Research status of autophagy in hepatocellular carcinoma
-
摘要: 细胞自噬是种“自我吞食”的现象,通过降解细胞内受损或多余的蛋白、细胞器和其他胞质成分,从而实现细胞本身的代谢需要和细胞器的更新。正常情况下,自噬有利于维持细胞的稳态,防止损伤的蛋白或细胞器在细胞内堆积。通过吞噬泡的形成和延伸,产生自噬小体,继而与溶酶体融合形成自噬溶酶体,降解细胞内聚物及损伤的细胞器,为细胞的更新提供营养和能量。肝脏在代谢和应激后可发生高水平的自噬反应,自噬紊乱会影响肝细胞内的稳态而导致多种疾病的发生,自噬的缺失是多种肝脏疾病发生发展的关键机制。肝癌作为常见的肝脏恶性肿瘤,肿瘤形成早期自噬作为肝细胞肝癌形成的抑制因素,晚期肝癌细胞通过自噬在营养缺乏和低氧环境下生存,自噬为癌细胞提供营养物质促进生长。目前大量研究表明,细胞自噬在肝细胞肝癌的发生发展中发挥重要作用,同时自噬对肿瘤治疗有细胞保护性和细胞毒性的双重影响,因此通过调控自噬能提高肝细胞肝癌的治愈率,为肝癌提供新的治疗靶点及方向。本文主要总结细胞自噬的发生机制,了解细胞自噬对肝细胞肝癌发生发展的影响和潜在的治疗价值。Abstract: Autophagy is a phenomenon of "self-engulfment" by degrading damaged or redundant proteins, organelles and other cytoplasmic components in cells to achieve the metabolic needs of cells and the renewal of organelles. Under normal circumstances, autophagy is conducive to maintaining the homeostasis of cells, prevents damaged proteins or organelles from accumulating in cells and generates autophagosomes through the formation and extension of phagosomes, which then fuse with lysosomes to form autophagolysosomes. It can degrade intracellular aggregates and damage organelles to provide nutrients and energy for cell renewal. High levels of autophagy can occur in the liver after metabolism and stress. Autophagy disorders can affect the homeostasis of hepatocytes and lead to the occurrence of various diseases. The lack of autophagy is the key to the development of various liver diseases. Hepatocellular carcinoma is a common hepatic malignant tumour. Autophagy in the early stage of tumour formation can be used as an inhibitory factor for the formation of hepatocellular carcinoma. Advanced hepatocellular carcinoma cells overcome nutrient deficiency and survive under hypoxic environment through autophagy and provide nutrients for cancer cells to promote growth. At present, a large number of studies have shown that autophagy plays an important role in the occurrence and development of hepatocellular carcinoma. Autophagy also has cytoprotective and cytotoxic effects on tumour treatment. Therefore, regulating autophagy can improve the cure rate of hepatocellular carcinoma. To provide new therapeutic targets and directions for liver cancer, this review mainly summarised the mechanism of autophagy and the influence of autophagy on the occurrence and development of hepatocellular carcinoma and its potential therapeutic value.
-
Key words:
- Hepatocellular carcinoma /
- Autophagy /
- Liver tumour
-
[1] SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. doi: 10.3322/caac.21660 [2] 王攀, 王毅超, 虞丹丹, 等. miR-1246在肝癌血清中的表达及对肝癌HepG2细胞生物学功能的影响[J]. 中华全科医学, 2021, 19(8): 1292-1295, 1313. doi: 10.16766/j.cnki.issn.1674-4152.002043WANG P, WANG Y C, YU D D, et al. Expression of microRNA-1246 in the serum of hepatocellular carcinoma and its effect on biological function of HepG2 cells[J]. Chinese Journal of General Practice, 2021, 19(8): 1292-1295, 1313. doi: 10.16766/j.cnki.issn.1674-4152.002043 [3] NOGUCHI M, HIRATA N, TANAKA T, et al. Autophagy as a modulator of cell death machinery[J]. Cell Death Dis, 2020, 11(7): 517. doi: 10.1038/s41419-020-2724-5 [4] SANKAR D S, HU Z H, DENGJEL J. The complex interplay between ULK1 and protein phosphatases in autophagy regulation[J]. Autophagy, 2022, 18(2): 455-456. doi: 10.1080/15548627.2021.2002546 [5] EITZEN G, SMITHERS C C, MURRAY A G, et al. Structure and function of the fgd family of divergent FYVE domain proteins1[J]. Biochem Cell Biol, 2019, 97(3): 257-264. doi: 10.1139/bcb-2018-0185 [6] 陈佳锋, 傅修涛, 丁振斌. 自噬调控多功能蛋白p62/SQSTM1参与肿瘤及其微环境的研究进展[J]. 中国临床医学, 2020, 27(2): 321-326. https://www.cnki.com.cn/Article/CJFDTOTAL-LCYX202002034.htmCHEN J F, FU X T, DING Z B. Advances in autophagy-regulated multifunctional protein p62/SQSTM1 in tumor and its microenvironment[J]. Chinese Journal of Clinical Medicine, 2020, 27(2): 321-326. https://www.cnki.com.cn/Article/CJFDTOTAL-LCYX202002034.htm [7] CAO W Y, LI J H, YANG K P, et al. An overview of autophagy: mechanism, regulation and research progress[J]. Bull Cancer, 2021, 108(3): 304-322. doi: 10.1016/j.bulcan.2020.11.004 [8] LIU G Y, SABATINI D M. mTOR at the nexus of nutrition, growth, ageing and disease[J]. Nat Rev Mol Cell Biol, 2020, 21(4): 183-203. http://d.wanfangdata.com.cn/periodical/31b5f70675ba1ae032e1c8d10a5592ad [9] LI X H, HE S K, MA B Y. Autophagy and autophagy-related proteins in cancer[J]. Mol Cancer, 2020, 19(1): 12. doi: 10.1186/s12943-020-1138-4 [10] SZWED A, KIM E, JACINTO E. Regulation and metabolic functions of mTORC1 and mTORC2[J]. Physiol Rev, 2021, 101(3): 1371-1426. doi: 10.1152/physrev.00026.2020 [11] WANG Y, ZHANG H B. Regulation of autophagy by mTOR signaling pathway[J]. Adv Exp Med Biol, 2019, 1206: 67-83. http://d.wanfangdata.com.cn/periodical/cbf1fa43d51a2b9e94ab23104bc32c91 [12] 高利昆, 袁静萍, 洪莉. 细胞自噬与肿瘤治疗的研究进展[J]. 中国组织化学与细胞化学杂志, 2020, 29(2): 183-187. https://www.cnki.com.cn/Article/CJFDTOTAL-GGZZ202002015.htmGAO L K, YUAN J P, HONG L. Recent progress in autophagy and tumor therapy[J]. Chinese Journal of Histochemistry and Cytochemistry, 2020, 29(2): 183-187. https://www.cnki.com.cn/Article/CJFDTOTAL-GGZZ202002015.htm [13] WANG X Y, LIN Y, LIU S, et al. O-GlcNAcylation modulates HBV replication through regulating cellular autophagy at multiple levels[J]. FASEB J, 2020, 34(11): 14473-14489. DOI: 10.1096/fj.202001168RR. [14] XIE M J, YANG Z G, LIU Y N, et al. The role of HBV-induced autophagy in HBV replication and HBV related-HCC[J]. Life Sci, 2018, 205: 107-112. doi: 10.1016/j.lfs.2018.04.051 [15] CHU J Y K, OU J J. Autophagy in HCV replication and protein trafficking[J]. Int J Mol Sci, 2021, 22(3): 1089. doi: 10.3390/ijms22031089 [16] DEVIS-JAUREGUI L, ERITJA N, DAVIS M L, et al. Autophagy in the physiological endometrium and cancer[J]. Autophagy, 2021, 17(5): 1077-1095. doi: 10.1080/15548627.2020.1752548 [17] POILLET-PEREZ L, WHITE E. Role of tumor and host autophagy in cancer metabolism[J]. Genes Dev, 2019, 33(11-12): 610-619. doi: 10.1101/gad.325514.119 [18] YAZDANI H O, HUANG H, TSUNG A. Autophagy: dual response in the development of hepatocellular carcinoma[J]. Cells, 2019, 8(2): 91. doi: 10.3390/cells8020091 [19] DERETIC V. Autophagy in inflammation, infection, and immunometabolism[J]. Immunity, 2021, 54(3): 437-453. doi: 10.1016/j.immuni.2021.01.018 [20] LARABI A, BARNICH N, NGUYEN H. New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD[J]. Autophagy, 2020, 16(1): 38-51. doi: 10.1080/15548627.2019.1635384 [21] WANG L P, LI H T, ZHEN Z J, et al. CXCL17 promotes cell metastasis and inhibits autophagy via the LKB1-AMPK pathway in hepatocellular carcinoma[J]. Gene, 2019, 690: 129-136. doi: 10.1016/j.gene.2018.12.043 [22] DENK H, STUMPTNER C, ABUJA P M, et al. Sequestosome 1/p62-related pathways as therapeutic targets in hepatocellular carcinoma[J]. Expert Opin Ther Targets, 2019, 23(5): 393-406. doi: 10.1080/14728222.2019.1601703 [23] XING M T, LI P, WANG X, et al. Overexpression of p62/IMP2 can promote cell migration in hepatocellular carcinoma via activation of the Wnt/beta-catenin pathway[J]. Cancers (Basel), 2019, 12(1): 7. doi: 10.3390/cancers12010007 [24] BARTOLINI D, DALLAGLIO K, TORQUATO P, et al. Nrf2-p62 autophagy pathway and its response to oxidative stress in hepatocellular carcinoma[J]. Transl Res, 2018, 193: 54-71. doi: 10.1016/j.trsl.2017.11.007 [25] LIANG C J, LI W, GE H, et al. Role of Beclin1 expression in patients with hepatocellular carcinoma: a meta-analysis[J]. Onco Targets Ther, 2018, 11: 2387-2397. doi: 10.2147/OTT.S151751 [26] KIRUTHIGA C, DEVI K P, NABAVI S M, et al. Autophagy: a potential therapeutic target of polyphenols in hepatocellular carcinoma[J]. Cancers (Basel), 2020, 12(3): 562. doi: 10.3390/cancers12030562 [27] HUANG F, WANG B R, WANG Y G. Role of autophagy in tumorigenesis, metastasis, targeted therapy and drug resistance of hepatocellular carcinoma[J]. World J Gastroentero, 2018, 24(41): 4643-4651. doi: 10.3748/wjg.v24.i41.4643 [28] SCHITO L, REY S. Cell-Autonomous metabolic reprogramming in hypoxia[J]. Trends Cell Biol, 2018, 28(2): 128-142. doi: 10.1016/j.tcb.2017.10.006 [29] HAZARI Y, BRAVO-SAN P J, HETZ C, et al. Autophagy in hepatic adaptation to stress[J]. J Hepatol, 2020, 72(1): 183-196. doi: 10.1016/j.jhep.2019.08.026 [30] MOWERS E E, SHARIFI M N, MACLEOD K F. Functions of autophagy in the tumor microenvironment and cancer metastasis[J]. FEBS J, 2018, 285(10): 1751-1766. doi: 10.1111/febs.14388 [31] LI X Q, GAO L, ZHENG L J, et al. BMP4-mediated autophagy is involved in the metastasis of hepatocellular carcinoma via JNK/Beclin1 signaling[J]. Am J Transl Res, 2020, 12(6): 3068-3077. [32] LIANG C, DONG Z B, CAI X L, et al. Hypoxia induces sorafenib resistance mediated by autophagy via activating FOXO3a in hepatocellular carcinoma[J]. Cell Death Dis, 2020, 11(11): 1017. doi: 10.1038/s41419-020-03233-y [33] CHEN H T, LIU H, MAO M J, et al. Crosstalk between autophagy and epithelial-mesenchymal transition and its application in cancer therapy[J]. Mol Cancer, 2019, 18(1): 101. http://www.socolar.com/Article/Index?aid=200269641350&jid=200000134032 [34] KMA L, BARUAH T J. The interplay of ROS and the PI3K/Akt pathway in autophagy regulation[J]. Biotechnol Appl Biochem, 2022, 69(1): 248-264. doi: 10.1002/bab.2104 [35] SEITZ H K, MUELLER S. The role of Cytochrom P4502E1 in alcoholic liver disease and alcohol mediated carcinogenesis[J]. Z Gastroenterol, 2019, 57(1): 37-45. [36] BARTOLINI D, DALLAGLIO K, TORQUATO P, et al. Nrf2-p62 autophagy pathway and its response to oxidative stress in hepatocellular carcinoma[J]. Transl Res, 2018, 193: 54-71. http://download.xuebalib.com/89drev3F8B.pdf [37] QIAN H, CHAO X J, WILLIAMS J, et al. Autophagy in liver diseases: a review[J]. Mol Aspects Med, 2021, 82: 100973. DOI: 10.1016/j.mam.2021.100973. [38] ZHENG Y H, HUANG C, LU L, et al. STOML2 potentiates metastasis of hepatocellular carcinoma by promoting PINK1-mediated mitophagy and regulates sensitivity to lenvatinib[J]. J Hematol Oncol, 2021, 14(1): 16. http://www.socolar.com/Article/Index?aid=200259985143&jid=200000133853 [39] WANG X H, LI M, REN K B, et al. On-Demand autophagy cascade amplification nanoparticles precisely enhanced oxaliplatin-induced cancer immunotherapy[J]. Adv Mater, 2020, 32(32): e2002160. DOI: 10.1002/adma.202002160. [40] FRICKER L D. Proteasome inhibitor drugs[J]. Annu Rev Pharmacol Toxicol, 2020, 60: 457-476. http://d.wanfangdata.com.cn/periodical/d14f7185eafdc1a11b7ddbc014116ab9 [41] BHAT P, KRIEL J, SHUBHA P B, et al. Modulating autophagy in cancer therapy: advancements and challenges for cancer cell death sensitization[J]. Biochem Pharmacol, 2018, 147: 170-182. http://www.onacademic.com/detail/journal_1000040132151810_9630.html [42] SHENG J Y, QIN H J, ZHANG K, et al. Targeting autophagy in chemotherapy-resistant of hepatocellular carcinoma[J]. Am J Cancer Res, 2018, 8(3): 354-365. [43] GAO C, FANG L, ZHANG H, et al. Metformin induces autophagy via the AMPK-mTOR signaling pathway in human hepatocellular carcinoma cells[J]. Cancer Manag Res, 2020, 12: 5803-5811. http://doc.paperpass.com/foreign/rgArti2020267290860.html [44] LAI H Y, TSAI H H, YEN C J, et al. Metformin resensitizes sorafenib-resistant HCC cells through AMPK-Dependent autophagy activation[J]. Front Cell Dev Biol, 2020, 8: 596655. DOI: 10.3389/fcell.2020.596655. [45] TANG W W, CHEN Z Y, ZHANG W L, et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects[J]. Signal Transduct Target Ther, 2020, 5(1): 87. http://www.xueshufan.com/publication/3035408975 [46] YANG Q Z, GAO L H, HUANG X L, et al. Sorafenib prevents the proliferation and induces the apoptosis of liver cancer cells by regulating autophagy and hypoxia-inducible factor-1[J]. Exp Ther Med, 2021, 22(3): 980. http://www.xueshufan.com/publication/3179639326
点击查看大图
计量
- 文章访问数: 211
- HTML全文浏览量: 73
- PDF下载量: 11
- 被引次数: 0