Skip to content
2000
Volume 20, Issue 3
  • ISSN: 1574-8928
  • E-ISSN: 2212-3970

Abstract

Background

Hepatocellular Carcinoma (HCC) is closely linked to inflammatory reactions, with chronic liver diseases acting as major risk factors. In the inflammatory microenvironment, repeated damage and repair of liver cells lead to genetic mutations, abnormal proliferation, and tumorigenesis.

Objective

This study aimed to investigate the expression profile of specific cell clusters under inflammatory stimulation in HCC and identify potential therapeutic drugs.

Methods

Comprehensive analysis of HCC transcriptome data and single-cell sequencing data from TCGA, ICGC, and GEO databases was conducted to explore the specific molecular mechanisms of epithelial cells. Virtual screening of natural compounds in the ZINC database and cell experiments were performed to identify drugs that regulate the expression of inflammatory factors in epithelial cells.

Results

Analysis of the single-cell dataset revealed cell clusters closely associated with HCC, notably Epithelial cells, Hepatocytes, MSC, and iPS cells, with Epithelial cells playing a pivotal role in HCC development. Further investigation of TCGA data unveiled 83 differentially expressed genes (DEGs) related to inflammatory responses in HCC. Intersection analysis of DEGs in epithelial cells and HCC DEGs identified 12 common DEGs, including ADRM1, ATP2B1, FZD5, GPC3, KIF1B, KLF6, LY6E, MET, NAMPT, SERPINE1, SPHK1, and SRI. Prognostic analysis revealed that CCL7, GPR132, ITGB8, PTAFR, SELL, and VIP were influential in the survival prognosis of HCC. A prognostic model based on the expression levels of these genes demonstrated an increased risk of HCC associated with higher differential expression of inflammatory response genes. Additionally, molecular dynamics simulations indicated that compounds NADH and Deferoxamine formed stable docking models with the inflammatory protein VIP, suggesting their potential as candidates for targeted therapy.

Conclusion

Inflammatory factors CCL7, GPR132, ITGB8, PTAFR, SELL, and VIP influence the inflammatory cascade response in HCC epithelial cells, and their expression correlates with the survival prognosis of HCC patients. Interfering with VIP expression effectively suppresses proliferation, migration, and invasion of HCC cells, as well as inhibiting the occurrence of inflammatory cascade reactions, thus slowing down the progression of hepatocellular carcinoma. Furthermore, compounds NADH and Deferoxamine have the potential to target and bind to the inflammatory protein VIP, highlighting their relevance in potential HCC treatment.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/pra/10.2174/0115748928256530240124093759
2024-01-30
2025-09-21

  • From This Site

    /content/journals/pra/10.2174/0115748928256530240124093759
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. VogelA. MeyerT. SapisochinG. SalemR. SaborowskiA. Hepatocellular carcinoma.Lancet2022400103601345136210.1016/S0140‑6736(22)01200‑4 36084663
     [Google Scholar]
  2. KulikL. El-SeragH.B. Epidemiology and management of hepatocellular carcinoma.Gastroenterology20191562477491.e110.1053/j.gastro.2018.08.065 30367835
     [Google Scholar]
  3. BertuccioP. TuratiF. CarioliG. Global trends and predictions in hepatocellular carcinoma mortality.J. Hepatol.201767230230910.1016/j.jhep.2017.03.011 28336466
     [Google Scholar]
  4. YangJ.D. HainautP. GoresG.J. AmadouA. PlymothA. RobertsL.R. A global view of hepatocellular carcinoma: Trends, risk, prevention and management.Nat. Rev. Gastroenterol. Hepatol.2019161058960410.1038/s41575‑019‑0186‑y 31439937
     [Google Scholar]
  5. SchulzeK. NaultJ.C. VillanuevaA. Genetic profiling of hepatocellular carcinoma using next-generation sequencing.J. Hepatol.20166551031104210.1016/j.jhep.2016.05.035 27262756
     [Google Scholar]
  6. PinyolR. MontalR. BassaganyasL. Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial.Gut20196861065107510.1136/gutjnl‑2018‑316408 30108162
     [Google Scholar]
  7. ImamuraT. OkamuraY. OhshimaK. Overview and clinical significance of multiple mutations in individual genes in hepatocellular carcinoma.BMC Cancer2022221104610.1186/s12885‑022‑10143‑z 36199046
     [Google Scholar]
  8. WangS. XuX. CheD. Reactive oxygen species mediate 6c-induced mitochondrial and lysosomal dysfunction, autophagic cell death, and DNA damage in hepatocellular carcinoma.Int. J. Mol. Sci.202122201098710.3390/ijms222010987 34681647
     [Google Scholar]
  9. Da FonsecaL. UrataniL. SoaresG. Early variation of inflammatory indexes refines prognostic prediction in patients with hepatocellular carcinoma under systemic treatment.Mol. Clin. Oncol.20231842910.3892/mco.2023.2625 36908977
     [Google Scholar]
  10. GaoY. LiS. HuangY. An inflammation-related gene landscape predicts prognosis and response to immunotherapy in virus-associated hepatocellular carcinoma.Front. Oncol.202313111815210.3389/fonc.2023.1118152 36969014
     [Google Scholar]
  11. SchneiderK.M. MohsA. GuiW. Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the] hepatic inflammatory microenvironment.Nat. Commun.2022131396410.1038/s41467‑022‑31312‑5 35803930
     [Google Scholar]
  12. BaeB.K. ParkH.C. YooG.S. ChoiM.S. OhJ.H. YuJ.I. The significance of systemic inflammation markers in intrahepatic recurrence of early-stage hepatocellular carcinoma after curative treatment.Cancers2022149208110.3390/cancers14092081 35565210
     [Google Scholar]
  13. YuJ.I. ParkH.C. YooG.S. Clinical significance of systemic inflammation markers in newly diagnosed, previously untreated hepatocellular carcinoma.Cancers2020125130010.3390/cancers12051300 32455607
     [Google Scholar]
  14. Roa-ColomoA. López GarridoM.Á. Molina-VallejoP. Hepatocellular carcinoma risk-stratification based on ASGR1 in circulating epithelial cells for cancer interception.Front. Mol. Biosci.20229107427710.3389/fmolb.2022.1074277 36518850
     [Google Scholar]
  15. NiuG. ZhangX. HongR. GJA1 promotes hepatocellular carcinoma progression by mediating TGF-β-induced activation and the epithelial–mesenchymal transition of hepatic stellate cells.Open Med.20211611459147110.1515/med‑2021‑0344 34693020
     [Google Scholar]
  16. WangX. XingZ. XuH. YangH. XingT. Development and validation of epithelial mesenchymal transition-related prognostic model for hepatocellular carcinoma.Aging20211310138221384510.18632/aging.202976 33929972
     [Google Scholar]
  17. IijimaK. NakamuraH. TakadaK. Six-transmembrane] epithelial antigen of the prostate 1 accelerates cell proliferation] by targeting c-Myc in liver cancer cells.Oncol. Lett.202122154610.3892/ol.2021.12807 34335918
     [Google Scholar]
  18. ZhangW. ZhangyuanG. WangF. The zinc finger protein Miz1 suppresses liver tumorigenesis by restricting hepatocyte-driven macrophage activation and inflammation.Immunity202154611681185.e810.1016/j.immuni.2021.04.027 34038747
     [Google Scholar]
  19. ArzumanyanA. ReisH.M.G.P.V. FeitelsonM.A. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma.Nat. Rev. Cancer201313212313510.1038/nrc3449 23344543
     [Google Scholar]
  20. SunB. KarinM. Obesity, inflammation, and liver cancer.J. Hepatol.201256370471310.1016/j.jhep.2011.09.020 22120206
     [Google Scholar]
  21. TaniguchiK. KarinM. NF-κB, inflammation, immunity and cancer: Coming of age.Nat. Rev. Immunol.201818530932410.1038/nri.2017.142 29379212
     [Google Scholar]
  22. GretenF.R. GrivennikovS.I. Inflammation and cancer: Triggers, mechanisms, and consequences.Immunity2019511274110.1016/j.immuni.2019.06.025 31315034
     [Google Scholar]
  23. RingelhanM. PfisterD. O’ConnorT. PikarskyE. HeikenwalderM. The immunology of hepatocellular carcinoma.Nat. Immunol.201819322223210.1038/s41590‑018‑0044‑z 29379119
     [Google Scholar]
  24. LiW. XiaoJ. ZhouX. STK4 regulates TLR pathways and protects against chronic inflammation–related hepatocellular carcinoma.J. Clin. Invest.2015125114239425410.1172/JCI81203 26457732
     [Google Scholar]
  25. JinY. ChenJ. FengZ. The expression of Survivin and] NF-κB associated with prognostically worse clinicopathologic] variables in hepatocellular carcinoma.Tumour Biol.201435109905991010.1007/s13277‑014‑2279‑0 24996542
     [Google Scholar]
  26. AndersonK.A. MadsenA.S. OlsenC.A. HirscheyM.D. Metabolic control by sirtuins and other enzymes that sense NAD+, NADH,] or their ratio.Biochim. Biophys. Acta Bioenerg.201718581299199810.1016/j.bbabio.2017.09.005 28947253
     [Google Scholar]
  27. McKeeR.W. DickeyA. ParksM.E. NAD-ase activity and glycolysis in Ehrlich-Lettre carcinoma and liver cell particulates.Arch. Biochem. Biophys.1968126376076310.1016/0003‑9861(68)90468‑2 4301096
     [Google Scholar]
  28. YukH. AbdullahM. KimD.H. LeeH. LeeS.J. Necrostatin-1 prevents ferroptosis in a RIPK1- and IDO-independent manner in hepatocellular carcinoma.Antioxidants2021109134710.3390/antiox10091347 34572979
     [Google Scholar]
  29. KimDH KimWD KimSK MoonDH LeeSJ TGF-β1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells.Cell Death Dis202011540610.1038/s41419‑020‑2618‑632471991
     [Google Scholar]
  30. BellottiD. RemelliM. DeferoxamineB. DeferoxamineB. A natural, excellent and versatile metal chelator.Molecules20212611325510.3390/molecules26113255 34071479
     [Google Scholar]
  31. YanH. ZouT. TuoQ. Ferroptosis: Mechanisms and links with diseases.Signal Transduct. Target. Ther.2021614910.1038/s41392‑020‑00428‑9 33536413
     [Google Scholar]
/content/journals/pra/10.2174/0115748928256530240124093759
Loading
Screening of Candidate Inflammatory Markers of Epithelial Cells in Hepatocellular Carcinoma based on Integration Analysis of TCGA/ICGC Databases and Single-cell Sequencing
Recent Patents on Anti-Cancer Drug Discovery 20, 364 (2025); https://doi.org/10.2174/0115748928256530240124093759
/content/journals/pra/10.2174/0115748928256530240124093759
/content/journals/pra/10.2174/0115748928256530240124093759
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): bioinformatics; epithelial cells; Hepatocellular carcinoma; inflammatory response; single-cell analysis; VIP

Most Cited Most Cited RSS feed

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