生物钟基因在肝癌发生发展与治疗中的研究进展

孔亚楠; 刘江凯

doi:10.12449/JCH250731

生物钟基因在肝癌发生发展与治疗中的研究进展

DOI: 10.12449/JCH250731

孔亚楠¹,
刘江凯^2, , ,

1.
河南中医药大学第一附属医院脾胃肝胆科，郑州 450008
2.
河南中医药大学第一临床医学院，郑州 450008

基金项目:

河南省中医管理局国家中医临床研究基地科研专项 (2021JDZY003);

河南省特色骨干学科中医学学科建设项目 (STG-ZYX04-202133);

河南省卫生健康委河南省中医药科学研究专项课题 (2023ZY2007)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：孔亚楠负责查阅文献，撰写论文；刘江凯负责指导撰写文章并最后定稿。

详细信息

通信作者:
刘江凯， 13592553982@126.com （ORCID： 0000-0002-1529-5089）

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出版历程
- 收稿日期: 2024-12-31
- 录用日期: 2025-02-20
- 出版日期: 2025-07-25

Research advances in circadian clock genes in the development， progression， and treatment of liver cancer

Yanan KONG¹,
Jiangkai LIU^{2
, ,
,}

1.
Spleen，Stomach and Hepatobiliary Department，The First Affiliated Hospital of Henan University of Chinese Medicine，Zhengzhou 450008，China
2.
The First Clinical Medical College of Henan University of Chinese Medicine，Zhengzhou 450008，China

Research funding:

Scientific Research Project of National Clinical Research Base of Traditional Chinese Medicine of Henan Provincial Administration (2021JDZY003);

Construction Project of Traditional Chinese Medicine in Henan Province (STG-ZYX04-202133);

Henan Provincial Health Commission Special Project of Traditional Chinese Medicine Scientific Research (2023ZY2007)

More Information

Corresponding author: LIU Jiangkai， 13592553982@126.com （ORCID： 0000-0002-1529-5089）

摘要

摘要: 原发性肝癌是最常见的消化系统恶性肿瘤之一，其发病率和病死率逐年上升。近年研究发现，生物钟基因失调与肝癌的发生发展密切相关，为肝癌的预防、诊疗及预后提供了新的视角。此外，靶向生物钟基因在治疗癌症方面也显示出一定的临床应用潜力。本文系统阐述了生物钟基因在肝癌发病机制、防治和预后等方面的最新研究进展，以期为肝癌临床诊疗提供新思路。
- 癌，肝细胞 /
- 生物钟 /
- 昼夜节律 /
- 基因，肿瘤抑制
Abstract: Primary liver cancer is one of the most common malignant tumors of the digestive system， and its morbidity and mortality rates are increasing year by year. Recent studies have shown that circadian clock gene disorders are closely associated with the development and progression of liver cancer， which provides a new perspective for the prevention， diagnosis， treatment， and prognosis of liver cancer. In addition， targeting circadian clock genes also shows a certain clinical application potential in the treatment of cancer. This article reviews the latest research advances in the role of circadian clock genes in the pathogenesis， prevention， treatment， and prognosis of liver cancer， in order to provide new ideas for the clinical diagnosis and treatment of liver cancer.
- Carcinoma， Hepatocellular /
- Biological Clocks /
- Circadian Rhythm /
- Genes， Tumor Suppressor

HTML全文

表 1 生物钟基因在肝癌发生发展中的作用机制

Table 1. The mechanism of clock genes in the tumorigenesis and development of hepatocellular carcinoma

生物钟基因	主要作用	与肝癌的关系
CLOCK	与BMAL1结合为异源二聚体，激活Cry、Per蛋白	CLOCK过表达促进细胞增殖，CLOCK过表达与预后负相关
BMAL1	与CLOCK/NPAS2结合为异源二聚体，激活Cry、 Per蛋白	BMAL1敲除可扰乱细胞周期，BMAL1低表达与预后正相关
Per（Per1、Per2、Per3）	与Cry形成异源二聚体，抑制CLOCK-BMAL1	Per2低表达/敲除可激活癌基因c-MYC和CCNB1、促进细胞增殖，Per2高DNA甲基化与预后正相关
Cry（Cry1、Cry2）	与Per形成异源二聚体，抑制CLOCK-BMAL1	Cry低表达/敲除可激活p53、细胞增殖和凋亡抑制，Cry2低表达与预后正相关
NPAS2	与BMAL1结合为异源二聚体，激活Cry、Per蛋白	NPAS2单核苷酸多态性与预后正相关
REV-ERB	与RORE位点结合，抑制BMAL1转录	REV-ERB过表达抑制细胞增殖
TIMELESS	参与Per-Cry异二聚体形成	TIMELESS过表达可抑制p53、促进糖酵解、抑制氧化磷酸化，促进细胞增殖

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参考文献(41)

[1]	JIANG SA, LU H, PAN YW, et al. Characterization of the distinct immune microenvironments between hepatocellular carcinoma and intrahepatic cholangiocarcinoma[J]. Cancer Lett, 2024, 588: 216799. DOI: 10.1016/j.canlet.2024.216799.
[2]	BARATI S, SAFFAR H, MEHRABADI S, et al. The circadian clock as a potential biomarker and therapeutic target in gastrointestinal cancers[J]. Curr Pharm Des, 2024, 30( 23): 1804- 1811. DOI: 10.2174/0113816128302762240515054444.
[3]	DELBÈS AS, QUIÑONES M, GOBET C, et al. Mice with humanized livers reveal the role of hepatocyte clocks in rhythmic behavior[J]. Sci Adv, 2023, 9( 20): eadf2982. DOI: 10.1126/sciadv.adf2982.
[4]	PADILLA J, OSMAN NM, BISSIG-CHOISAT B, et al. Circadian dysfunction induces NAFLD-related human liver cancer in a mouse model[J]. J Hepatol, 2024, 80( 2): 282- 292. DOI: 10.1016/j.jhep.2023.10.018.
[5]	LI SJ, SHUI K, ZHANG Y, et al. CGDB a database of circadian genes in eukaryotes[J]. Nucleic Acids Res, 2017, 45( D1): D397- D403. DOI: 10.1093/nar/gkw1028.
[6]	ZHANG C, MIAO JR, FAN X. The role of circadian clock-controlled mitochondrial dynamics in nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2024, 40( 8): 1670- 1676. DOI: 10.12449/JCH240826. 张策, 苗嘉芮, 樊旭. 生物钟调控的线粒体动力学在非酒精性脂肪性肝病中的作用[J]. 临床肝胆病杂志, 2024, 40( 8): 1670- 1676. DOI: 10.12449/JCH240826.
[7]	CELA O, SCRIMA R, PACELLI C, et al. Autonomous oscillatory mitochondrial respiratory activity: Results of a systematic analysis show heterogeneity in different in vitro-synchronized cancer cells[J]. Int J Mol Sci, 2024, 25( 14): 7797. DOI: 10.3390/ijms25147797.
[8]	DANIELS LJ, KAY D, MARJOT T, et al. Circadian regulation of liver metabolism: Experimental approaches in human, rodent, and cellular models[J]. Am J Physiol Cell Physiol, 2023, 325( 5): C1158- C1177. DOI: 10.1152/ajpcell.00551.2022.
[9]	CHEN SY, ZHANG WX, LI X, et al. DNA polymerase beta connects tumorigenicity with the circadian clock in liver cancer through the epigenetic demethylation of Per1[J]. Cell Death Dis, 2024, 15( 1): 78. DOI: 10.1038/s41419-024-06462-7.
[10]	SINGH A, ANJUM B, NAZ Q, et al. Night shift-induced circadian disruption: Links to initiation of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and risk of hepatic cancer[J]. Hepatoma Res, 2024: 2394- 5079.2024.88. DOI: 10.20517/2394-5079.2024.88.
[11]	YE ZY, DU Y, YU WG, et al. Construction of a circadian rhythm-relevant gene signature for hepatocellular carcinoma prognosis, immunotherapy and chemosensitivity prediction[J]. Heliyon, 2024, 10( 13): e33682. DOI: 10.1016/j.heliyon.2024.e33682.
[12]	de MARTINO M, RATHMELL JC, GALLUZZI L, et al. Cancer cell metabolism and antitumour immunity[J]. Nat Rev Immunol, 2024, 24( 9): 654- 669. DOI: 10.1038/s41577-024-01026-4.
[13]	ZHAO BM, NEPOVIMOVA E, WU QH. The role of circadian rhythm regulator PERs in oxidative stress, immunity, and cancer development[J]. Cell Commun Signal, 2025, 23( 1): 30. DOI: 10.1186/s12964-025-02040-2.
[14]	NIAN ZG, DOU YC, SHEN YQ, et al. Interleukin-34-orchestrated tumor-associated macrophage reprogramming is required for tumor immune escape driven by p53 inactivation[J]. Immunity, 2024, 57( 10): 2344- 2361. e 7. DOI: 10.1016/j.immuni.2024.08.015.
[15]	KONG MY, SHI XY, GAO J, et al. BTF3 affects hepatocellular carcinoma progression by transcriptionally upregulating PDCD2L and inactivating p53 signaling[J]. Mol Med, 2024, 30( 1): 252. DOI: 10.1186/s10020-024-01044-x.
[16]	QU M, ZHANG GX, QU H, et al. Circadian regulator BMAL1:: CLOCK promotes cell proliferation in hepatocellular carcinoma by controlling apoptosis and cell cycle[J]. Proc Natl Acad Sci USA, 2023, 120( 2): e2214829120. DOI: 10.1073/pnas.2214829120.
[17]	YANG SL, YU C, JIANG JX, et al. Hepatitis B virus X protein disrupts the balance of the expression of circadian rhythm genes in hepatocellular carcinoma[J]. Oncol Lett, 2014, 8( 6): 2715- 2720. DOI: 10.3892/ol.2014.2570.
[18]	CHEN XL, ZHAO QS, WANG HB, et al. Period2 is associated with immune cell infiltration and is a potential diagnostic and prognostic marker for hepatocellular carcinoma[J]. Front Mol Biosci, 2023, 10: 1264553. DOI: 10.3389/fmolb.2023.1264553.
[19]	RAJAN PK, UDOH US, FINLEY R, et al. The biological clock of liver metabolism in metabolic dysfunction-associated steatohepatitis progression to hepatocellular carcinoma[J]. Biomedicines, 2024, 12( 9): 1961. DOI: 10.3390/biomedicines12091961.
[20]	SANCAR A, van GELDER RN. Clocks, cancer, and chronochemotherapy[J]. Science, 2021, 371( 6524): eabb0738. DOI: 10.1126/science.abb0738.
[21]	FELLOWS RC, CHUN SK, LARSON N, et al. Disruption of the intestinal clock drives dysbiosis and impaired barrier function in colorectal cancer[J]. Sci Adv, 2024, 10( 39): eado1458. DOI: 10.1126/sciadv.ado1458.
[22]	LIU YQ, SU ZY, TAVANA O, et al. Understanding the complexity of p53 in a new era of tumor suppression[J]. Cancer Cell, 2024, 42( 6): 946- 967. DOI: 10.1016/j.ccell.2024.04.009.
[23]	MILLER S, KESHERWANI M, CHAN P, et al. CRY2 isoform selectivity of a circadian clock modulator with antiglioblastoma efficacy[J]. Proc Natl Acad Sci USA, 2022, 119( 40): e2203936119. DOI: 10.1073/pnas.2203936119.
[24]	GU WJ, LI T, HUANG YX, et al. Metabolic profile and lipid metabolism phenotype in mice with conditional deletion of hepatic BMAL1[J]. Int J Mol Sci, 2024, 25( 11): 6070. DOI: 10.3390/ijms25116070.
[25]	FERRELL JM. Chronobiology of cancers in the liver and gut[J]. Cancers(Basel), 2024, 16( 17): 2925. DOI: 10.3390/cancers16172925.
[26]	SHENG MF, ZHANG YY, WANG YY, et al. Decoding the role of aberrant RNA alternative splicing in hepatocellular carcinoma: A comprehensive review[J]. J Cancer Res Clin Oncol, 2023, 149( 19): 17691- 17708. DOI: 10.1007/s00432-023-05474-8.
[27]	HUANG CJ, XIAO X, ZHOU L, et al. Chinese expert consensus statement on the clinical application of AFP/AFP-L3%/DCP using GALAD and GALAD-like algorithm in HCC[J]. J Clin Lab Anal, 2023, 37( 23-24): e24990. DOI: 10.1002/jcla.24990.
[28]	YAN C, CHEN XG, JIN HL, et al. Role of the criteria based on preoperative serological indexes of AFP and GGT in predicting long-term survival of patients with hepatocellular carcinoma after liver transplantation[J]. Organ Transpl, 2023, 14( 2): 248- 256. DOI: 10.3969/j.issn.1674-7445.2023.02.011. 严成, 陈新国, 金海龙, 等. 基于术前血清学指标AFP和GGT的标准在预测肝细胞癌患者肝移植术后长期生存中的作用研究[J]. 器官移植, 2023, 14( 2): 248- 256. DOI: 10.3969/j.issn.1674-7445.2023.02.011.
[29]	ZHU XJ, ZHANG ZX, ZHANG JX, et al. Single-cell and bulk transcriptomic analyses reveal a stemness and circadian rhythm disturbance-related signature predicting clinical outcome and immunotherapy response in hepatocellular carcinoma[J]. Curr Gene Ther, 2025, 25( 2): 178- 193. DOI: 10.2174/0115665232298240240529131358.
[30]	CHI H, YANG JY, PENG GG, et al. Circadian rhythm-related genes index: A predictor for HNSCC prognosis, immunotherapy efficacy, and chemosensitivity[J]. Front Immunol, 2023, 14: 1091218. DOI: 10.3389/fimmu.2023.1091218.
[31]	LIU G, LUO YR, LIU JH, et al. Identification of a novel circadian rhythm-related signature for predicting prognosis and therapies in hepatocellular carcinoma based on bulk and single-cell RNA sequencing[J]. Eur J Cancer Care, 2024, 2024: 1834636. DOI: 10.1155/2024/1834636.
[32]	WANG C, ZENG Q, GÜL ZM, et al. Circadian tumor infiltration and function of CD8⁺ T cells dictate immunotherapy efficacy[J]. Cell, 2024, 187( 11): 2690- 2702. e 17. DOI: 10.1016/j.cell.2024.04.015.
[33]	HUANG MX, DUAN SY, ZHANG QW, et al. Deciphering the diurnal rhythm regulating mechanism of flavin-containing monooxygenase 3 in mouse liver[J]. Int J Biochem Cell Biol, 2024, 169: 106538. DOI: 10.1016/j.biocel.2024.106538.
[34]	OKYAR A, OZTURK CIVELEK D, AKYEL YK, et al. The role of the circadian timing system on drug metabolism and detoxification: An update[J]. Expert Opin Drug Metab Toxicol, 2024, 20( 6): 503- 517. DOI: 10.1080/17425255.2024.2356167.
[35]	HRUSHESKY WJ. Circadian timing of cancer chemotherapy[J]. Science, 1985, 228( 4695): 73- 75. DOI: 10.1126/science.3883493.
[36]	WADA K, HATTORI A, MARUYAMA Y, et al. Dietary melatonin and liver cancer incidence in Japan: From the Takayama study[J]. Cancer Sci, 2024, 115( 5): 1688- 1694. DOI: 10.1111/cas.16103.
[37]	NABIH HK, HAMED AR, YAHYA SMM. Anti-proliferative effect of melatonin in human hepatoma HepG2 cells occurs mainly through cell cycle arrest and inflammation inhibition[J]. Sci Rep, 2023, 13( 1): 4396. DOI: 10.1038/s41598-023-31443-9.
[38]	HAMED AR, YAHYA SMM, NABIH HK. Anti-drug resistance, anti-inflammation, and anti-proliferation activities mediated by melatonin in doxorubicin-resistant hepatocellular carcinoma: in vitro investigations[J]. Naunyn Schmiedebergs Arch Pharmacol, 2023, 396( 6): 1117- 1128. DOI: 10.1007/s00210-023-02385-w.
[39]	QIN P, LI YR, SU YJ, et al. Bifidobacterium adolescentis-derived hypaphorine alleviates acetaminophen hepatotoxicity by promoting hepatic Cry1 expression[J]. J Transl Med, 2024, 22( 1): 525. DOI: 10.1186/s12967-024-05312-6.
[40]	ANABTAWI N, CVAMMEN W, KEMP MG. Pharmacological inhibition of cryptochrome and REV-ERB promotes DNA repair and cell cycle arrest in cisplatin-treated human cells[J]. Sci Rep, 2021, 11( 1): 17997. DOI: 10.1038/s41598-021-97603-x.
[41]	GOMATOU G, KARACHALIOU A, VELOUDIOU OZ, et al. The role of REV-ERB receptors in cancer pathogenesis[J]. Int J Mol Sci, 2023, 24( 10): 8980. DOI: 10.3390/ijms24108980.