NR0B1 Augments Sorafenib Resistance in Hepatocellular Carcinoma Through Promoting Autophagy and Inhibiting Apoptosis

Overview

Journal Cancer Sci

Specialty Oncology

Date 2023 Nov 22

PMID 37991109

Authors

Xiao Lan Tan

Zhaokun Wang

Shunyao Liao

Ming Yi

Dachang Tao

Xinyue Zhang

Xiangyou Leng

Jiaying Shi

Shengyu Xie

Yuan Yang

Yun Qiang Liu

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Targeting STK26 and ATG4B: miR-22-3p as a modulator of autophagy and tumor progression in HCC.

Li K, Bai Y, Wang J, Ren L, Mo A, Liu R Transl Oncol. 2024; 51:102214.

PMID: 39608212 PMC: 11635773. DOI: 10.1016/j.tranon.2024.102214.

Targeting cell death mechanisms: the potential of autophagy and ferroptosis in hepatocellular carcinoma therapy.

Liu B, Liu L, Liu Y Front Immunol. 2024; 15:1450487.

PMID: 39315094 PMC: 11416969. DOI: 10.3389/fimmu.2024.1450487.

Dendritic Cell-Related Gene Signatures in Hepatocellular Carcinoma: An Analysis for Prognosis and Therapy Efficacy Evaluation.

Huang H, Peng S, Wei Y, Lan C, Qin W, Liao X J Hepatocell Carcinoma. 2024; 11:1743-1761.

PMID: 39309303 PMC: 11416124. DOI: 10.2147/JHC.S481338.

AMPK: The energy sensor at the crossroads of aging and cancer.

Penugurti V, Manne R, Bai L, Kant R, Lin H Semin Cancer Biol. 2024; 106-107:15-27.

PMID: 39197808 PMC: 11625618. DOI: 10.1016/j.semcancer.2024.08.002.

NR0B1 augments sorafenib resistance in hepatocellular carcinoma through promoting autophagy and inhibiting apoptosis.

Tan X, Wang Z, Liao S, Yi M, Tao D, Zhang X Cancer Sci. 2023; 115(2):465-476.

PMID: 37991109 PMC: 10859617. DOI: 10.1111/cas.16029.

References

Ao L, Guo Y, Song X, Guan Q, Zheng W, Zhang J . Evaluating hepatocellular carcinoma cell lines for tumour samples using within-sample relative expression orderings of genes. Liver Int. 2017; 37(11):1688-1696. DOI: 10.1111/liv.13467. View

Reig M, Forner A, Rimola J, Ferrer-Fabrega J, Burrel M, Garcia-Criado A . BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol. 2021; 76(3):681-693. PMC: 8866082. DOI: 10.1016/j.jhep.2021.11.018. View

Mendiola M, Carrillo J, Garcia E, Lalli E, Hernandez T, de Alava E . The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors. Int J Cancer. 2005; 118(6):1381-9. DOI: 10.1002/ijc.21578. View

Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A . p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol. 2005; 171(4):603-14. PMC: 2171557. DOI: 10.1083/jcb.200507002. View

Li S, Dai W, Mo W, Li J, Feng J, Wu L . By inhibiting PFKFB3, aspirin overcomes sorafenib resistance in hepatocellular carcinoma. Int J Cancer. 2017; 141(12):2571-2584. DOI: 10.1002/ijc.31022. View

Reutens A, Achermann J, Ito M, Gu W, Habiby R, Donohoue P . Clinical and functional effects of mutations in the DAX-1 gene in patients with adrenal hypoplasia congenita. J Clin Endocrinol Metab. 1999; 84(2):504-11. DOI: 10.1210/jcem.84.2.5468. View

Gozuacik D, Kimchi A . Autophagy and cell death. Curr Top Dev Biol. 2007; 78:217-45. DOI: 10.1016/S0070-2153(06)78006-1. View

Kroemer G, Jaattela M . Lysosomes and autophagy in cell death control. Nat Rev Cancer. 2005; 5(11):886-97. DOI: 10.1038/nrc1738. View

Swain A, Lovell-Badge R . Mammalian sex determination: a molecular drama. Genes Dev. 1999; 13(7):755-67. DOI: 10.1101/gad.13.7.755. View

10.

Lanczky A, Gyorffy B . Web-Based Survival Analysis Tool Tailored for Medical Research (KMplot): Development and Implementation. J Med Internet Res. 2021; 23(7):e27633. PMC: 8367126. DOI: 10.2196/27633. View

11.

Simon D, Hammer G . Adrenocortical stem and progenitor cells: implications for adrenocortical carcinoma. Mol Cell Endocrinol. 2012; 351(1):2-11. PMC: 3288146. DOI: 10.1016/j.mce.2011.12.006. View

12.

Kondo Y, Kanzawa T, Sawaya R, Kondo S . The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005; 5(9):726-34. DOI: 10.1038/nrc1692. View

13.

Lu S, Yao Y, Xu G, Zhou C, Zhang Y, Sun J . CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma. Cell Death Dis. 2018; 9(6):646. PMC: 5974417. DOI: 10.1038/s41419-018-0681-z. View

14.

Wu H, Wang T, Liu Y, Li X, Xu S, Wu C . Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis. J Exp Clin Cancer Res. 2020; 39(1):274. PMC: 7720487. DOI: 10.1186/s13046-020-01768-8. View

15.

Song C, Tang H, Ran L, Ko B, Zhang Z, Chen X . Sirtuin 3 inhibits hepatocellular carcinoma growth through the glycogen synthase kinase-3β/BCL2-associated X protein-dependent apoptotic pathway. Oncogene. 2015; 35(5):631-41. DOI: 10.1038/onc.2015.121. View

16.

Zhang C, Liu Z, Bunker E, Ramirez A, Lee S, Peng Y . Sorafenib targets the mitochondrial electron transport chain complexes and ATP synthase to activate the PINK1-Parkin pathway and modulate cellular drug response. J Biol Chem. 2017; 292(36):15105-15120. PMC: 5592685. DOI: 10.1074/jbc.M117.783175. View

17.

Weiskirchen R . Commentary: Crocetin protected human hepatocyte LO2 cell from TGF-β-induced oxygen stress and apoptosis but promoted proliferation and autophagy AMPK/m-TOR pathway. Front Public Health. 2022; 10:1002484. PMC: 9701700. DOI: 10.3389/fpubh.2022.1002484. View

18.

Evans R . The steroid and thyroid hormone receptor superfamily. Science. 1988; 240(4854):889-95. PMC: 6159881. DOI: 10.1126/science.3283939. View

19.

Zhang Z, Dong S, Liu Y, Zhang M, Zhang J, Zhu H . Enhanced anticancer activity by the combination of vinpocetine and sorafenib via PI3K/AKT/GSK-3β signaling axis in hepatocellular carcinoma cells. Anticancer Drugs. 2021; 32(7):727-733. DOI: 10.1097/CAD.0000000000001056. View

20.

Gu X, Guan J, Xu J, Zheng Q, Chen C, Yang Q . Model based on five tumour immune microenvironment-related genes for predicting hepatocellular carcinoma immunotherapy outcomes. J Transl Med. 2021; 19(1):26. PMC: 7788940. DOI: 10.1186/s12967-020-02691-4. View