The role of tumor necrosis factor-<b>α</b> in the development and progression of hepatocellular carcinoma

Lingling ZHU; Yani ZHANG; Tingting SHI; Yang WU; Chun GAO; Xiaohui YU; Yujing HE; Jiucong ZHANG

doi:10.12449/JCH241129

Volume 40 Issue 11

Nov. 2024

Turn off MathJax

Article Contents

Abstract

References

Article Navigation > Journal of Clinical Hepatology > 2024 > 40(11): 2320-2325

PDF( 1143 KB)

The role of tumor necrosis factor-α in the development and progression of hepatocellular carcinoma

DOI: 10.12449/JCH241129

Lingling ZHU^{1, 2},
Yani ZHANG^{1, 2},
Tingting SHI^{1, 2},
Yang WU^{1, 2},
Chun GAO¹,
Xiaohui YU¹,
Yujing HE^{1
,
,
,},
Jiucong ZHANG^{1
,
,
,}

1.
Department of Gastroenterology，The 940 Hospital of Joint Logistic Support Force of PLA，Lanzhou 730050，China
2.
The First Clinical Medical College of Gansu University of Chinese Medicine，Lanzhou 730000，China

Research funding:

Central University Excellent Youth Team Cultivation Project (31920220065);

Gansu Province Health Industry Scientific Research Plan Project Contract (GSWSKY2022-76);

Gansu Planning Project on Science and Technology (23JRRA1673)

More Information

Corresponding author: HE Yujing， heyujing2019@163.com （ORCID： 0009-0000-5577-6867）; ZHANG Jiucong， zhangjiucong@163.com （ORCID： 0000-0003-4006-3033）
Received Date: 2024-01-27
Accepted Date: 2024-03-15
Published Date: 2024-11-25

Abstract

Abstract

Tumor necrosis factor-α （TNF-α） is involved in the regulation of multiple biological processes such as the proliferation， invasion， migration， and chemotherapy resistance of hepatocellular carcinoma （HCC） cells through TNF receptor-mediated signaling pathways. At the same time， TNF-α also plays a role in inducing the apoptosis of HCC cells. Some TNF-α inhibitors have been shown to inhibit the progression of HCC and prolong survival time. At present， the potential mechanism of action of TNF-α in HCC remains unclear， and exploration of the interaction between TNF-α and HCC can help to determine the potential therapeutic targets for HCC. This article summarizes the latest research advances in the mechanism of action of TNF-α in HCC and introduces the possibility of targeting TNF-α as a treatment method for HCC， in order to provide a theoretical basis for the prevention and treatment of liver cancer and drug research and development.
- Carcinoma， Hepatocellular,
- Tumor Necrosis Factor-alpha,
- Signal Transduction,
- Molecular Targeted Therapy

FullText(HTML)

References(50)

References

[1]	CHEN YX, WEN HH, ZHOU C, et al. TNF-α derived from M2 tumor-associated macrophages promotes epithelial-mesenchymal transition and cancer stemness through the Wnt/β‍-catenin pathway in SMMC-7721 hepatocellular carcinoma cells[J]. Exp Cell Res, 2019, 378( 1): 41- 50. DOI: 10.1016/j.yexcr.2019.03.005.
[2]	JANG MK, KIM HS, CHUNG YH. Clinical aspects of tumor necrosis factor-α signaling in hepatocellular carcinoma[J]. Curr Pharm Des, 2014, 20( 17): 2799- 2808. DOI: 10.2174/13816128113199990587.
[3]	TIEGS G, HORST AK. TNF in the liver: Targeting a central player in inflammation[J]. Semin Immunopathol, 2022, 44( 4): 445- 459. DOI: 10.1007/s00281-022-00910-2.
[4]	TSENG WC, LAI HC, HUANG YH, et al. Tumor necrosis factor alpha: Implications of anesthesia on cancers[J]. Cancers, 2023, 15( 3): 739. DOI: 10.3390/cancers15030739.
[5]	LAHA D, GRANT R, MISHRA P, et al. The role of tumor necrosis factor in manipulating the immunological response of tumor microenvironment[J]. Front Immunol, 2021, 12: 656908. DOI: 10.3389/fimmu.2021.656908.
[6]	COUSSENS LM, WERB Z. Inflammation and cancer[J]. Nature, 2002, 420( 6917): 860- 867. DOI: 10.1038/nature01322.
[7]	WANG X, LIN Y. Tumor necrosis factor and cancer, buddies or foes?[J]. Acta Pharmacol Sin, 2008, 29( 11): 1275- 1288. DOI: 10.1111/j.1745-7254.2008.00889.x.
[8]	KALLIOLIAS GD, IVASHKIV LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies[J]. Nat Rev Rheumatol, 2016, 12( 1): 49- 62. DOI: 10.1038/nrrheum.2015.169.
[9]	CHEN AY, WOLCHOK JD, BASS AR. TNF in the era of immune checkpoint inhibitors: Friend or foe?[J]. Nat Rev Rheumatol, 2021, 17( 4): 213- 223. DOI: 10.1038/s41584-021-00584-4.
[10]	MERCOGLIANO MF, BRUNI S, MAURO F, et al. Harnessing tumor necrosis factor alpha to achieve effective cancer immunotherapy[J]. Cancers, 2021, 13( 3): 564. DOI: 10.3390/cancers13030564.
[11]	JING YY, SUN K, LIU WT, et al. Tumor necrosis factor-α promotes hepatocellular carcinogenesis through the activation of hepatic progenitor cells[J]. Cancer Lett, 2018, 434: 22- 32. DOI: 10.1016/j.canlet.2018.07.001.
[12]	YANG X, SHAO CC, DUAN LX, et al. Oncostatin M promotes hepatic progenitor cell activation and hepatocarcinogenesis via macrophage-derived tumor necrosis factor-α[J]. Cancer Lett, 2021, 517: 46- 54. DOI: 10.1016/j.canlet.2021.05.039.
[13]	XIA LM, MO P, HUANG WJ, et al. The TNF-α/ROS/HIF-1-induced upregulation of FoxMI expression promotes HCC proliferation and resistance to apoptosis[J]. Carcinogenesis, 2012, 33( 11): 2250- 2259. DOI: 10.1093/carcin/bgs249.
[14]	XU ZW, YAN SX, WU HX, et al. The influence of TNF-α and Ang II on the proliferation, migration and invasion of HepG2 cells by regulating the expression of GRK2[J]. Cancer Chemother Pharmacol, 2017, 79( 4): 747- 758. DOI: 10.1007/s00280-017-3267-z.
[15]	XU ZW, YAN SX, WU HX, et al. Angiotensin II and tumor necrosis factor-α stimulate the growth, migration and invasion of BEL-7402 cells via down-regulation of GRK2 expression[J]. Dig Liver Dis, 2019, 51( 2): 263- 274. DOI: 10.1016/j.dld.2018.06.007.
[16]	SHI JN, SONG SP, LI SX, et al. TNF-α/NF-κB signaling epigenetically represses PSD4 transcription to promote alcohol-related hepatocellular carcinoma progression[J]. Cancer Med, 2021, 10( 10): 3346- 3357. DOI: 10.1002/cam4.3832.
[17]	ZHANG GP, YUE X, LI SQ. Cathepsin C interacts with TNF-α/p38 MAPK signaling pathway to promote proliferation and metastasis in hepatocellular carcinoma[J]. Cancer Res Treat, 2020, 52( 1): 10- 23. DOI: 10.4143/crt.2019.145.
[18]	ZONG C, MENG Y, YE F, et al. AIF1+CSF1R+MSCs, induced by TNF-α, act to generate an inflammatory microenvironment and promote hepatocarcinogenesis[J]. Hepatology, 2023, 78( 2): 434- 451. DOI: 10.1002/hep.32738.
[19]	MENG Y, ZHAO QD, AN LW, et al. A TNFR2-hnRNPK axis promotes primary liver cancer development via activation of YAP signaling in hepatic progenitor cells[J]. Cancer Res, 2021, 81( 11): 3036- 3050. DOI: 10.1158/0008-5472.CAN-20-3175.
[20]	QI DD, LU M, XU PF, et al. Transcription factor ETV4 promotes the development of hepatocellular carcinoma by driving hepatic TNF-α signaling[J]. Cancer Commun, 2023, 43( 12): 1354- 1372. DOI: 10.1002/cac2.12482.
[21]	LIU ZC, NING F, WANG HF, et al. Epidermal growth factor and tumor necrosis factor α cooperatively promote the motility of hepatocellular carcinoma cell lines via synergistic induction of fibronectin by NF-κB/p65[J]. Biochim Biophys Acta Gen Subj, 2017, 1861( 11 Pt A): 2568- 2582. DOI: 10.1016/j.bbagen.2017.08.010.
[22]	KASTL L, SAUER SW, RUPPERT T, et al. TNF-α mediates mitochondrial uncoupling and enhances ROS-dependent cell migration via NF-κB activation in liver cells[J]. FEBS Lett, 2014, 588( 1): 175- 183. DOI: 10.1016/j.febslet.2013.11.033.
[23]	HUANG BP, LIN CS, WANG CJ, et al. Upregulation of heat shock protein 70 and the differential protein expression induced by tumor necrosis factor-alpha enhances migration and inhibits apoptosis of hepatocellular carcinoma cell HepG2[J]. Int J Med Sci, 2017, 14( 3): 284- 293. DOI: 10.7150/ijms.17861.
[24]	ZHU Y, CHENG Y, GUO YB, et al. Protein kinase D2 contributes to TNF-α-induced epithelial mesenchymal transition and invasion via the PI3K/GSK-3β/β-catenin pathway in hepatocellular carcinoma[J]. Oncotarget, 2016, 7( 5): 5327- 5341. DOI: 10.18632/oncotarget.6633.
[25]	SHRESTHA R, BRIDLE KR, CRAWFORD DHG, et al. TNF-α-mediated epithelial-to-mesenchymal transition regulates expression of immune checkpoint molecules in hepatocellular carcinoma[J]. Mol Med Rep, 2020, 21( 4): 1849- 1860. DOI: 10.3892/mmr.2020.10991.
[26]	DASH S, SARASHETTI PM, RAJASHEKAR B, et al. TGF-β2-induced EMT is dampened by inhibition of autophagy and TNF-α treatment[J]. Oncotarget, 2018, 9( 5): 6433- 6449. DOI: 10.18632/oncotarget.23942.
[27]	TAN WL, LUO X, LI WD, et al. TNF-α is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma[J]. EBioMedicine, 2019, 40: 446- 456. DOI: 10.1016/j.ebiom.2018.12.047.
[28]	ZHOU C, SUN BY, ZHOU PY, et al. MAIT cells confer resistance to Lenvatinib plus anti-PD1 antibodies in hepatocellular carcinoma through TNF-TNFRSF1B pathway[J]. Clin Immunol, 2023, 256: 109770. DOI: 10.1016/j.clim.2023.109770.
[29]	LI N, WANG JN, ZHANG N, et al. Cross-talk between TNF-α and IFN-γ signaling in induction of B7-H1 expression in hepatocellular carcinoma cells[J]. Cancer Immunol Immunother, 2018, 67( 2): 271- 283. DOI: 10.1007/s00262-017-2086-8.
[30]	ZHAO L, JIN Y, YANG C, et al. HBV-specific CD8 T cells present higher TNF-α expression but lower cytotoxicity in hepatocellular carcinoma[J]. Clin Exp Immunol, 2020, 201( 3): 289- 296. DOI: 10.1111/cei.13470.
[31]	ZHENG XX, CHEN XD, WU WC. The regulatory axis of PD-L1 isoform 2/TNF/T cell proliferation is required for the canonical immune-suppressive effects of PD-L1 isoform 1 in liver cancer[J]. Int J Mol Sci, 2023, 24( 7): 6314. DOI: 10.3390/ijms24076314.
[32]	TOKAY E, SAGKAN RI, KOCKAR F. TNF-α induces URG-4/URGCP gene expression inHepatoma cells through starvation dependent manner[J]. Biochem Genet, 2021, 59( 1): 300- 314. DOI: 10.1007/s10528-020-09972-z.
[33]	KOU XR, JING YY, DENG WJ, et al. Tumor necrosis factor-α attenuates starvation-induced apoptosis through upregulation of ferritin heavy chain in hepatocellular carcinoma cells[J]. BMC Cancer, 2013, 13: 438. DOI: 10.1186/1471-2407-13-438.
[34]	SUN QM, HU B, FU PY, et al. Long non-coding RNA 00607 as a tumor suppressor by modulating NF-κB p65/p53 signaling axis in hepatocellular carcinoma[J]. Carcinogenesis, 2018, 39( 12): 1438- 1446. DOI: 10.1093/carcin/bgy113.
[35]	LI D, FU J, DU M, et al. Hepatocellular carcinoma repression by TNFα-mediated synergistic lethal effect of mitosis defect-induced senescence and cell death sensitization[J]. Hepatology, 2016, 64( 4): 1105- 1120. DOI: 10.1002/hep.28637.
[36]	HOU JW, ZHAO RC, XIA WY, et al. PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis[J]. Nat Cell Biol, 2020, 22( 10): 1264- 1275. DOI: 10.1038/s41556-020-0575-z.
[37]	VERMA HK, MERCHANT N, BHASKAR LVKS. Tumor necrosis factor-alpha gene promoter(TNF-α G-308A) polymorphisms increase the risk of hepatocellular carcinoma in asians: A meta-analysis[J]. Crit Rev Oncog, 2020, 25( 1): 11- 20. DOI: 10.1615/CritRevOncog.2020034846.
[38]	LI HR, WANG YH, ZHANG M, et al. The high expression of TNF-α and NF-κB in tumor microenvironment predicts good prognosis of patients with BCLC-0-B hepatocellular carcinoma[J]. Transl Cancer Res, 2019, 8( 2): 532- 541. DOI: 10.21037/tcr.2019.03.09.
[39]	GUO DD, QIN L, SUN JP, et al. Dynamic changes of cytokine profiles and their correlation with tumor recurrence following thermal ablation in hepatocellular carcinoma[J]. Technol Cancer Res Treat, 2023, 22: 15330338231190644. DOI: 10.1177/15330338231190644.
[40]	LU MY, YEH ML, HUANG CI, et al. Dynamics of cytokines predicts risk of hepatocellular carcinoma among chronic hepatitis C patients after viral eradication[J]. World J Gastroenterol, 2022, 28( 1): 140- 153. DOI: 10.3748/wjg.v28.i1.140.
[41]	ZHANG M, HU J, LI HR, et al. High TNF-α and/or p38MAPK expression predicts a favourable prognosis in patients with T₁N₀M₀ hepatocellular carcinoma: An immunohistochemical study[J]. Oncol Lett, 2019, 17( 6): 4948- 4956. DOI: 10.3892/ol.2019.10193.
[42]	IIDA-UENO A, ENOMOTO M, UCHIDA-KOBAYASHI S, et al. Changes in plasma interleukin-8 and tumor necrosis factor-α levels during the early treatment period as a predictor of the response to sorafenib in patients with unresectable hepatocellular carcinoma[J]. Cancer Chemother Pharmacol, 2018, 82( 5): 857- 864. DOI: 10.1007/s00280-018-3681-x.
[43]	BRENNER D, BLASER H, MAK TW. Regulation of tumour necrosis factor signalling: Live or let die[J]. Nat Rev Immunol, 2015, 15( 6): 362- 374. DOI: 10.1038/nri3834.
[44]	LI W, JIAN YB. Antitumor necrosis factor-α antibodies as a noveltherapy for hepatocellular carcinoma[J]. Exp Ther Med, 2018, 16( 2): 529- 536. DOI: 10.3892/etm.2018.6235.
[45]	LI K, LI XH, WU ZJ, et al. Adenovirus encoding XAF-1 and TNF-α in the same open reading frame efficiently inhibits hepatocellular cancer cells[J]. Mol Med Rep, 2016, 13( 6): 5169- 5176. DOI: 10.3892/mmr.2016.5193.
[46]	WANG HM, LIU JM, HU XM, et al. Prognostic and therapeutic values of tumor necrosis factor-alpha in hepatocellular carcinoma[J]. Med Sci Monit, 2016, 22: 3694- 3704. DOI: 10.12659/msm.899773.
[47]	WANG MD, WU MC, YANG T. The synergistic effect of sorafenib and TNF-α inhibitor on hepatocellular carcinoma[J]. EBioMedicine, 2019, 40: 11- 12. DOI: 10.1016/j.ebiom.2019.01.007.
[48]	LEONE GM, MANGANO K, PETRALIA MC, et al. Past, present and(foreseeable) future of biological anti-TNF alpha therapy[J]. J Clin Med, 2023, 12( 4): 1630. DOI: 10.3390/jcm12041630.
[49]	BAI L, WANG K. Research progress of immune-related adverse reactions caused by immune checkpoint inhibitors[J]. J Changchun Univ Chin Med, 2023, 39( 2): 229- 236. DOI: 10.13463/j.cnki.cczyy.2023.02.025. 白黎, 王珂. 免疫检查点抑制剂导致免疫相关不良反应的研究进展[J]. 长春中医药大学学报, 2023, 39( 2): 229- 236. DOI: 10.13463/j.cnki.cczyy.2023.02.025.
[50]	FISCHER R, KONTERMANN RE, PFIZENMAIER K. Selective targeting of TNF receptors as a novel therapeutic approach[J]. Front Cell Dev Biol, 2020, 8: 401. DOI: 10.3389/fcell.2020.00401.

Relative Articles

[1]	Jiahao CHEN, Zhenhua ZHOU. Effect of Qizhu prescription on a mouse model of non-alcoholic fatty liver disease incluced by high-fat， high-fructose， and high-cholesterol diet and its mechanism[J]. Journal of Clinical Hepatology, 2024, 40(11): 2205-2212. doi: 10.12449/JCH241113
[2]	Haoxin DUAN, Yuyong JIANG, Tingyu WU, Feixiang XIONG, Yandan JIANG, Qin ZHANG, Saisai ZHAO, Hao YU. The genetic association between nonalcoholic fatty liver disease and type 2 diabetes mellitus in different body mass index categories： A bidirectional Mendelian randomization study[J]. Journal of Clinical Hepatology, 2024, 40(10): 1992-1999. doi: 10.12449/JCH241011
[3]	Jingjie ZHAO, Xinyu ZHAO, Chaoru HAN, Kaihui XIAO, Zhengzhao LU, Linyan QIN, Dong XU, Hong YOU. Association between sleep disorders and different stages of nonalcoholic fatty liver disease[J]. Journal of Clinical Hepatology, 2024, 40(7): 1354-1359. doi: 10.12449/JCH240712
[4]	Kaihao DU, Lizhao HOU, Lanminghui LUO, Xiaoge DONG, Wei JIANG, Zhan WANG. Current status and prospects of the application of Mendelian randomization in pancreatic cancer research[J]. Journal of Clinical Hepatology, 2024, 40(10): 2127-2136. doi: 10.12449/JCH241033
[5]	Lingwei LI, Junjie QIN, Yunlong JIA, Hao LYU. Application of Mendelian randomization in liver cancer[J]. Journal of Clinical Hepatology, 2024, 40(2): 391-396. doi: 10.12449/JCH240228
[6]	Ziwei GUO, Qingjuan WU, Yongan YE, Lanyu CHEN, Wenliang LYU. Application of Mendelian randomization analysis in exploring the etiology of nonalcoholic fatty liver disease[J]. Journal of Clinical Hepatology, 2024, 40(3): 589-593. doi: 10.12449/JCH240325
[7]	Zhenqi LI, Ning DU, Hongyang He. Association between primary sclerosing cholangitis and the risk of colorectal cancer: A two-sample Mendelian randomization study[J]. Journal of Clinical Hepatology, 2023, 39(3): 567-572. doi: 10.3969/j.issn.1001-5256.2023.03.013
[8]	Jiahui LYU, Xiaofei LI, Lianyi GUO. Association between metabolic associated fatty liver disease and sleep disorders[J]. Journal of Clinical Hepatology, 2021, 37(12): 2854-2860. doi: 10.3969/j.issn.1001-5256.2021.12.024
[9]	Zhao MengYu, Zou HuaiBin, Chen Yu, Zheng SuJun, Duan ZhongPing. Characteristics and mechanism of virological and liver function changes in pregnant women with chronic hepatitis B virus infection during pregnancy and after delivery[J]. Journal of Clinical Hepatology, 2019, 35(6): 1353-1357. doi: 10.3969/j.issn.1001-5256.2019.06.038
[10]	Wu JianJin, Yao DingKang. Recent advances in understanding the relations between liver cirrhosis and sleep disorders[J]. Journal of Clinical Hepatology, 2013, 29(5): 397-400.
[11]	Zhang GuiLi, Li Qiang, Li YouSheng, Tan LiJie, Zhang Hong, Liu ShiPing, Fan YanJu, Zhou ShuFang. The relation between serum adiponectin levels and liver function correlated factors in patients with chronic hepatitis B[J]. Journal of Clinical Hepatology, 2010, 26(2): 184-186.
[13]	Chen Sheng, Lin ChaoShuang. The relationship between liver function and immune system and viral replication in patients with viral hepatitis[J]. Journal of Clinical Hepatology, 2007, 23(2): 94-95.
[14]	Luo KaiZhong, Su XianShi, Jiang YongFang. Measurement of serum level of insulin-like growth factor binding protein-3 in patients with viral hepatitis and its assessment on liver function[J]. Journal of Clinical Hepatology, 2006, 22(1): 24-26.
[15]	Ding Hong, Lu ZhongHua, Jiang XiangHu. The relationship between the liver function and contents of serum HBVDNA and hepatic pathology in patiens with chronic hepatitis B.[J]. Journal of Clinical Hepatology, 2006, 22(3): 173-174.
[17]	Liu LongGen, Zhai DeFang, Liu JianHong, Qian MeiYun, Fang GuoPing. Researeh on the correlation between the contents of serum HBV DNA and liver function and liver tissue injury in hepatitis B patients.[J]. Journal of Clinical Hepatology, 2005, 21(1): 7-8.
[19]	Zhang JiWan, Wang HaiBin, Zhou JianLi, Liu TongFa, He PengFei, Wang YeDong, Zhang HaiLing, Long Li, Wang BinRong. Relationship between the serum complement receptor 1 of patients with hepatitis gravis and the degree of liver damage[J]. Journal of Clinical Hepatology, 2003, 19(3): 174-175.
[20]	Ye XiaoGuang, Liao YunZhen, Yu Xian. Study on the relationship between serum transforming growth factor-alpha level and liver function index in different type of liver diseases.[J]. Journal of Clinical Hepatology, 2001, 17(2): 83-84.

Supplements(0)

Cited By

Cited by

Periodical cited type(2)

1.	陈剑双，朱礼明，乐博昕，王成义，刘效峰，何凡. 宝山区吸毒人群丙型肝炎病毒感染状况调查. 预防医学. 2025(02): 168-172 .
2.	蔡超，高婧，王晓红，王欣然，范月冬，张庆娟，柳建强. 唐山市2005—2022年丙型病毒性肝炎监测结果分析. 国际病毒学杂志. 2024(04): 331-334 .

Other cited types(0)

Proportional views

Proportional views

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

Figures(2)

Get Citation

PDF

XML

Article Metrics

Article views (284) PDF downloads(22)