Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders)
  4. Volume 25, Issue 2
  5. Article
Volume 25, Issue 2
  • ISSN: 1871-5303
  • E-ISSN: 2212-3873

Abstract

Background

Hepatocellular carcinoma (HCC) is a globally prevalent malignancy accompanied by high incidence, poor outcomes, and high mortality. Anthocyanins can inhibit tumor proliferation, migration, invasion, and promote apoptosis. Moreover, autophagy-related genes (ARGs) may play vital roles in HCC progression. This study aimed to decipher the mechanisms through which anthocyanins influence HCC ARGs and to establish a novel prognostic model.

Methods

Based on data from public databases, differential analysis and the Venn algorithm were employed to detect intersecting genes among differentially expressed genes (DEGs), anthocyanin-related targets, and ARGs. Consensus clustering was implemented to delineate molecular subtypes of HCC. The prognostic model was developed by Cox regression analyses. CIBIRSORT was engaged to assess the immune cell infiltration. Kaplan-Meier (KM) analysis and receiver operating characteristic (ROC) curve were utilized to evaluate the predictive efficiency of the prognostic signature.

Results

A total of 36 intersecting genes were identified from overlapping 1524 ARGs, 537 anthocyanin-related targets, and 5247 DEGs. Consensus clustering determined three molecular subtypes (cluster 1, cluster 2, and cluster 3). Cluster 1 showed worse outcomes and remarkably higher abundances of plasma cells and T follicular helper cells. Furthermore, four prognostic signatures (KDR (Kinase insert domain receptor), BAK1 (BCL2 antagonist/killer 1), HDAC1 (Histone deacetylase 1), and CDK2 (Cyclin-dependent kinase 2)) were identified and showing substantial predictive efficacy.

Conclusion

This investigation identified three molecular subtypes of HCC patients and proposed a promising prognostic signature comprising KDR, BAK1, HDAC1, and CDK2, which could supply further robust evidence for additional clinical and functional studies.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/emiddt/10.2174/0118715303280877240130065512
2024-04-08
2025-05-16

  • From This Site

    /content/journals/emiddt/10.2174/0118715303280877240130065512
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. WenN. CaiY. LiF. YeH. TangW. SongP. ChengN. The clinical management of hepatocellular carcinoma worldwide: A concise review and comparison of current guidelines: 2022 update.Biosci. Trends2022161203010.5582/bst.2022.0106135197399
     [Google Scholar]
  2. HanafiahK. GroegerJ. FlaxmanA.D. WiersmaS.T. Global epidemiology of hepatitis C virus infection: New estimates of age-specific antibody to HCV seroprevalence.Hepatology20135741333134210.1002/hep.2614123172780
     [Google Scholar]
  3. ChuangS.C. VecchiaC.L. BoffettaP. Liver cancer: Descriptive epidemiology and risk factors other than HBV and HCV infection.Cancer Lett.2009286191410.1016/j.canlet.2008.10.04019091458
     [Google Scholar]
  4. 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]
  5. SangroB. SarobeP. Hervás-StubbsS. MeleroI. Advances in immunotherapy for hepatocellular carcinoma.Nat. Rev. Gastroenterol. Hepatol.202118852554310.1038/s41575‑021‑00438‑033850328
     [Google Scholar]
  6. DhanasekaranR. LimayeA. Cabrera, R Hepatocellular carcinoma: Current trends in worldwide epidemiology, risk factors, diagnosis, and therapeutics.Hepat. Med.201241937
     [Google Scholar]
  7. LevineB. KroemerG. Autophagy in the pathogenesis of disease.Cell20081321274210.1016/j.cell.2007.12.01818191218
     [Google Scholar]
  8. GalluzziL. PedroJ.M. LevineB. GreenD.R. KroemerG. Pharmacological modulation of autophagy: Therapeutic potential and persisting obstacles.Nat. Rev. Drug Discov.201716748751110.1038/nrd.2017.2228529316
     [Google Scholar]
  9. DegenhardtK. MathewR. BeaudoinB. BrayK. AndersonD. ChenG. MukherjeeC. ShiY. GélinasC. FanY. NelsonD.A. JinS. WhiteE. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis.Cancer Cell2006101516410.1016/j.ccr.2006.06.00116843265
     [Google Scholar]
  10. AmaravadiR.K. YuD. LumJ.J. BuiT. ChristophorouM.A. EvanG.I. Thomas-TikhonenkoA. ThompsonC.B. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma.J. Clin. Invest.2007117232633610.1172/JCI2883317235397
     [Google Scholar]
  11. AmaravadiR. KimmelmanA.C. WhiteE. Recent insights into the function of autophagy in cancer.Genes Dev.201630171913193010.1101/gad.287524.11627664235
     [Google Scholar]
  12. ThorburnA. Autophagy and its effects: Making sense of double-edged swords.PLoS Biol.20141210e100196710.1371/journal.pbio.100196725313680
     [Google Scholar]
  13. KocaturkN.M. AkkocY. KigC. Autophagy as a molecular target for cancer treatment.Eur. J. Pharm. Sci.201913411613710.1016/j.ejps.2019.04.011
     [Google Scholar]
  14. HouD.X. YanagitaT. UtoT. MasuzakiS. FujiiM. Anthocyanidins inhibit cyclooxygenase-2 expression in LPS-evoked macrophages: Structure–activity relationship and molecular mechanisms involved.Biochem. Pharmacol.200570341742510.1016/j.bcp.2005.05.00315963474
     [Google Scholar]
  15. PanM.H. LaiC.S. DushenkovS. HoC.T. Modulation of inflammatory genes by natural dietary bioactive compounds.J. Agric. Food Chem.200957114467447710.1021/jf900612n19489612
     [Google Scholar]
  16. ShinD.Y. RyuC.H. LeeW.S. Induction of apoptosis and inhibition of invasion in human hepatoma cells by anthocyanins from meoru.Ann. N. Y. Acad. Sci.2009117113714810.1111/j.1749‑6632.2009.04689.x
     [Google Scholar]
  17. de Souza MesquitaL.M. ContieriL.S. Sanches, VL Fast and green universal method to analyze and quantify anthocyanins in natural products by UPLC-PDA.Food Chem.202342813681410.1016/j.foodchem.2023.136814
     [Google Scholar]
  18. PaceE. JiangY. ClemensA. CrossmanT. RupasingheH.P. Impact of thermal degradation of cyanidin-3-o-glucoside of haskap berry on cytotoxicity of hepatocellular carcinoma HepG2 and breast cancer MDA-MB-231 cells.Antioxidants2018722410.3390/antiox702002429382057
     [Google Scholar]
  19. FengR. WangS.Y. ShiY.H. FanJ. YinX.M. Delphinidin induces necrosis in hepatocellular carcinoma cells in the presence of 3-methyladenine, an autophagy inhibitor.J. Agric. Food Chem.20105873957396410.1021/jf902545820025272
     [Google Scholar]
  20. WangY. LinJ. TianJ. SiX. JiaoX. ZhangW. GongE. LiB. Blueberry Malvidin-3-galactoside suppresses hepatocellular carcinoma by regulating apoptosis, proliferation, and metastasis pathways in vivo and in vitro.J. Agric. Food Chem.201967262563610.1021/acs.jafc.8b0620930586992
     [Google Scholar]
  21. BabuG.R. AnandT. IlaiyarajaN. KhanumF. GopalanN. Pelargonidin modulates keap1/nrf2 pathway gene expression and ameliorates citrinin-induced oxidative stress in HepG2 cells.Front. Pharmacol.20178868
     [Google Scholar]
  22. LongH.L. ZhangF.F. WangH.L. YangW.S. HouH.T. YuJ.K. LiuB. Mulberry anthocyanins improves thyroid cancer progression mainly by inducing apoptosis and autophagy cell death.Kaohsiung J. Med. Sci.201834525526210.1016/j.kjms.2017.11.00429699632
     [Google Scholar]
  23. WeiT. JiX. XueJ. GaoY. ZhuX. XiaoG. Cyanidin-3- O -glucoside represses tumor growth and invasion in vivo by suppressing autophagy via inhibition of the JNK signaling pathways.Food Funct.202112138739610.1039/D0FO02107E33326533
     [Google Scholar]
  24. LeeD.Y. ParkY.J. SongM.G. KimD.R. ZadaS. KimD.H. Cytoprotective effects of delphinidin for human chondrocytes against oxidative stress through activation of autophagy.Antioxidants2020918310.3390/antiox901008331963866
     [Google Scholar]
  25. LiY. XuY. XieJ. ChenW. Malvidin-3- O -arabinoside ameliorates ethyl carbamate-induced oxidative damage by stimulating AMPK-mediated autophagy.Food Funct.20201112103171032810.1039/D0FO01562H33215619
     [Google Scholar]
  26. SuH. XieL. XuY. KeH. BaoT. LiY. ChenW. Pelargonidin-3-O-glucoside derived from wild raspberry exerts antihyperglycemic effect by inducing autophagy and modulating gut microbiota.J. Agric. Food Chem.20206846130251303710.1021/acs.jafc.9b0333831322351
     [Google Scholar]
  27. WangN.N. DongJ. ZhangL. OuyangD. ChengY. ChenA.F. LuA.P. CaoD.S. HAMdb: a database of human autophagy modulators with specific pathway and disease information.J. Cheminform.20181013410.1186/s13321‑018‑0289‑430066211
     [Google Scholar]
  28. ChenK. YangD. Zhao, F Autophagy and Tumor Database: ATdb, a novel database connecting autophagy and tumor.Database20202020baa052
     [Google Scholar]
  29. DainaA. MichielinO. ZoeteV. SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules.Nucleic Acids Res.201947W1W357W36410.1093/nar/gkz38231106366
     [Google Scholar]
  30. LiuZ. GuoF. WangY. BATMAN-TCM: A bioinformatics analysis tool for molecular mechanism of traditional chinese medicine.Sci. Rep.20162114610.1038/srep21146
     [Google Scholar]
  31. GalloK. GoedeA. PreissnerR. GohlkeB.O. SuperPred 3.0: Drug classification and target prediction-a machine learning approach.Nucleic Acids Res.202250W1W726W73110.1093/nar/gkac29735524552
     [Google Scholar]
  32. RitchieM.E. PhipsonB. WuD. HuY. LawC.W. ShiW. SmythG.K. limma powers differential expression analyses for RNA-sequencing and microarray studies.Nucleic Acids Res.2015437e4710.1093/nar/gkv00725605792
     [Google Scholar]
  33. YuG. WangL.G. HanY. HeQ.Y. clusterProfiler: An R package for comparing biological themes among gene clusters.OMICS201216528428710.1089/omi.2011.011822455463
     [Google Scholar]
  34. KohnC.G. SinghP. KorytowskyB. Humanistic and economic burden of hepatocellular carcinoma: Systematic literature review.Am. J. Manag. Care2019256173
     [Google Scholar]
  35. BruixJ. ReigM. ShermanM. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma.Gastroenterology2016150483585310.1053/j.gastro.2015.12.04126795574
     [Google Scholar]
  36. ChenL. GuoP. HeY. ChenZ. ChenL. LuoY. QiL. LiuY. WuQ. CuiY. FangF. ZhangX. SongT. GuoH. HCC-derived exosomes elicit HCC progression and recurrence by epithelial-mesenchymal transition through MAPK/ERK signalling pathway.Cell Death Dis.20189551310.1038/s41419‑018‑0534‑929725020
     [Google Scholar]
  37. HuangG. TangB. TangK. DongX. DengJ. LiaoL. LiaoZ. YangH. HeS. Isoquercitrin inhibits the progression of liver cancer in vivo and in vitro via the MAPK signalling pathway.Oncol. Rep.20143152377238410.3892/or.2014.309924676882
     [Google Scholar]
  38. HoW.J. JaffeeE.M. ZhengL. The tumour microenvironment in pancreatic cancer — clinical challenges and opportunities.Nat. Rev. Clin. Oncol.202017952754010.1038/s41571‑020‑0363‑532398706
     [Google Scholar]
  39. ZhangQ.F. YinW.W. XiaY. YiY.Y. HeQ.F. WangX. RenH. ZhangD.Z. Liver-infiltrating CD11b−CD27− NK subsets account for NK-cell dysfunction in patients with hepatocellular carcinoma and are associated with tumor progression.Cell. Mol. Immunol.2017141081982910.1038/cmi.2016.2827321064
     [Google Scholar]
  40. HanY. GuoW. RenT. Tumor-associated macrophages promote lung metastasis and induce epithelial-mesenchymal transition in osteosarcoma by activating the COX-2/STAT3 axis.Cancer Lett.2019440441
     [Google Scholar]
  41. WangH. YangC. LiD. WangR. LiY. LvL. Bioinformatics analysis and experimental validation of a novel autophagy-related signature relevant to immune infiltration for recurrence prediction after curative hepatectomy.Aging20231572610263010.18632/aging.20463237014321
     [Google Scholar]
  42. XuW. GuoW. LuP. MaD. LiuL. YuF. Identification of an autophagy-related gene signature predicting overall survival for hepatocellular carcinoma.Biosci. Rep.2021411BSR2020323110.1042/BSR2020323133351066
     [Google Scholar]
  43. CasanovasO. HicklinD.J. BergersG. HanahanD. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors.Cancer Cell20058429930910.1016/j.ccr.2005.09.00516226705
     [Google Scholar]
  44. GiatromanolakiA. KoukourakisM.I. TurleyH. SivridisE. HarrisA.L. GatterK.C. Phosphorylated KDR expression in endometrial cancer cells relates to HIF1α/VEGF pathway and unfavourable prognosis.Mod. Pathol.200619570170710.1038/modpathol.380057916557278
     [Google Scholar]
  45. DadsenaS. KingL.E. García-SáezA.J. Apoptosis regulation at the mitochondria membrane level.Biochim. Biophys. Acta Biomembr.202118631218371610.1016/j.bbamem.2021.18371634343535
     [Google Scholar]
  46. AlaviM.V. Targeted OMA1 therapies for cancer.Int. J. Cancer201914592330234110.1002/ijc.3217730714136
     [Google Scholar]
  47. YanZ. XuT. AnZ. HuY. ChenW. MaJ. ShaoC. ZhuF. Costunolide induces mitochondria-mediated apoptosis in human gastric adenocarcinoma BGC-823 cells.BMC Complement. Altern. Med.201919115110.1186/s12906‑019‑2569‑631242894
     [Google Scholar]
  48. RoperoS. EstellerM. The role of histone deacetylases (HDACs) in human cancer.Mol. Oncol.200711192510.1016/j.molonc.2007.01.00119383284
     [Google Scholar]
  49. NakagawaM. OdaY. EguchiT. AishimaS.I. YaoT. HosoiF. BasakiY. OnoM. KuwanoM. TanakaM. TsuneyoshiM. Expression profile of class I histone deacetylases in human cancer tissues.Oncol. Rep.200718476977410.3892/or.18.4.76917786334
     [Google Scholar]
  50. SeneseS. ZaragozaK. MinardiS. MuradoreI. RonzoniS. PassafaroA. BernardL. DraettaG.F. AlcalayM. SeiserC. ChioccaS. Role for histone deacetylase 1 in human tumor cell proliferation.Mol. Cell. Biol.200727134784479510.1128/MCB.00494‑0717470557
     [Google Scholar]
  51. SunT.Y. XieH.J. LiZ. KongL.F. GouX.N. LiD.J. ShiY.J. DingY.Z. miR-34a regulates HDAC1 expression to affect the proliferation and apoptosis of hepatocellular carcinoma.Am. J. Transl. Res.20179110311428123637
     [Google Scholar]
  52. TadesseS. CaldonE.C. TilleyW. WangS. Cyclin-dependent kinase 2 inhibitors in cancer therapy: An update.J. Med. Chem.20196294233425110.1021/acs.jmedchem.8b0146930543440
     [Google Scholar]
/content/journals/emiddt/10.2174/0118715303280877240130065512
Loading
Anthocyanin-Mediated Autophagy in Hepatocellular Carcinoma: Gene Associations and Prognostic Implications
Endocr Metab Immune Disord Drug Targets 25, 140 (2025); https://doi.org/10.2174/0118715303280877240130065512
/content/journals/emiddt/10.2174/0118715303280877240130065512
/content/journals/emiddt/10.2174/0118715303280877240130065512
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article. Supplementary Table 1. Totally 1524 autophagy-related genes (ARGs) and 537 anthocyanin-related targets were obtained from online databases. Supplementary Table 2. Totally 5247 DEGs between normal and HCC cases were detected from the GSE84402 dataset. Supplementary Table 3. Totally 36 intersecting genes were identified by overlapping ARGs, anthocyanin-related targets, and DEGs. Supplementary Table 4. A total of 133 KEGG pathways were enriched by GSEA. Supplementary Table 5. A total of 787 GO and 140 KEGG pathways were enriched for 36 intersecting genes.

file format download Download

  • Article Type:     Research Article
Keyword(s): anthocyanin; autophagy; Hepatocellular carcinoma; immune cell infiltration; molecular subtype; prognostic signature

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