Sorafenib在肝癌中的耐药问题一直是研究的难点和热点。研究表明细胞衰老相关分泌表型(SASP)通过分泌多种细胞因子促进肿瘤耐药，我们前期报道了p16介导的SASP在肝癌sorafenib耐药中的作用，之后我们发现LINC00341在肝癌耐药细胞株中低表达，且过表达LINC00341能通过下调p16/SASP逆转耐药，进一步的，我们发现p16表达下调与其mRNA半衰期缩短有关，文献报道NSun2可通过甲基化稳定p16 mRNA表达，RNA pull down实验表明LINC00341能够与NSun2蛋白发生结合，我们推测LINC00341可能通过靶向NSun2调控p16 mRNA表达，从而发挥逆转耐药的作用。在本项目中，我们拟阐明LINC00341调控p16/SASP的具体机制及对sorafenib耐药的影响，为克服sorafenib耐药提供新的理论依据。

Sorafenib is the only FDA-approved drug for the treatment of advanced hepatocellular carcinoma (HCC). However, its efficacy is largely limited by the emergence of primary and/or acquired resistance. Nowadays, effect of senescence-associated secretory phenotype (SASP) on cancer chemo-resistance has attracted increasing attention. We previously reported p16-mediated SASP is responsible for the resistance of sorafenib in HCC, however, the up-stream mechanism remains unclear, our preliminary results identified that long noncoding RNA LINC00341 is inhibited in resistant cells, and overexpression of LINC00341 improved sorafenib efficacy through p16 down-regulation. We further found LINC00341 reduces p16 expression by shortening the half-life of the p16 mRNA. It has been reported Nsun2 mediates methylation of the p16 3’UTR to stabilize p16 mRNA. RNA pull down assay proved LINC00341 is interacted with Nsun2, we therefore speculated that LINC00341 regulates p16 mRNA by interacting with Nsun2. In this study, we will confirm the effect of LINC00341 on sorafenib efficacy through mediating p16/SASP expression by in vivo and in vitro experiments, and elucidate the mechanism of LINC00341 interacts with Nsun2 to regulate p16 mRNA. Our study aims to provide novel theoretical basis to overcome sorafenib resistance for HCC patients.