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

Abstract

Background

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, but molecular complexity and tumor heterogeneity make predictive models for HCC prognosis ineffective. Many recent studies have suggested that autophagy is important in tumor progression. Using autophagy-related genes (ARGs), we attempted to create a novel signature for individual prognosis prediction in patients with HCC.

Methods

Differentially expressed ARGs (DE-ARGs) in HCC and normal samples were screened using TCGA datasets. Univariate Cox and multivariate Cox regression analyses were performed to determine ARGs related to survival in HCC. An autophagy-based signature was constructed using LASSO, and its correlation with the prognosis and the immune infiltration of HCC patients was explored.

Results

In this study, we screened 32 survival-related DE-ARGs by analyzing TCGA datasets. Functional enrichment indicated that the 32 DE-ARGs may play important functional and regulatory roles in cellular autophagy, the regulation of multiple signaling pathways, as well as in the context of cancer and neurological diseases. Based on PPI Network, we identified several hub genes. LASSO Cox regression analysis selected five genes (CASP8, FOXO1, PRKCD, SPHK1, and SQSTM1) for a novel prognostic model. AUCs of 0.752, 0.686, and 0.665 in the TCGA whole set indicated that the model accurately predicted 1-, 3-, and 5-year overall survival, respectively. Cox regression analysis showed that the five-gene signature is an independent and robust predictor in patients with HCC. The high-risk group demonstrated higher levels of immune cell infiltration and exhibited a strong correlation with the immune microenvironment and tumor stem cells. In addition, we further identified PRKCD and SQSTM1 as critical regulators involved in HCC progression. The expression levels of PRKCD and SQSTM1 genes play a crucial role in chemotherapy drug sensitivity and resistance.

Conclusion

We introduce here a novel ARG-based predictive feature for HCC patients. Effective use of this signature will aid in determining a patient's prognosis and may lead to novel approaches to clinical decision-making and therapy.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/pra/10.2174/0115748928275025231213103658
2024-01-09
2025-09-21

  • From This Site

    /content/journals/pra/10.2174/0115748928275025231213103658
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. MillerK.D. NogueiraL. DevasiaT. Cancer treatment and survivorship statistics, 2022.CA Cancer J. Clin.202272540943610.3322/caac.21731 35736631
     [Google Scholar]
  2. RajendranL. IvanicsT. ClaasenM.P.A.W. MuaddiH. SapisochinG. The management of post-transplantation recurrence of hepatocellular carcinoma.Clin. Mol. Hepatol.202228111610.3350/cmh.2021.0217 34610652
     [Google Scholar]
  3. TabrizianP. JibaraG. ShragerB. SchwartzM. RoayaieS. Recurrence of hepatocellular cancer after resection: Patterns, treatments, and prognosis.Ann. Surg.2015261594795510.1097/SLA.0000000000000710 25010665
     [Google Scholar]
  4. De MartinE. SenzoloM. BoninsegnaS. HCV histological recurrence and survival following liver transplantation in patients with and without hepatocellular carcinoma.Transplant. Proc.20084061974197510.1016/j.transproceed.2008.05.040 18675104
     [Google Scholar]
  5. RoayaieS. SchwartzJ.D. SungM.W. Recurrence of hepatocellular carcinoma after liver transplant: Patterns and prognosis.Liver Transpl.200410453454010.1002/lt.20128 15048797
     [Google Scholar]
  6. YuanJ. LvT. YangJ. The lipid transporter HDLBP promotes hepatocellular carcinoma metastasis through BRAF-dependent epithelial-mesenchymal transition.Cancer Lett.202254921592110.1016/j.canlet.2022.215921 36122630
     [Google Scholar]
  7. LuY. GaoY. YangH. HuY. LiX. Nanomedicine‐boosting icaritin-based immunotherapy of advanced hepatocellular carcinoma.Mil. Med. Res.2022916910.1186/s40779‑022‑00433‑9 36503490
     [Google Scholar]
  8. GuoR. DaiH. LiuF. The prognostic and drug-targeting value of lymphoid enhancer-binding factor-1 in hepatocellular carcinoma.Recent Patents Anticancer Drug Discov.202318221122310.2174/1574892817666220831122226 36045537
     [Google Scholar]
  9. D’ArcyM.S. Cell death: A review of the major forms of apoptosis, necrosis and autophagy.Cell Biol. Int.201943658259210.1002/cbin.11137 30958602
     [Google Scholar]
  10. MaS. CaiW. ZhuL. LiK. LiuM. LiuK. Anti-cancer research on arnebiae radix-derived naphthoquinone in recent five years.Recent Patents Anticancer Drug Discov.202217321823010.2174/1574892816666211209164745 34886780
     [Google Scholar]
  11. MizushimaN. KomatsuM. Autophagy: Renovation of cells and tissues.Cell2011147472874110.1016/j.cell.2011.10.026 22078875
     [Google Scholar]
  12. GlickD. BarthS. MacleodK.F. Autophagy: Cellular and molecular mechanisms.J. Pathol.2010221131210.1002/path.2697 20225336
     [Google Scholar]
  13. LevyJ.M.M. TowersC.G. ThorburnA. Targeting autophagy in cancer.Nat. Rev. Cancer201717952854210.1038/nrc.2017.53 28751651
     [Google Scholar]
  14. OnoratiA.V. DyczynskiM. OjhaR. AmaravadiR.K. Targeting autophagy in cancer.Cancer2018124163307331810.1002/cncr.31335 29671878
     [Google Scholar]
  15. SahaS. PanigrahiD.P. PatilS. BhutiaS.K. Autophagy in health and disease: A comprehensive review.Biomed. Pharmacother.201810448549510.1016/j.biopha.2018.05.007
     [Google Scholar]
  16. PengX. ZhangS. JiaoW. Hydroxychloroquine synergizes with the PI3K inhibitor BKM120 to exhibit antitumor efficacy independent of autophagy.J. Exp. Clin. Cancer Res.202140137410.1186/s13046‑021‑02176‑2 34844627
     [Google Scholar]
  17. HuangM. LinY. WangC. New insights into antiangiogenic therapy resistance in cancer: Mechanisms and therapeutic aspects.Drug Resist. Updat.20226410084910.1016/j.drup.2022.100849
     [Google Scholar]
  18. KimK.H. LeeM.S. Autophagy-a key player in cellular and body metabolism.Nat. Rev. Endocrinol.201410632233710.1038/nrendo.2014.35 24663220
     [Google Scholar]
  19. FerroF. ServaisS. BessonP. RogerS. DumasJ.F. BrissonL. Autophagy and mitophagy in cancer metabolic remodelling.Semin. Cell Dev. Biol.20209812913810.1016/j.semcdb.2019.05.029 31154012
     [Google Scholar]
  20. GaoL. LvG. LiR. Glycochenodeoxycholate promotes hepatocellular carcinoma invasion and migration by AMPK/mTOR dependent autophagy activation.Cancer Lett.201945421522310.1016/j.canlet.2019.04.009 30980867
     [Google Scholar]
  21. QianH. ChaoX. WilliamsJ. Autophagy in liver diseases: A review.Mol. Aspects Med.20218210097310.1016/j.mam.2021.100973 34120768
     [Google Scholar]
  22. WangK. Autophagy and apoptosis in liver injury.Cell Cycle201514111631164210.1080/15384101.2015.1038685 25927598
     [Google Scholar]
  23. Filali-MouncefY. HunterC. RoccioF. The ménage à trois of autophagy, lipid droplets and liver disease.Autophagy2022181507210.1080/15548627.2021.1895658 33794741
     [Google Scholar]
  24. WuJ ZhuY Cong Q, Xu Q. Non-coding RNAs: Role of miRNAs and lncRNAs in the regulation of autophagy in hepatocellular carcinoma (Review).Oncol Rep202349611310.3892/or.2023.8550 37083063
     [Google Scholar]
  25. LvT. XiongX. YanW. LiuM. XuH. HeQ. Targeting of GSDMD sensitizes HCC to anti-PD-1 by activating cGAS pathway and downregulating PD-L1 expression.J. Immunother. Cancer2022106e00476310.1136/jitc‑2022‑004763 35688553
     [Google Scholar]
  26. XuG. FengD. YaoY. Listeria-based hepatocellular carcinoma vaccine facilitates anti-PD-1 therapy by regulating macrophage polarization.Oncogene20203971429144410.1038/s41388‑019‑1072‑3 31659256
     [Google Scholar]
  27. BaderG.D. HogueC.W.V. An automated method for finding molecular complexes in large protein interaction networks.BMC Bioinformatics200341210.1186/1471‑2105‑4‑2 12525261
     [Google Scholar]
  28. KimD.W. TalatiC. KimR. Hepatocellular carcinoma (HCC): Beyond sorafenib—chemotherapy.J. Gastrointest. Oncol.20178225626510.21037/jgo.2016.09.07 28480065
     [Google Scholar]
  29. JabbourT.E. LaganaS.M. LeeH. Update on hepatocellular carcinoma: Pathologists’ review.World J. Gastroenterol.201925141653166510.3748/wjg.v25.i14.1653 31011252
     [Google Scholar]
  30. JiangY. HanQ. ZhaoH. ZhangJ. The mechanisms of HBV-induced hepatocellular carcinoma.J. Hepatocell. Carcinoma2021843545010.2147/JHC.S307962 34046368
     [Google Scholar]
  31. WenN. CaiY. LiF. The clinical management of hepatocellular carcinoma worldwide: A concise review and comparison of current guidelines: 2022 update.Biosci. Trends2022161203010.5582/bst.2022.01061 35197399
     [Google Scholar]
  32. LlovetJ.M. Zucman-RossiJ. PikarskyE. Hepatocellular carcinoma.Nat. Rev. Dis. Primers2016211601810.1038/nrdp.2016.18 27158749
     [Google Scholar]
  33. CouriT. PillaiA. Goals and targets for personalized therapy for HCC.Hepatol. Int.201913212513710.1007/s12072‑018‑9919‑1 30600478
     [Google Scholar]
  34. TianY. XiaoH. YangY. Crosstalk between 5-methylcytosine and N6-methyladenosine machinery defines disease progression, therapeutic response and pharmacogenomic landscape in hepatocellular carcinoma.Mol. Cancer2023221510.1186/s12943‑022‑01706‑6 36627693
     [Google Scholar]
  35. LiM.Z. LiuE.J. ZhouQ.Z. Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling.Mil. Med. Res.2022913810.1186/s40779‑022‑00396‑x 35799293
     [Google Scholar]
  36. MizushimaN. LevineB. CuervoA.M. KlionskyD.J. Autophagy fights disease through cellular self-digestion.Nature200845171821069107510.1038/nature06639 18305538
     [Google Scholar]
  37. ChmurskaA. MatczakK. MarczakA. Two faces of autophagy in the struggle against cancer.Int. J. Mol. Sci.2021226298110.3390/ijms22062981 33804163
     [Google Scholar]
  38. TaoD. WangY. ZhangX. Identification of angiogenesis-related prognostic biomarkers associated with immune cell infiltration in breast cancer.Front. Cell Dev. Biol.20221085332410.3389/fcell.2022.853324 35602610
     [Google Scholar]
  39. LiX. JinF. LiY. A novel autophagy‐related lncRNA prognostic risk model for breast cancer.J. Cell. Mol. Med.202125141410.1111/jcmm.15980 33216456
     [Google Scholar]
  40. WangJ. GongM. FanX. HuangD. ZhangJ. HuangC. Autophagy-related signaling pathways in non-small cell lung cancer.Mol. Cell. Biochem.2022477238539310.1007/s11010‑021‑04280‑5 34757567
     [Google Scholar]
  41. LvB. WangY. MaD. Immunotherapy: Reshape the tumor immune microenvironment.Front. Immunol.20221384414210.3389/fimmu.2022.844142 35874717
     [Google Scholar]
  42. LeiX. LeiY. LiJ.K. Immune cells within the tumor microenvironment: Biological functions and roles in cancer immunotherapy.Cancer Lett.202047012613310.1016/j.canlet.2019.11.009 31730903
     [Google Scholar]
  43. MarzagalliM. EbeltN.D. ManuelE.R. Unraveling the crosstalk between melanoma and immune cells in the tumor microenvironment.Semin. Cancer Biol.20195923625010.1016/j.semcancer.2019.08.002 31404607
     [Google Scholar]
  44. OzgaA.J. ChowM.T. LusterA.D. Chemokines and the immune response to cancer.Immunity202154585987410.1016/j.immuni.2021.01.012 33838745
     [Google Scholar]
  45. YinX. ChenS. EisenbarthS.C. Dendritic cell regulation of T helper cells.Annu. Rev. Immunol.202139175979010.1146/annurev‑immunol‑101819‑025146 33710920
     [Google Scholar]
  46. LiS HuangQ ZhouD HeB. PRKCD as a potential therapeutic target for chronic obstructive pulmonary disease.Int Immunopharmacol2022113(Pt A)10937410.1016/j.intimp.2022.109374
     [Google Scholar]
  47. MunsonM.J. MathaiB.J. NgM.Y.W. GAK and PRKCD are positive regulators of PRKN-independent mitophagy.Nat. Commun.2021121610110.1038/s41467‑021‑26331‑7 34671015
     [Google Scholar]
  48. MunsonM.J. MathaiB.J. NgM.Y.W. Trachsel-MonchoL. de la BallinaL.R. SimonsenA. GAK and PRKCD kinases regulate basal mitophagy.Autophagy202218246746910.1080/15548627.2021.2015154 35001811
     [Google Scholar]
  49. KeG. LiangL. YangJ.M. MiR-181a confers resistance of cervical cancer to radiation therapy through targeting the pro-apoptotic PRKCD gene.Oncogene201332253019302710.1038/onc.2012.323 22847611
     [Google Scholar]
  50. LiuJ. DuF. ChenC. CircRNA ITCH increases bortezomib sensitivity through regulating the miR-615-3p/PRKCD axis in multiple myeloma.Life Sci.202026211850610.1016/j.lfs.2020.118506 33031827
     [Google Scholar]
/content/journals/pra/10.2174/0115748928275025231213103658
Loading
Comprehensive Bioinformatic Analysis Reveals an Autophagy-related Gene Signature for Predicting Outcome, Immune Status, and Drug Sensitivity in Hepatocellular Carcinoma
Recent Patents on Anti-Cancer Drug Discovery 20, 397 (2025); https://doi.org/10.2174/0115748928275025231213103658
/content/journals/pra/10.2174/0115748928275025231213103658
/content/journals/pra/10.2174/0115748928275025231213103658
Loading

Data & Media loading...

Supplements

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

file format download Download

  • Article Type:     Research Article
Keyword(s): autophagy-related gene; Bioinformatic; drug; hepatocellular carcinoma; immune status; neoplasm

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