NOD样受体蛋白3（NLRP3）炎性小体在肝细胞癌发生发展中的作用

余学海; 陈本栋; 刘伊敏; 马勇新; 张旭升; 周红才; 马海燕

doi:10.12449/JCH240229

NOD样受体蛋白3（NLRP3）炎性小体在肝细胞癌发生发展中的作用

DOI: 10.12449/JCH240229

余学海^1a,
陈本栋^{1b, 2, , ,},
刘伊敏²,
马勇新²,
张旭升²,
周红才²,
马海燕²

1a.
宁夏医科大学总医院小儿外科，银川 750000
1b.
宁夏医科大学总医院肝胆外科，银川 750000
2.
宁夏医科大学，银川 750000

基金项目:

宁夏自然科学基金重点项目 (2023AAC02073);

宁夏医科大学校级项目 (XM2023022)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：余学海负责课题设计，查阅文献，撰写论文；刘伊敏、马勇新、张旭升、周红才负责查阅收集文献，修改论文；马海燕负责图片制作和格式修改；陈本栋负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
陈本栋， chenbendong@nxmu.edu.cn （ORCID： 0009-0001-8566-9269）

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- 被引次数: 0
出版历程
- 收稿日期: 2023-06-02
- 录用日期: 2023-08-01
- 出版日期: 2024-02-19

Role of NOD-like receptor protein 3 inflammasome in the development and progression of hepatocellular carcinoma

1a.
Department of Pediatric Surgery，General Hospital of Ningxia Medical University，Yinchuan 750000，China
1b.
Department of Hepatobiliary Surgery，General Hospital of Ningxia Medical University，Yinchuan 750000，China
2.
Ningxia Medical University，Yinchuan 750000，China

Research funding:

Key Project of Ningxia Natural Science Foundation (2023AAC02073);

School Level Project of Ningxia Medical University (XM2023022)

More Information

Corresponding author: CHEN Bendong， chenbendong@nxmu.edu.cn （ORCID： 0009-0001-8566-9269）

摘要

摘要: 近年来，关于NOD样受体蛋白3（NLRP3）炎性小体在肿瘤中的研究已成为热点话题，尤其是在黑色素瘤、结直肠癌、肺癌、乳腺癌等肿瘤中，越来越多的证据表明炎症在促进肿瘤的发生发展、血管生成和肿瘤侵袭中具有重要的作用。肝细胞癌（HCC）是原发性肝癌中最常见的类型，而关于NLRP3炎性小体在HCC发生发展中的作用仍争议不断。因此，本文就NLRP3炎性小体在HCC进展过程中的潜在影响以及在抗癌治疗中的作用机制作一综述，认为NLRP3炎性小体可以作为HCC患者的有效治疗靶点。
- 癌，肝细胞 /
- NLR家族，热蛋白结构域包含蛋白3 /
- 细胞焦亡
Abstract: In recent years， NOD-like receptor protein 3 （NLRP3） inflammasome in tumors has become a research hotspot， especially in melanoma， colorectal cancer， lung cancer， and breast cancer， and more and more evidence has shown that inflammation plays a role in the development， progression， angiogenesis， and invasion of cancer. Hepatocellular carcinoma （HCC） is the most common type of primary liver cancer， and there are still controversies over the role of NLRP3 inflammasome in the development and progression of HCC. Therefore， this article reviews the potential impact of NLRP3 inflammasome in the progression of HCC and its mechanism of action in anticancer therapy， and it is believed that NLRP3 inflammasome can be used as an effective therapeutic target for HCC patients.
- Carcinoma， Hepatocellular /
- NLR Family， Pyrin Domain-Containing 3 Protein /
- Pyroptosis

HTML全文

代谢相关脂肪性肝病（MASLD）是一种以肝脂质异常沉积为特征，同时伴随心脏代谢危险因素的代谢性疾病，现已成为全世界最常见的慢性肝病。MASLD的发展与肠道稳态的失衡紧密相连，紊乱的肠道菌群及其代谢物通过受损的肠道屏障到达肝脏，引起肝脏的代谢紊乱和炎症。IL-33在黏膜屏障部位高表达，通过影响肠上皮细胞和免疫细胞调控肠道稳态。目前IL-33在MASLD中的作用尚未阐明，但考虑到IL-33在肝脏中的表达水平较低以及作用的局限性，探索肠源性IL-33在肝脏疾病中的作用对于深入理解MASLD的病理机制具有重要意义。

华中科技大学同济医学院附属同济医院宁琴教授、王晓晶教授团队研究发现，在MASLD患者及小鼠模型中，肝脏IL-33及其受体ST2的表达与对照组相比无显著变化，而MASLD患者血清可溶性ST2水平以及小鼠肠道IL-33和ST2表达均显著升高。在高脂饮食诱导的MASLD模型中，脂毒性物质刺激肠上皮细胞增加IL-33合成，肠源性IL-33通过诱导肠道稳态失调，即增加肠道内与三甲胺-N-氧化物（TMAO）合成相关菌群的丰度，包括 Lachnoclostridium、 Providencia、 Desulfovibrio、 Blautia、 Prevotella等，以及血清TMAO水平，造成肝脏的氧化应激损伤，最终加重MASLD的代谢紊乱、炎症和纤维化进展。机制上，一方面，肠上皮细胞合成的IL-33进入细胞核中与缺氧诱导因子1α（HIF-1α）结合，抑制HIF-1α激活以及下游基因 Tff3、 Cdh1、 Adora2b表达，直接损伤肠屏障；另一方面，肠上皮细胞损伤后释放的IL-33与肠道固有层CD4 ⁺T淋巴细胞表面的ST2结合，通过增加HIF-1α表达促进辅助性T淋巴细胞（Th）1分化和干扰素γ合成，破坏肠道Th1/Th17平衡并增加肠道炎症损伤，破坏肠道稳态。

总之，该研究强调了肠源性IL-33在MASLD发病机制中的关键作用，IL-33通过双重调控肠上皮细胞和固有层Th1的HIF-1α信号通路，促进肠道稳态破坏和肠道菌群TMAO合成，最终推动MASLD进展。该研究为理解肠道IL-33在MASLD中的作用提供了新的视角，并指出靶向IL-33及其影响的肠道菌群可能成为治疗MASLD的有效策略。

摘译自HAI S, LI X, XIE E, et al. Intestinal IL-33 promotes microbiota-derived trimethylamine N-oxide synthesis and drives metabolic dysfunction-associated steatotic liver disease progression by exerting dual regulation on HIF-1α[J]. Hepatology, 2024. DOI: 10.1097/HEP.0000000000000985. [Online ahead of print]

(华中科技大学同济医学院附属同济医院海素平报道）

注： a，NLRP3受体蛋白结构包含N端pyrin结构域（PYD）、中央NACHT结构域和C端富含亮氨酸的重复结构域（LRR）；ASC包含PYD和CARD结构域；pro-Caspase-1包含Caspase和CARD结构域；b，NLRP3、ASC、pro-Caspase-1依次结合组装成轮状炎性复合物；c，NLRP3炎性小体激活和激活后作用。

图 1 NLRP3炎性小体的结构和功能

Figure 1. Schematic diagram of the structure and function of the NLRP3 inflammasome complex

下载: 全尺寸图片幻灯片

图 2 NLRP3炎性小体促进HCC的发生

Figure 2. Schematic diagram of NLRP3 inflammasomes promotes the development of HCC

下载: 全尺寸图片幻灯片

注： NLRP3炎性小体通过细胞焦亡途径激活Caspase-1裂解炎性因子前体和GSDMD，产生N-GSDMD具有穿孔细胞膜作用，破裂溶解后释放各种促炎因子，从而抑制HCC的进展。

图 3 NLRP3炎性小体介导细胞焦亡抑制HCC的发展

Figure 3. Schematic diagram of NLRP3 inflammasome inhibits the development of HCC through classical pyroptosis

下载: 全尺寸图片幻灯片

参考文献(38)

[1]	LI Z, ZHU JY. Interpretation of standard for diagnosis and treatment of primary liver cancer(2022 edition)[J]. J Clin Hepatol, 2022, 38( 5): 1027- 1029. DOI: 10.3969/j.issn.1001-5256.2022.05.010. 李照, 朱继业.《原发性肝癌诊疗指南(2022年版)》解读[J]. 临床肝胆病杂志, 2022, 38( 5): 1027- 1029. DOI: 10.3969/j.issn.1001-5256.2022.05.010.
[2]	YANG JD, HAINAUT P, GORES GJ, et al. A global view of hepatocellular carcinoma: Trends, risk, prevention and management[J]. Nat Rev Gastroenterol Hepatol, 2019, 16( 10): 589- 604. DOI: 10.1038/s41575-019-0186-y.
[3]	HUANG XY, CHAO X, HUANG F. Research progress on role of pyroptosis in progress of primary liver cancer[J]. Drug Eval Res, 2021, 44( 7): 1535- 1540. DOI: 10.7501/j.issn.1674-6376.2021.07.026. 黄鑫悦, 晁旭, 黄峰. 细胞焦亡在原发性肝癌进展中的作用研究进展[J]. 药物评价研究, 2021, 44( 7): 1535- 1540. DOI: 10.7501/j.issn.1674-6376.2021.07.026.
[4]	KARKI R, KANNEGANTI TD. Diverging inflammasome signals in tumorigenesis and potential targeting[J]. Nat Rev Cancer, 2019, 19( 4): 197- 214. DOI: 10.1038/s41568-019-0123-y.
[5]	KANTONO M, GUO BC. Inflammasomes and cancer: The dynamic role of the inflammasome in tumor development[J]. Front Immunol, 2017, 8: 1132. DOI: 10.3389/fimmu.2017.01132.
[6]	XIA XJ, WANG X, CHENG Z, et al. The role of pyroptosis in cancer: Pro-cancer or pro-“host”?[J]. Cell Death Dis, 2019, 10( 9): 650. DOI: 10.1038/s41419-019-1883-8.
[7]	DAGENAIS M, SKELDON A, SALEH M. The inflammasome: In memory of Dr. Jurg Tschopp[J]. Cell Death Differ, 2012, 19( 1): 5- 12. DOI: 10.1038/cdd.2011.159.
[8]	SCHRODER K, TSCHOPP J. The inflammasomes[J]. Cell, 2010, 140( 6): 821- 832. DOI: 10.1016/j.cell.2010.01.040.
[9]	MISSIROLI S, PERRONE M, BONCOMPAGNI C, et al. Targeting the NLRP3 inflammasome as a new therapeutic option for overcoming cancer[J]. Cancers, 2021, 13( 10): 2297. DOI: 10.3390/cancers13102297.
[10]	MALIK A, KANNEGANTI TD. Inflammasome activation and assembly at a glance[J]. J Cell Sci, 2017, 130( 23): 3955- 3963. DOI: 10.1242/jcs.207365.
[11]	PATEL MN, CARROLL RG, GALVÁN-PEÑA S, et al. Inflammasome priming in sterile inflammatory disease[J]. Trends Mol Med, 2017, 23( 2): 165- 180. DOI: 10.1016/j.molmed.2016.12.007.
[12]	MOOSSAVI M, PARSAMANESH N, BAHRAMI A, et al. Role of the NLRP3 inflammasome in cancer[J]. Mol Cancer, 2018, 17( 1): 158. DOI: 10.1186/s12943-018-0900-3.
[13]	TSAI YM, CHIANG KH, HUNG JY, et al. Der f1 induces pyroptosis in human bronchial epithelia via the NLRP3 inflammasome[J]. Int J Mol Med, 2018, 41( 2): 757- 764. DOI: 10.3892/ijmm.2017.3310.
[14]	TANG YL, TAO Y, ZHU L, et al. Role of NLRP3 inflammasome in hepatocellular carcinoma: A double-edged sword[J]. Int Immunopharmacol, 2023, 118: 110107. DOI: 10.1016/j.intimp.2023.110107.
[15]	SHI JJ, ZHAO Y, WANG K, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death[J]. Nature, 2015, 526( 7575): 660- 665. DOI: 10.1038/nature15514.
[16]	HAMARSHEH S, ZEISER R. NLRP3 inflammasome activation in cancer: A double-edged sword[J]. Front Immunol, 2020, 11: 1444. DOI: 10.3389/fimmu.2020.01444.
[17]	MAMUN A AL, MIMI AA, AZIZ MA, et al. Role of pyroptosis in cancer and its therapeutic regulation[J]. Eur J Pharmacol, 2021, 910: 174444. DOI: 10.1016/j.ejphar.2021.174444.
[18]	INCHINGOLO R, POSA A, MARIAPPAN M, et al. Locoregional treatments for hepatocellular carcinoma: Current evidence and future directions[J]. World J Gastroenterol, 2019, 25( 32): 4614- 4628. DOI: 10.3748/wjg.v25.i32.4614.
[19]	CHEN WQ, ZHENG RS, BAADE PD, et al. Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66( 2): 115- 132. DOI: 10.3322/caac.21338.
[20]	ZENG HM, CHEN WQ, ZHENG RS, et al. Changing cancer survival in China during 2003-15: A pooled analysis of 17 population-based cancer registries[J]. Lancet Glob Health, 2018, 6( 5): e555- e567. DOI: 10.1016/S2214-109X(18)30127-X.
[21]	SUNG H, FERLAY J, SIEGEL RL, 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.
[22]	VOGEL A, MEYER T, SAPISOCHIN G, et al. Hepatocellular carcinoma[J]. Lancet, 2022, 400( 10360): 1345- 1362. DOI: 10.1016/S0140-6736(22)01200-4.
[23]	WEI Q, MU K, LI T, et al. Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression[J]. Lab Invest, 2014, 94( 1): 52- 62. DOI: 10.1038/labinvest.2013.126.
[24]	LIU BY, ZHOU ZW, JIN Y, et al. Hepatic stellate cell activation and senescence induced by intrahepatic microbiota disturbances drive progression of liver cirrhosis toward hepatocellular carcinoma[J]. J Immunother Cancer, 2022, 10( 1): e003069. DOI: 10.1136/jitc-2021-003069.
[25]	THI HTH, HONG S. Inflammasome as a therapeutic target for cancer prevention and treatment[J]. J Cancer Prev, 2017, 22( 2): 62- 73. DOI: 10.15430/JCP.2017.22.2.62.
[26]	JIANG S, ZHANG Y, ZHENG JH, et al. Potentiation of hepatic stellate cell activation by extracellular ATP is dependent on P2X7R-mediated NLRP3 inflammasome activation[J]. Pharmacol Res, 2017, 117: 82- 93. DOI: 10.1016/j.phrs.2016.11.040.
[27]	FAN SH, WANG YY, LU J, et al. Luteoloside suppresses proliferation and metastasis of hepatocellular carcinoma cells by inhibition of NLRP3 inflammasome[J]. PLoS One, 2014, 9( 2): e89961. DOI: 10.1371/journal.pone.0089961.
[28]	DALEY D, MANI VR, MOHAN N, et al. NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma[J]. J Exp Med, 2017, 214( 6): 1711- 1724. DOI: 10.1084/jem.20161707.
[29]	DING Y, YAN YL, DONG YH, et al. NLRP3 promotes immune escape by regulating immune checkpoints: A pan-cancer analysis[J]. Int Immunopharmacol, 2022, 104: 108512. DOI: 10.1016/j.intimp.2021.108512.
[30]	WAN LF, YUAN X, LIU MT, et al. miRNA-223-3p regulates NLRP3 to promote apoptosis and inhibit proliferation of hep3B cells[J]. Exp Ther Med, 2018, 15( 3): 2429- 2435. DOI: 10.3892/etm.2017.5667.
[31]	SONOHARA F, INOKAWA Y, KANDA M, et al. Association of inflammasome components in background liver with poor prognosis after curatively-resected hepatocellular carcinoma[J]. Anticancer Res, 2017, 37( 1): 293- 300. DOI: 10.21873/anticanres.11320.
[32]	WANG L, QIN XW, LIANG JM, et al. Induction of pyroptosis: A promising strategy for cancer treatment[J]. Front Oncol, 2021, 11: 635774. DOI: 10.3389/fonc.2021.635774.
[33]	CHEN YF, LI S, SHI Y, et al. Research progress on atherosclerosis induced by clonal hematopoiesis of indeterminate potential and the therapeutic effect of NLRP3 inflammasome[J]. China Med Herald, 2023, 20( 21): 40- 44. DOI: 10.20047/j.issn1673-7210.2023.21.08. 陈雅芳, 李思, 史洋, 等. 潜质未定克隆性造血致动脉粥样硬化及NLRP3炎性小体治疗作用研究进展[J]. 中国医药导报, 2023, 20( 21): 40- 44. DOI: 10.20047/j.issn1673-7210.2023.21.08.
[34]	CHU Q, JIANG YN, ZHANG W, et al. Pyroptosis is involved in the pathogenesis of human hepatocellular carcinoma[J]. Oncotarget, 2016, 7( 51): 84658- 84665. DOI: 10.18632/oncotarget.12384.
[35]	CHEN YF, QI HY, WU FL. Euxanthone exhibits anti-proliferative and anti-invasive activities in hepatocellular carcinoma by inducing pyroptosis: Preliminary results[J]. Eur Rev Med Pharmacol Sci, 2018, 22( 23): 8186- 8196. DOI: 10.26355/eurrev_201812_16511.
[36]	WEI Q, ZHU R, ZHU JY, et al. E2-induced activation of the NLRP3 inflammasome triggers pyroptosis and inhibits autophagy in HCC cells[J]. Oncol Res, 2019, 27( 7): 827- 834. DOI: 10.3727/096504018X15462920753012.
[37]	SHARIF H, WANG L, WANG WL, et al. Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome[J]. Nature, 2019, 570( 7761): 338- 343. DOI: 10.1038/s41586-019-1295-z.
[38]	YAN ZL, DA QG, LI ZF, et al. Inhibition of NEK7 suppressed hepatocellular carcinoma progression by mediating cancer cell pyroptosis[J]. Front Oncol, 2022, 12: 812655. DOI: 10.3389/fonc.2022.812655.