原发性肝细胞癌（HCC）是世界上致死性排名第二的恶性肿瘤，我国HCC患者占全球总发病的50.5%。乐伐替尼是进展期HCC一线靶向药物，抑制络氨酸激酶受体及下游RAS/RAF/MEK/ERK和PI3K/AKT/mTOR通路发挥抗癌活性。YRDC参与NNU-tRNA反密码子环第37位A的修饰t6A37。前期研究发现YRDC显著影响肝癌细胞对乐伐替尼的敏感性。初步机制探索表明YRDC可能通过t6A37修饰影响NNU-tRNA与密码子结合能力，和/或影响tiRNA生成，调控乐伐替尼作用通路上靶基因表达，从而调控肝癌细胞对乐伐替尼的敏感性。本项目旨在通过质谱分析蛋白氨基酸构成，tiRNA干扰/过表达，RNA-蛋白和RNA/RNA共沉淀等分子生物学技术，阐明YRDC调控HCC乐伐替尼敏感性的分子机制；研究YRDC多态性对HCC患者乐伐替尼疗效的影响，为HCC患者乐伐替尼个体化治疗提供依据。

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death globally. There are over 50% of global morbidity of HCC in China. Lenvatinib is recently approved as a first-line treatment in advanced HCC. Its antitumor activity is primarily through inhibiting receptors of tyrosine kinase(RTK) and its downstream pathways including the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways. YRDC is responsible for t6A37 modification in NNU-tRNA. In our previous studies, we observed that the expression of YRDC markedly affected the sensitivity of hepatocarcinoma cells to lenvatinib. Our previous pilot study showed that the expression of YRDC regulated the level of t6A37, and may subsequently affect the binding between NNU-tRNAs and ANN-codons and the level of tiRNA, eventually modulate the expression of target genes involved in the lenvatinib anti-tumor pathways. This project aims to clarify the mechanism of YRDC modulating the sensitivity of hepatocellular carcinoma to lenvatinib, using a series of cell and molecular biotechnologies and bioinformatics analysis. Meanwhile, we aim to investigate the effect of the polymorphism of YRDC on the efficacy of lenvatinib in patients with HCC. Our study may provide a theoretical basis for clinical personalized therapy of lenvatinib in patients with HCC.