Department of Medical Genetics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Institute of Gerontology and Center for Geriatrics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
Cancer Sci. 2024 Feb;115(2):465-476. doi: 10.1111/cas.16029. Epub 2023 Nov 22.
NR0B1 is frequently activated in hepatocellular carcinoma (HCC). However, the role of NR0B1 is controversial in HCC. In this study, we observed that NR0B1 was an independent poor prognostic factor, negatively correlated with the overall survival of HCC and the relapse-free survival of patients treated with sorafenib. Meanwhile, NR0B1 promoted the proliferation, migration, and invasion of HCC cells, inhibited sorafenib-induced apoptosis, and elevated the IC50 of sorafenib in HCC cells. NR0B1 was further displayed to increase sorafenib-induced autophagic vesicles and activate Beclin1/LC3-II-dependent autophagy pathway. Finally, NR0B1 was revealed to transcriptionally suppress GSK3β that restrains AMPK/mTOR-driven autophagy and increases BAX-mediated apoptosis. Collectively, our study uncovered that the ectopic expression of NR0B1 augmented sorafenib-resistance in HCC cells by activating autophagy and inhibiting apoptosis. Our findings supported that NR0B1 was a detrimental factor for HCC prognosis.
NR0B1 在肝细胞癌 (HCC) 中经常被激活。然而，NR0B1 在 HCC 中的作用存在争议。在这项研究中，我们观察到 NR0B1 是一个独立的预后不良因素，与 HCC 的总生存率和接受索拉非尼治疗的患者的无复发生存率呈负相关。同时，NR0B1 促进 HCC 细胞的增殖、迁移和侵袭，抑制索拉非尼诱导的细胞凋亡，并提高 HCC 细胞中索拉非尼的 IC50。NR0B1 进一步显示增加索拉非尼诱导的自噬小体，并激活 Beclin1/LC3-II 依赖性自噬途径。最后，NR0B1 被揭示转录抑制 GSK3β，抑制 AMPK/mTOR 驱动的自噬，并增加 BAX 介导的细胞凋亡。总之，我们的研究揭示了 NR0B1 通过激活自噬和抑制凋亡，增强 HCC 细胞对索拉非尼的耐药性。我们的研究结果支持 NR0B1 是 HCC 预后的有害因素。
