Skip to content
2000
Volume 25, Issue 1
  • ISSN: 1568-0096
  • E-ISSN: 1873-5576

Abstract

Background

Hepatocellular carcinoma (HCC) remains one of the most lethal cancers globally. Despite advancements in immunotherapy, the prognosis for patients with HCC continues to be poor. As oxidative stress plays a significant role in the onset and progression of various diseases, including metabolism-related HCC, comprehending its mechanism in HCC is critical for effective diagnosis and treatment.

Methods

This study utilized the TCGA dataset and a collection of oxidative stress genes to identify the expression of oxidative stress-related genes in HCC and their association with overall survival using diverse bioinformatics methods. A novel prognostic risk model was developed, and the TCGA cohort was divided into high-risk and low-risk groups based on each tumor sample's risk score. Levels of immune cell infiltration and the expression of immune checkpoint-related genes in different risk subgroups were analyzed to investigate the potential link between tumor immunity and oxidative stress-related features. The expression of model genes in actual samples was validated through immunohistochemistry, and their mRNA and protein expression levels were measured in cell cultures.

Results

Four oxidative stress-related genes (EZH2, ANKZF1, G6PD, and HMOX1) were identified and utilized to create a predictive risk model for HCC patient overall survival, which was subsequently validated in an independent cohort. A correlation was found between the expression of these prognostic genes and the infiltration of tumor immune cells. Elevated expression of EZH2, ANKZF1, G6PD, and HMOX1 was observed in both HCC tissues and cell lines.

Conclusion

The combined assessment of EZH2, ANKZF1, G6PD, and HMOX1 gene expression can serve as an oxidative stress risk model for assessing HCC prognosis. Furthermore, there is a correlation between the expression of these risk model genes and tumor immunity.

Loading

Article metrics loading...

/content/journals/ccdt/10.2174/0115680096284532231220061048
2024-02-19
2024-11-21
Loading full text...

Full text loading...

References

  1. SungH. FerlayJ. SiegelR.L. LaversanneM. SoerjomataramI. JemalA. BrayF. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin.202171320924910.3322/caac.2166033538338
    [Google Scholar]
  2. McGlynnK.A. PetrickJ.L. El-SeragH.B. Epidemiology of hepatocellular carcinoma.Hepatology202173S1Suppl. 141310.1002/hep.3128832319693
    [Google Scholar]
  3. LlovetJ.M. KelleyR.K. VillanuevaA. SingalA.G. PikarskyE. RoayaieS. LencioniR. KoikeK. Zucman-RossiJ. FinnR.S. Hepatocellular carcinoma.Nat. Rev. Dis. Primers202171610.1038/s41572‑020‑00240‑333479224
    [Google Scholar]
  4. MoonA.M. SingalA.G. TapperE.B. Contemporary epidemiology of chronic liver disease and cirrhosis.Clin. Gastroenterol. Hepatol.202018122650266610.1016/j.cgh.2019.07.06031401364
    [Google Scholar]
  5. RebouissouS. NaultJ.C. Advances in molecular classification and precision oncology in hepatocellular carcinoma.J. Hepatol.202072221522910.1016/j.jhep.2019.08.01731954487
    [Google Scholar]
  6. SiesH. Oxidative stress: A concept in redox biology and medicine.Redox Biol.2015418018310.1016/j.redox.2015.01.00225588755
    [Google Scholar]
  7. FilomeniG. De ZioD. CecconiF. Oxidative stress and autophagy: The clash between damage and metabolic needs.Cell Death Differ.201522337738810.1038/cdd.2014.15025257172
    [Google Scholar]
  8. LiuY. HaoC. LiL. ZhangH. ZhaW. MaL. ChenL. GanJ. The role of oxidative stress in the development and therapeutic intervention of hepatocellular carcinoma.Curr. Cancer Drug Targets2023231079280410.2174/156800962366623041812113037073651
    [Google Scholar]
  9. ChengY.T. YangC.C. ShyurL.F. Phytomedicine-modulating oxidative stress and the tumor microenvironment for cancer therapy.Pharmacol. Res.201611412814310.1016/j.phrs.2016.10.02227794498
    [Google Scholar]
  10. SherN.M. NazliR. ZafarH. FatimaS. Effects of lipid based Multiple Micronutrients Supplement on the birth outcome of underweight pre-eclamptic women: A randomized clinical trial.Pak. J. Med. Sci.202138121922610.12669/pjms.38.1.439635035429
    [Google Scholar]
  11. AminA. LotfyM. Mahmoud-GhoneimD. AdeghateE. Al-AkhrasM.A. Al-SaadiM. Al-RahmounS. HameedR. Pancreas-protective effects of chlorella in STZ-induced diabetic animal model: Insights into the mechanism.J. Diabetes Mellitus201113364510.4236/jdm.2011.13006
    [Google Scholar]
  12. XieY. MuC. KazybayB. SunQ. KutzhanovaA. NazarbekG. XuN. NurtayL. WangQ. AminA. LiX. Network pharmacology and experimental investigation of Rhizoma polygonati extract targeted kinase with herbzyme activity for potent drug delivery.Drug Deliv.20212812187219710.1080/10717544.2021.197742234662244
    [Google Scholar]
  13. BouabdallahS. Al-MaktoumA. AminA. Steroidal Saponins: Naturally occurring compounds as inhibitors of the hallmarks of cancer.Cancers20231515390010.3390/cancers1515390037568716
    [Google Scholar]
  14. NarayanankuttyA. NambiattilS. MannarakkalS. Phytochemicals and nanoparticles in the modulation of PI3K/Akt/mTOR kinases and its implications in the development and progression of gastrointestinal cancers: A review of preclinical and clinical evidence.Recent Patents Anticancer Drug Discov.202318330732410.2174/157489281766622060610471235670354
    [Google Scholar]
  15. LozonL. SalehE. MenonV. RamadanW.S. AminA. El-AwadyR. Effect of safranal on the response of cancer cells to topoisomerase I inhibitors: Does sequence matter?Front. Pharmacol.20221393847110.3389/fphar.2022.93847136120345
    [Google Scholar]
  16. CastroL. FreemanB.A. Reactive oxygen species in human health and disease.Nutrition2001172161165, 163-16510.1016/S0899‑9007(00)00570‑011240347
    [Google Scholar]
  17. JaganjacM. MilkovicL. ZarkovicN. ZarkovicK. Oxidative stress and regeneration.Free Radic. Biol. Med.202218115416510.1016/j.freeradbiomed.2022.02.00435149216
    [Google Scholar]
  18. SenonerT. DichtlW. Oxidative stress in cardiovascular diseases: Still a therapeutic target?Nutrients2019119209010.3390/nu1109209031487802
    [Google Scholar]
  19. van der PolA. van GilstW.H. VoorsA.A. van der MeerP. Treating oxidative stress in heart failure: Past, present and future.Eur. J. Heart Fail.201921442543510.1002/ejhf.132030338885
    [Google Scholar]
  20. ChenZ. ZhongC. Oxidative stress in Alzheimer’s disease.Neurosci. Bull.201430227128110.1007/s12264‑013‑1423‑y24664866
    [Google Scholar]
  21. KimballJ.S. JohnsonJ.P. CarlsonD.A. Oxidative stress and osteoporosis.J. Bone Joint Surg. Am.2021103151451146110.2106/JBJS.20.0098934014853
    [Google Scholar]
  22. VitaleG. SalvioliS. FranceschiC. Oxidative stress and the ageing endocrine system.Nat. Rev. Endocrinol.20139422824010.1038/nrendo.2013.2923438835
    [Google Scholar]
  23. SosaV. MolinéT. SomozaR. PaciucciR. KondohH. LLeonartM.E. Oxidative stress and cancer: An overview.Ageing Res. Rev.201312137639010.1016/j.arr.2012.10.00423123177
    [Google Scholar]
  24. LuoY. MaJ. LuW. The significance of mitochondrial dysfunction in cancer.Int. J. Mol. Sci.20202116559810.3390/ijms2116559832764295
    [Google Scholar]
  25. ZengW. LongX. LiuP.S. XieX. The interplay of oncogenic signaling, oxidative stress and ferroptosis in cancer.Int. J. Cancer2023153591893110.1002/ijc.3448636843262
    [Google Scholar]
  26. PopracP. JomovaK. SimunkovaM. KollarV. RhodesC.J. ValkoM. Targeting free radicals in oxidative stress-related human diseases.Trends Pharmacol. Sci.201738759260710.1016/j.tips.2017.04.00528551354
    [Google Scholar]
  27. OthmanE.M. HabibH.A. ZahranM.E. AminA. HeebaG.H. Mechanistic protective effect of Cilostazol in Cisplatin-induced testicular damage via regulation of oxidative stress and TNF-α/NF-κB/Caspase-3 pathways.Int. J. Mol. Sci.202324161265110.3390/ijms24161265137628836
    [Google Scholar]
  28. HamzaA.A. HeebaG.H. HassaninS.O. ElwyH.M. BekhitA.A. AminA. Hibiscus-cisplatin combination treatment decreases liver toxicity in rats while increasing toxicity in lung cancer cells via oxidative stress- apoptosis pathway.Biomed. Pharmacother.202316511514810.1016/j.biopha.2023.11514837450997
    [Google Scholar]
  29. MuraliC. MudgilP. GanC.Y. TaraziH. El-AwadyR. AbdallaY. AminA. MaqsoodS. Camel whey protein hydrolysates induced G2/M cellcycle arrest in human colorectal carcinoma.Sci. Rep.2021111706210.1038/s41598‑021‑86391‑z33782460
    [Google Scholar]
  30. GorriniC. HarrisI.S. MakT.W. Modulation of oxidative stress as an anticancer strategy.Nat. Rev. Drug Discov.2013121293194710.1038/nrd400224287781
    [Google Scholar]
  31. MormoneE. GeorgeJ. NietoN. Molecular pathogenesis of hepatic fibrosis and current therapeutic approaches.Chem. Biol. Interact.2011193322523110.1016/j.cbi.2011.07.00121803030
    [Google Scholar]
  32. NelsonD.R. HroutA.A. AlzahmiA.S. ChaiboonchoeA. AminA. Salehi-AshtianiK. Molecular mechanisms behind Safranal’s Toxicity to HepG2 cells from dual omics.Antioxidants2022116112510.3390/antiox1106112535740022
    [Google Scholar]
  33. Abdel-latifR. HeebaG.H. HassaninS.O. WazS. AminA. TLRs-JNK/ NF-κB pathway underlies the protective effect of the sulfide salt against liver toxicity.Front. Pharmacol.20221385006610.3389/fphar.2022.85006635517830
    [Google Scholar]
  34. AbduS. JuaidN. AminA. Effects of sorafenib and quercetin alone or in combination in treating hepatocellular carcinoma: In vitro and in vivo approaches.202210.3390/molecules27228082
    [Google Scholar]
  35. AbdallaY. AbdallaA. HamzaA.A. AminA. Safranal prevents liver cancer through inhibiting oxidative stress and alleviating inflammation.Front. Pharmacol.20221277750010.3389/fphar.2021.77750035177980
    [Google Scholar]
  36. AwadB. HamzaA.A. Al-MaktoumA. Al-SalamS. AminA. Combining crocin and sorafenib improves their tumor-inhibiting effects in a rat model of diethylnitrosamine-induced cirrhotic-hepatocellular carcinoma.Cancers20231516406310.3390/cancers1516406337627094
    [Google Scholar]
  37. AbduS. JuaidN. AminA. MoulayM. MiledN. Therapeutic effects of crocin alone or in combination with sorafenib against hepatocellular carcinoma: In vivo & in vitro insights.Antioxidants2022119164510.3390/antiox1109164536139719
    [Google Scholar]
  38. GabbiaD. CannellaL. De MartinS. The role of oxidative stress in NAFLD–NASH–HCC transition-focus on NADPH oxidases.Biomedicines20219668710.3390/biomedicines906068734204571
    [Google Scholar]
  39. WangZ. LiZ. YeY. XieL. LiW. Oxidative stress and liver cancer: Etiology and therapeutic targets.Oxid. Med. Cell. Longev.2016201611010.1155/2016/789157427957239
    [Google Scholar]
  40. WuJ. LiL. ZhangH. ZhaoY. ZhangH. WuS. XuB. A risk model developed based on tumor microenvironment predicts overall survival and associates with tumor immunity of patients with lung adenocarcinoma.Oncogene202140264413442410.1038/s41388‑021‑01853‑y34108619
    [Google Scholar]
  41. XuD. WangY. WuJ. LinS. ChenY. ZhengJ. Identification and clinical validation of EMT-associated prognostic features based on hepatocellular carcinoma.Cancer Cell Int.202121162110.1186/s12935‑021‑02326‑834819088
    [Google Scholar]
  42. ZhouX. ShangY.N. LuR. FanC.W. MoX.M. High ANKZF1 expression is associated with poor overall survival and recurrence-free survival in colon cancer.Future Oncol.201915182093210610.2217/fon‑2018‑092031257922
    [Google Scholar]
  43. SajadiM. FaziltiM. NazemH. MahdevarM. GhaediK. The expression changes of transcription factors including ANKZF1, LEF1, CASZ1, and ATOH1 as a predictor of survival rate in colorectal cancer: A large-scale analysis.Cancer Cell Int.202222133910.1186/s12935‑022‑02751‑336344988
    [Google Scholar]
  44. LiuZ. LiuZ. ZhouX. LuY. YaoY. WangW. LuS. WangB. LiF. FuW. A glycolysis-related two-gene risk model that can effectively predict the prognosis of patients with rectal cancer.Hum. Genomics2022161510.1186/s40246‑022‑00377‑035109912
    [Google Scholar]
  45. ChenS. CaoG. WuW. LuY. HeX. YangL. ChenK. ChenB. XiongM. Mining novel cell glycolysis related gene markers that can predict the survival of colon adenocarcinoma patients.Biosci. Rep.2020408BSR2020142710.1042/BSR2020142732744303
    [Google Scholar]
  46. KongJ. YuG. SiW. LiG. ChaiJ. LiuY. LiuJ. Identification of a glycolysis-related gene signature for predicting prognosis in patients with hepatocellular carcinoma.BMC Cancer202222114210.1186/s12885‑022‑09209‑935123420
    [Google Scholar]
  47. XiaoG. JinL.L. LiuC.Q. WangY.C. MengY.M. ZhouZ.G. ChenJ. YuX.J. ZhangY.J. XuJ. ZhengL. EZH2 negatively regulates PD-L1 expression in hepatocellular carcinoma.J. Immunother. Cancer20197130010.1186/s40425‑019‑0784‑931727135
    [Google Scholar]
  48. ZhangL. LiH.T. SheredaR. LuQ. WeisenbergerD.J. O’ConnellC. MachidaK. AnW. LenzH.J. El-KhoueiryA. JonesP.A. LiuM. LiangG. DNMT and EZH2 inhibitors synergize to activate therapeutic targets in hepatocellular carcinoma.Cancer Lett.202254821589910.1016/j.canlet.2022.21589936087682
    [Google Scholar]
  49. WangB. LiuY. LiaoZ. WuH. ZhangB. ZhangL. EZH2 in hepatocellular carcinoma: Progression, immunity, and potential targeting therapies.Exp. Hematol. Oncol.20231215210.1186/s40164‑023‑00405‑237268997
    [Google Scholar]
  50. GuoB. TanX. CenH. EZH2 is a negative prognostic biomarker associated with immunosuppression in hepatocellular carcinoma.PLoS One20201511e024219110.1371/journal.pone.024219133180829
    [Google Scholar]
  51. BugideS. GreenM.R. WajapeyeeN. Inhibition of Enhancer of zeste homolog 2 (EZH2) induces natural killer cell-mediated eradication of hepatocellular carcinoma cells.Proc. Natl. Acad. Sci. USA201811515E3509E351810.1073/pnas.180269111529581297
    [Google Scholar]
  52. BachmannI.M. HalvorsenO.J. CollettK. StefanssonI.M. StraumeO. HaukaasS.A. SalvesenH.B. OtteA.P. AkslenL.A. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast.J. Clin. Oncol.200624226827310.1200/JCO.2005.01.518016330673
    [Google Scholar]
  53. GanL. XuM. HuaR. TanC. ZhangJ. GongY. WuZ. WengW. ShengW. GuoW. The polycomb group protein EZH2 induces epithelial–mesenchymal transition and pluripotent phenotype of gastric cancer cells by binding to PTEN promoter.J. Hematol. Oncol.2018111910.1186/s13045‑017‑0547‑329335012
    [Google Scholar]
  54. DuanR. DuW. GuoW. EZH2: A novel target for cancer treatment.J. Hematol. Oncol.202013110410.1186/s13045‑020‑00937‑832723346
    [Google Scholar]
  55. RaoX. DuanX. MaoW. LiX. LiZ. LiQ. ZhengZ. XuH. ChenM. WangP.G. WangY. ShenB. YiW. O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth.Nat. Commun.201561846810.1038/ncomms946826399441
    [Google Scholar]
  56. LiuB. FuX. DuY. FengZ. ChenR. LiuX. YuF. ZhouG. BaY. Pan-cancer analysis of G6PD carcinogenesis in human tumors.Carcinogenesis202344652553410.1093/carcin/bgad04337335542
    [Google Scholar]
  57. DengP. LiK. GuF. ZhangT. ZhaoW. SunM. HouB. LINC00242/miR-1-3p/G6PD axis regulates Warburg effect and affects gastric cancer proliferation and apoptosis.Mol. Med.2021271910.1186/s10020‑020‑00259‑y33514309
    [Google Scholar]
  58. MengQ. ZhangY. HaoS. SunH. LiuB. ZhouH. WangY. XuZ.X. Recent findings in the regulation of G6PD and its role in diseases.Front. Pharmacol.20221393215410.3389/fphar.2022.93215436091812
    [Google Scholar]
  59. YangH.C. SternA. ChiuD.T.Y. G6PD: A hub for metabolic reprogramming and redox signaling in cancer.Biomed. J.202144328529210.1016/j.bj.2020.08.00133097441
    [Google Scholar]
  60. ZhangY. XuY. LuW. LiJ. YuS. BrownE.J. StangerB.Z. RabinowitzJ.D. YangX. G6PD-mediated increase in de novo NADP + biosynthesis promotes antioxidant defense and tumor metastasis.Sci. Adv.2022829eabo040410.1126/sciadv.abo040435857842
    [Google Scholar]
  61. LuM. LuL. DongQ. YuG. ChenJ. QinL. WangL. ZhuW. JiaH. Elevated G6PD expression contributes to migration and invasion of hepatocellular carcinoma cells by inducing epithelial-mesenchymal transition.Acta Biochim. Biophys. Sin.201850437038010.1093/abbs/gmy00929471502
    [Google Scholar]
  62. DuD. LiuC. QinM. ZhangX. XiT. YuanS. HaoH. XiongJ. Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma.Acta Pharm. Sin. B202212255858010.1016/j.apsb.2021.09.01935256934
    [Google Scholar]
  63. CaoF. LuoA. YangC. G6PD inhibits ferroptosis in hepatocellular carcinoma by targeting cytochrome P450 oxidoreductase.Cell. Signal.20218711009810.1016/j.cellsig.2021.11009834325001
    [Google Scholar]
  64. ZhangX. GaoF. AiH. WangS. SongZ. ZhengL. WangG. SunY. BaoY. TSP50 promotes hepatocyte proliferation and tumour formation by activating glucose-6-phosphate dehydrogenase (G6PD).Cell Prolif.2021544e1301510.1111/cpr.1301533630390
    [Google Scholar]
  65. JiangH.Y. NingG. WangY.S. LvW.B. Ahypoxia-related signature enhances the prediction of the prognosis in hepatocellular carcinoma patients and correlates with sorafenib treatment response.Am. J. Transl. Res.202012127762778133437359
    [Google Scholar]
  66. ChiangS.K. ChenS.E. ChangL.C. The role of HO-1 and its crosstalk with oxidative stress in cancer cell survival.Cells2021109240110.3390/cells1009240134572050
    [Google Scholar]
  67. ConsonniF.M. BleveA. TotaroM.G. StortoM. KunderfrancoP. TermaniniA. PasqualiniF. AlìC. PandolfoC. SgambelluriF. GraziaG. SantinamiM. MaurichiA. MilioneM. ErreniM. DoniA. FabbriM. GribaldoL. RulliE. SoaresM.P. TorriV. MortariniR. AnichiniA. SicaA. Heme catabolism by tumor-associated macrophages controls metastasis formation.Nat. Immunol.202122559560610.1038/s41590‑021‑00921‑533903766
    [Google Scholar]
  68. LinH. ChenX. ZhangC. YangT. DengZ. SongY. HuangL. LiF. LiQ. LinS. JinD. EF24 induces ferroptosis in osteosarcoma cells through HMOX1.Biomed. Pharmacother.202113611120210.1016/j.biopha.2020.11120233453607
    [Google Scholar]
  69. ChangL.C. ChiangS.K. ChenS.E. YuY.L. ChouR.H. ChangW.C. Heme oxygenase-1 mediates BAY 11–7085 induced ferroptosis.Cancer Lett.201841612413710.1016/j.canlet.2017.12.02529274359
    [Google Scholar]
  70. SungP.S. Crosstalk between tumor-associated macrophages and neighboring cells in hepatocellular carcinoma.Clin. Mol. Hepatol.202228333335010.3350/cmh.2021.030834665953
    [Google Scholar]
  71. HuangH. JiangJ. ChenR. LinY. ChenH. LingQ. The role of macrophage TAM receptor family in the acute-to-chronic progression of liver disease: From friend to foe?Liver Int.202242122620263110.1111/liv.1538035900248
    [Google Scholar]
  72. HedrichV. BreiteneckerK. DjerlekL. OrtmayrG. MikulitsW. Intrinsic and extrinsic control of hepatocellular carcinoma by TAM receptors.Cancers20211321544810.3390/cancers1321544834771611
    [Google Scholar]
  73. CinierJ. HubertM. BessonL. Di RoioA. RodriguezC. LombardiV. CauxC. Ménétrier-CauxC. Recruitment and expansion of tregs cells in the tumor environment-how to target them?Cancers2021138185010.3390/cancers1308185033924428
    [Google Scholar]
  74. HuangY. JiaA. WangY. LiuG. CD8 + T cell exhaustion in anti-tumour immunity: The new insights for cancer immunotherapy.Immunology20231681304810.1111/imm.1358836190809
    [Google Scholar]
  75. ZanderR. SchauderD. XinG. NguyenC. WuX. ZajacA. CuiW. CD4+ T cell help is required for the formation of a cytolytic CD8+ T cell subset that protects against chronic infection and cancer.Immunity201951610281042.e410.1016/j.immuni.2019.10.00931810883
    [Google Scholar]
  76. ZhengY. WangX. HuangM. Metabolic regulation of CD8+T cells: From mechanism to therapy.Antioxid. Redox Signal.20223716-181234125310.1089/ars.2022.004035345890
    [Google Scholar]
  77. XiaM. WangB. WangZ. ZhangX. WangX. Epigenetic regulation of NK cell-mediated antitumor immunity.Front. Immunol.20211267232810.3389/fimmu.2021.67232834017344
    [Google Scholar]
  78. YanS. ZhangY. SunB. The function and potential drug targets of tumour-associated Tregs for cancer immunotherapy.Sci. China Life Sci.201962217918610.1007/s11427‑018‑9428‑930610537
    [Google Scholar]
/content/journals/ccdt/10.2174/0115680096284532231220061048
Loading
/content/journals/ccdt/10.2174/0115680096284532231220061048
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s web site along with the published article.

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test