内质网应激在癌症中具有多种调节作用。当mRNA翻译速率与蛋白折叠效率之间平衡被破坏，错误折叠或未折叠的蛋白质在内质网腔中的积累时，引起内质网应激，并触发未折叠蛋白质反应，以恢复蛋白质合成或者诱导细胞死亡。肝细胞癌是全球最常见和最致命的癌症之一，预后极差。内质网应激为肝细胞癌的关键因素，与肝细胞癌的发生和发展、耐药性和死亡调节密切相关，靶向内质网应激已成为潜在的抗肿瘤策略。本文结合近5年的相关文献，针对内质网应激对肝癌的影响进行概述。 ER stress was confirmed to be multiple regulators of cancer. When there are imbalances between the rate of mRNA translation and the efficiency of protein folding and unfolded or incompletely folded proteins accumulating in the ER, the cell experiences ER stress. This process triggers the unfolded protein response in order to restore protein synthesis or induce cell death. Hepatocellular carcinoma is one of the most common and deadly cancers worldwide with an extremely poor prognosis. ER stress has gradually been shown to be a major mechanism of hepatocellular carcinoma and was associated with tumorigenesis, development, drug resistance and cell death, targeting ER stress has emerged as a potential anti-tumor strategy. We searched for relevant publications in the last five years and present an overview of the current knowledge that links ER stress and HCC.
肝细胞癌，内质网应激，未折叠蛋白反应，抗癌治疗，耐药, Hepatocellular Carcinoma
Endoplasmic Reticulum Stress
Unfolded Protein Response
Anti-Cancer Therapy
Drug Resistance
摘要
ER stress was confirmed to be multiple regulators of cancer. When there are imbalances between the rate of mRNA translation and the efficiency of protein folding and unfolded or incompletely folded proteins accumulating in the ER, the cell experiences ER stress. This process triggers the unfolded protein response in order to restore protein synthesis or induce cell death. Hepatocellular carcinoma is one of the most common and deadly cancers worldwide with an extremely poor prognosis. ER stress has gradually been shown to be a major mechanism of hepatocellular carcinoma and was associated with tumorigenesis, development, drug resistance and cell death, targeting ER stress has emerged as a potential anti-tumor strategy. We searched for relevant publications in the last five years and present an overview of the current knowledge that links ER stress and HCC.
Keywords:Hepatocellular Carcinoma, Endoplasmic Reticulum Stress, Unfolded Protein Response, Anti-Cancer Therapy, Drug Resistance
徐佳怡,吴 亮. 肝细胞癌相关内质网应激的研究进展Research Progress of Endoplasmic Reticulum Stress in Hepatocellular Carcinoma[J]. 世界肿瘤研究, 2023, 13(02): 30-36. https://doi.org/10.12677/WJCR.2023.132005
参考文献References
Villanueva, A. (2019) Hepatocellular Carcinoma. The New England Journal of Medicine, 380, 1450-1462. https://doi.org/10.1056/NEJMra1713263
中华人民共和国国家卫生健康委员会. 原发性肝癌诊疗指南(2022年版) [J]. 临床肝胆病杂志, 2022, 38(5): 1027-1029.
Vogel, A., Meyer, T., Sapisochin, G., et al. (2022) Hepatocellular Carcinoma. The Lancet, 400, 1345-1362. https://doi.org/10.1016/S0140-6736(22)01200-4
Wu, J., Qiao, S., Xiang, Y., et al. (2021) Endoplasmic Reticulum Stress: Multiple Regulatory Roles in Hepatocellular Carcinoma. Biomedicine & Pharmacotherapy, 142, Article ID: 112005. https://doi.org/10.1016/j.biopha.2021.112005
Marciniak, S.J., Chambers, J.E. and Ron, D. (2022) Pharmacological Targeting of Endoplasmic Reticulum Stress in Disease. Nature Reviews Drug Discovery, 21, 115-140. https://doi.org/10.1038/s41573-021-00320-3
Pavlović, N. and Heindryckx, F. (2022) Targeting ER Stress in the Hepatic Tumor Microenvironment. FEBS Journal, 289, 7163-7176. https://doi.org/10.1111/febs.16145
Oakes, S.A. and Papa, F.R. (2015) The Role of Endoplasmic Reticulum Stress in Human Pathology. Annual Review of Pathology, 10, 173-194. https://doi.org/10.1146/annurev-pathol-012513-104649
Oakes, S.A. (2020) Endoplasmic Reticulum Stress Signaling in Cancer Cells. The American Journal of Pathology, 190, 934-946. https://doi.org/10.1016/j.ajpath.2020.01.010
Shore, G.C., Papa, F.R. and Oakes, S.A. (2011) Signaling Cell Death from the Endoplasmic Reticulum Stress Response. Current Opinion in Cell Biology, 23, 143-149. https://doi.org/10.1016/j.ceb.2010.11.003
Bommiasamy, H., Back, S.H., Fagone, P., et al. (2009) ATF6alpha Induces XBP1-Independent Expansion of the Endoplasmic Reticulum. Journal of Cell Science, 122, 1626-1636. https://doi.org/10.1242/jcs.045625
Khaled, J., Kopsida, M., Lennernäs, H., et al. (2022) Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma. Cells, 11, 632. https://doi.org/10.3390/cells11040632
Hong, F., Lin, C.Y., Yan, J., et al. (2022) Canopy Homolog 2 Contributes to Liver Oncogenesis by Promoting Unfolded Protein Response-Dependent Destabilization of Tumor Protein P53. Hepatology, 76, 1587-1601. https://doi.org/10.1002/hep.32318
Qi, Q., Niture, S., Gadi, S., et al. (2023) Per- and Polyfluoroalkyl Substances Activate UPR Pathway, Induce Steatosis and Fibrosis in Liver Cells. Environmental Toxicology, 38, 225-242. https://doi.org/10.1002/tox.23680
Song, J., Ding, W., Liu, B., et al. (2020) Anticancer Effect of Caudatin in Diethylnitrosamine‑Induced Hepatocarcinogenesis in Rats. Molecular Medicine Reports, 22, 697-706. https://doi.org/10.3892/mmr.2020.11135
Lu, Y., Wang, L.R., Lee, J., et al. (2022) The Unfolded Protein Response to PI*Z Alpha-1 Antitrypsin in Human Hepatocellular and Murine Models. Hepatology Communications, 6, 2354-2367. https://doi.org/10.1002/hep4.1997
Aran, G., Sanjurjo, L., Bárcena, C., et al. (2018) CD5L Is Upregulated in Hepatocellular Carcinoma and Promotes Liver Cancer Cell Proliferation and Antiapoptotic Responses by Binding to HSPA5 (GRP78). FASEB Journal, 32, 3878-3891. https://doi.org/10.1096/fj.201700941RR
Papaioannou, A., Higa, A., Jégou, G., et al. (2018) Alterations of EDEM1 Functions Enhance ATF6 Pro-Survival Signaling. FEBS Journal, 285, 4146-4164. https://doi.org/10.1111/febs.14669
Barnault, R., Lahlali, T., Plissonnier, M.-L., et al. (2018) Hepatocellular Carcinoma-Associated Depletion of the Netrin-1 Receptor Uncoordinated Phenotype-5A (UNC5A) Skews the Hepatic Unfolded Protein Response towards Prosurvival Outcomes. Biochemical and Biophysical Research Communications, 495, 2425-2431. https://doi.org/10.1016/j.bbrc.2017.12.129
Wei, C., Yang, X., Liu, N., et al. (2019) Tumor Microenvironment Regulation by the Endoplasmic Reticulum Stress Transmission Mediator Golgi Protein 73 in Mice. Hepatology, 70, 851-870. https://doi.org/10.1002/hep.30549
Pavlović, N., Kopsida, M., Gerwins, P., et al. (2020) Inhibiting P2Y12 in Macrophages Induces Endoplasmic Reticulum Stress and Promotes an Anti-Tumoral Phenotype. International Journal of Molecular Sciences, 21, 8177. https://doi.org/10.3390/ijms21218177
Li, Y., Xia, Y., Cheng, X., et al. (2019) Hepatitis B Surface Antigen Activates Unfolded Protein Response in Forming Ground Glass Hepatocytes of Chronic Hepatitis B. Viruses, 11, 386. https://doi.org/10.3390/v11040386
Liang, Y.-J., Teng, W., Chen, C.-L., et al. (2021) Clinical Implications of HBV PreS/S Mutations and the Effects of PreS2 Deletion on Mitochondria, Liver Fibrosis, and Cancer Development. Hepatology, 74, 641-655. https://doi.org/10.1002/hep.31789
Wu, S.-X., Ye, S.-S., Hong, Y.-X., et al. (2022) Hepatitis B Virus Small Envelope Protein Promotes Hepatocellular Carcinoma Angiogenesis via Endoplasmic Reticulum Stress Signaling to Upregulate the Expression of Vascular Endothelial Growth Factor A. Journal of Virology, 96, e0197521. https://doi.org/10.1128/jvi.01975-21
Armentano, M.F., Caterino, M., Miglionico, R., et al. (2018) New Insights on the Functional Role of URG7 in the Cellular Response to ER Stress. Biology of the Cell, 110, 147-158. https://doi.org/10.1111/boc.201800004
Aydin, Y., Kurt, R., Song, K., et al. (2019) Hepatic Stress Response in HCV Infection Promotes STAT3-Mediated Inhibition of HNF4A-miR-122 Feedback Loop in Liver Fibrosis and Cancer Progression. Cancers (Basel), 11, 1407. https://doi.org/10.3390/cancers11101407
Zhou, B., Lu, Q., Liu, J., et al. (2019) Melatonin Increases the Sensitivity of Hepatocellular Carcinoma to Sorafenib through the PERK-ATF4-Beclin1 Pathway. International Journal of Biological Sciences, 15, 1905-1920. https://doi.org/10.7150/ijbs.32550
Lin, J.-C., Yang, P.-M. and Liu, T.-P. (2021) PERK/ATF4-Dependent ZFAS1 Upregulation Is Associated with Sorafenib Resistance in Hepatocellular Carcinoma Cells. International Journal of Molecular Sciences, 22, 5848. https://doi.org/10.3390/ijms22115848
Guo, B., Xu, X., Shao, M., et al. (2022) UDP-Glucose 6-Dehydrogenase Lessens Sorafenib Sensitivity via Modulating Unfolded Protein Response. Biochemical and Biophysical Research Communications, 613, 207-213. https://doi.org/10.1016/j.bbrc.2022.05.048
Chiu, C.-C., Chen, Y.-C., Bow, Y.-D., et al. (2022) diTFPP, a Phenoxyphenol, Sensitizes Hepatocellular Carcinoma Cells to C2-Ceramide-Induced Autophagic Stress by Increasing Oxidative Stress and ER Stress Accompanied by LAMP2 Hypoglycosylation. Cancers (Basel), 14, 2528. https://doi.org/10.3390/cancers14102528
Liu, Y., Tao, S., Liao, L., et al. (2020) TRIM25 Promotes the Cell Survival and Growth of Hepatocellular Carcinoma through Targeting Keap1-Nrf2 Pathway. Nature Communications, 11, 348. https://doi.org/10.1038/s41467-019-14190-2
Liu, H., Xie, S., Fang, F., et al. (2020) SHQ1 Is an ER Stress Response Gene That Facilitates Chemotherapeutics-Induced Apoptosis via Sensitizing ER-Stress Response. Cell Death & Disease, 11, 445. https://doi.org/10.1038/s41419-020-2656-0
Munakarmi, S., Shrestha, J., Shin, H.-B., et al. (2021) 3,3’-Diindolylmethane Suppresses the Growth of Hepatocellular Carcinoma by Regulating Its Invasion, Migration, and ER Stress-Mediated Mitochondrial Apoptosis. Cells, 10, 1178. https://doi.org/10.3390/cells10051178
Rinaldi, R., Miglionico, R., Nigro, I., et al. (2021) Two Novel Precursors of the HIV-1 Protease Inhibitor Darunavir Target the UPR/Proteasome System in Human Hepatocellular Carcinoma Cell Line HepG2. Cells, 10, 3052. https://doi.org/10.3390/cells10113052
Li, X., Chen, Q., Liu, J., et al. (2022) Orphan Nuclear Receptor Nur77 Mediates the Lethal Endoplasmic Reticulum Stress and Therapeutic Efficacy of Cryptomeridiol in Hepatocellular Carcinoma. Cells, 11, 3870. https://doi.org/10.3390/cells11233870
Choi, C., Cho, Y., Son, A., et al. (2020) Therapeutic Potential of (-)-Agelamide D, a Diterpene Alkaloid from the Marine Sponge Agelas sp., as a Natural Radiosensitizer in Hepatocellular Carcinoma Models. Marine Drugs, 18, 500. https://doi.org/10.3390/md18100500
Ding, Y., Chen, X., Wang, B., et al. (2018) Deubiquitinase Inhibitor b-AP15 Activates Endoplasmic Reticulum (ER) Stress and Inhibits Wnt/Notch1 Signaling Pathway Leading to the Reduction of Cell Survival in Hepatocellular Carcinoma Cells. European Journal of Pharmacology, 825, 10-18. https://doi.org/10.1016/j.ejphar.2018.02.020
Shi, T.-L., Zhang, L., Cheng, Q.-Y., et al. (2019) Xanthatin Induces Apoptosis by Activating Endoplasmic Reticulum Stress in Hepatoma Cells. European Journal of Pharmacology, 843, 1-11. https://doi.org/10.1016/j.ejphar.2018.10.041
Kim, S.Y., Hwang, S., Lee, B.R., et al. (2022) Inhibition of Histone Demethylase KDM4 by ML324 Induces Apoptosis through the Unfolded Protein Response and Bim Upregulation in Hepatocellular Carcinoma Cells. Chemico-Biological Interactions, 353, Article ID: 109806. https://doi.org/10.1016/j.cbi.2022.109806
Hwang, S., Kim, S., Kim, K., et al. (2020) Euchromatin Histone Methyltransferase II (EHMT2) Regulates the Expression of Ras-Related GTP Binding C (RRAGC) Protein. BMB Reports, 53, 576-581. https://doi.org/10.5483/BMBRep.2020.53.11.055
Pomlok, K., Pata, S., Kulaphisit, M., et al. (2022) An IgM Monoclonal Antibody against Domain 1 of CD147 Induces Non-Canonical RIPK-Independent Necroptosis in a Cell Type Specific Manner in Hepatocellular Carcinoma Cells. BBA Molecular Cell Research, 1869, Article ID: 119295. https://doi.org/10.1016/j.bbamcr.2022.119295
Chen, J., Zhang, Z.-Q., Song, J., et al. (2018) 18β-Glycyrrhetinic-Acid-Mediated Unfolded Protein Response Induces Autophagy and Apoptosis in Hepatocellular Carcinoma. Scientific Reports, 8, 9365. https://doi.org/10.1038/s41598-018-27142-5
Pibiri, M., Sulas, P., Camboni, T., et al. (2020) α-Lipoic Acid Induces Endoplasmic Reticulum Stress-Mediated Apoptosis in Hepatoma Cells. Scientific Reports, 10, 7139. https://doi.org/10.1038/s41598-020-64004-5
Al-Hrout, A.A., Chaiboonchoe, A., Khraiwesh, B., et al. (2018) Safranal Induces DNA Double-Strand Breakage and ER-Stress-Mediated Cell Death in Hepatocellular Carcinoma Cells. Scientific Reports, 8, 16951. https://doi.org/10.1038/s41598-018-34855-0
Zheng, X., Liu, B., Liu, X., et al. (2022) PERK Regulates the Sensitivity of Hepatocellular Carcinoma Cells to High-LET Carbon Ions via either Apoptosis or Ferroptosis. Journal of Cancer, 13, 669-680. https://doi.org/10.7150/jca.61622
Forno, F., Maatuf, Y., Boukeileh, S., et al. (2020) Aripiprazole Cytotoxicity Coincides with Activation of the Unfolded Protein Response in Human Hepatic Cells. Journal of Pharmacology and Experimental Therapeutics, 374, 452-461. https://doi.org/10.1124/jpet.119.264481
Goyal, H., Sharma, R., Lamba, D., et al. (2023) Folic Acid Depletion along with Inhibition of the PERK Arm of Endoplasmic Reticulum Stress Pathway Promotes a Less Aggressive Phenotype of Hepatocellular Carcinoma Cells. Molecular and Cellular Biochemistry. https://doi.org/10.1007/s11010-022-04651-6
