Show full item recordAbstract
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.Sponsors
National Natural Science Foundation of ChinaKeyword
lenvatinibAntineoplastic Agents
Carcinoma, Hepatocellular--drug therapy
Drug Tolerance--physiology
Identifier to cite or link to this item
http://hdl.handle.net/10713/16899ae974a485f413a2113503eed53cd6c53
10.3389/fphar.2021.744578
Scopus Count
Collections
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0/
Related articles
- Modulation of YrdC promotes hepatocellular carcinoma progression via MEK/ERK signaling pathway.
- Authors: Huang S, Zhu P, Sun B, Guo J, Zhou H, Shu Y, Li Q
- Issue date: 2019 Jun
- METTL1-Mediated m7G tRNA Modification Promotes Lenvatinib Resistance in Hepatocellular Carcinoma.
- Authors: Huang M, Long J, Yao Z, Zhao Y, Zhao Y, Liao J, Lei K, Xiao H, Dai Z, Peng S, Lin S, Xu L, Kuang M
- Issue date: 2023 Jan 4
- Co-administration of MDR1 and BCRP or EGFR/PI3K inhibitors overcomes lenvatinib resistance in hepatocellular carcinoma.
- Authors: Sun D, Liu J, Wang Y, Dong J
- Issue date: 2022
- IRF2 regulates cellular survival and Lenvatinib-sensitivity of hepatocellular carcinoma (HCC) through regulating β-catenin.
- Authors: Guo Y, Xu J, Du Q, Yan Y, Geller DA
- Issue date: 2021 Jun
- YRDC is upregulated in non-small cell lung cancer and promotes cell proliferation by decreasing cell apoptosis.
- Authors: Shen H, Zheng E, Yang Z, Yang M, Xu X, Zhou Y, Ni J, Li R, Zhao G
- Issue date: 2020 Jul