Cao Mingbo, Li Yuxuan, Su Xiaorui, Tang Yongchang, Yuan Feng, Ren Yupeng, Deng Meihai, Yao Zhicheng
Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.
Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China.
Noncoding RNA Res. 2025 May 15;14:1-13. doi: 10.1016/j.ncrna.2025.05.007. eCollection 2025 Oct.
Hepatocellular carcinoma (HCC) is a highly heterogeneous solid tumor, with its incidence showing a troubling upward trend over the past decade. Lenvatinib is one of the first-line medications for treating advanced HCC, however, the development of resistance significantly undermines its potential to improve patient prognosis. In recent years, exosomal circRNAs have been implicated in the resistance mechanisms of various cancers, yet their role in mediating lenvatinib resistance (LR) remains largely unexplored. In this study, we identified hsa_circ_0007132, which is upregulated in the serum exosomes of HCC patients exhibiting progressive disease (PD) following lenvatinib treatment. Subsequently, we employed LR cell lines to conduct both and experiments, which provided compelling evidence that hsa_circ_0007132 significantly promotes LR in HCC. Mechanistically, hsa_circ_0007132 interacts with the NONO protein, impairing its ubiquitination and leading to increased stability and upregulation of NONO expression, thereby enhancing NONO-mediated nuclear export of ZEB1 mRNA and elevating ZEB1 protein expression, which ultimately contributes to LR. In summary, our findings unveil a critical mechanism through which HCC mediates tumor progression and LR via exosomal hsa_circ_0007132, while also emphasizing that targeting NONO may represent a promising therapeutic strategy to overcome LR.
肝细胞癌（HCC）是一种高度异质性的实体瘤，在过去十年中其发病率呈令人担忧的上升趋势。仑伐替尼是治疗晚期HCC的一线药物之一，然而，耐药性的产生显著削弱了其改善患者预后的潜力。近年来，外泌体环状RNA已被证明与多种癌症的耐药机制有关，但其在介导仑伐替尼耐药（LR）中的作用仍 largely unexplored。在本研究中，我们鉴定出hsa_circ_0007132，其在接受仑伐替尼治疗后出现疾病进展（PD）的HCC患者血清外泌体中上调。随后，我们使用LR细胞系进行了 both 和 实验，这些实验提供了令人信服的证据，表明hsa_circ_0007132显著促进HCC中的LR。机制上，hsa_circ_0007132与NONO蛋白相互作用，损害其泛素化并导致NONO表达的稳定性增加和上调，从而增强NONO介导的ZEB1 mRNA核输出并提高ZEB1蛋白表达，最终导致LR。总之，我们的研究结果揭示了HCC通过外泌体hsa_circ_0007132介导肿瘤进展和LR的关键机制，同时也强调靶向NONO可能是克服LR的一种有前景的治疗策略。
