Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Biomedical Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 2049-9434 Online ISSN: 2049-9442
Journal Cover
September-2025 Volume 23 Issue 3

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
September-2025 Volume 23 Issue 3

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article Open Access

Combined serum IFN‑γ and IL‑22 levels as predictive biomarkers for hepatocellular carcinoma risk: A clinical investigation

  • Authors:
    • Hui Huang
    • Xueying Sun
    • Qiqi Zhang
    • Chunyan Liu
    • Xu Cao
    • Duo Zhang
    • Gongchen Wang
    • Chunwen Pu
  • View Affiliations / Copyright

    Affiliations: Department of Biobank, Dalian Public Health Clinical Center, Dalian, Liaoning 116001, P.R. China
    Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 149
    |
    Published online on: July 1, 2025
       https://doi.org/10.3892/br.2025.2027
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Hepatocellular carcinoma (HCC) is predominantly diagnosed at advanced stages due to a lack of reliable biomarkers for early detection. Consequently, identifying predictive biomarkers for HCC development in patients with chronic liver diseases holds significant potential for improving early diagnosis and clinical outcomes of this aggressive malignancy. Serum levels of immune checkpoint proteins and cytokines were quantified by ELISA in patients with chronic hepatitis B, liver cirrhosis, and HCC, with healthy subjects serving as controls. Cytokine profiles were compared between patients with HCC and without HCC using one‑way ANOVA and multivariate logistic regression. The diagnostic performance of interferon (IFN)‑γ, interleukin (IL)‑22, and α‑fetoprotein (AFP) was evaluated by receiver operating characteristic (ROC) curve analysis. The serum levels of programmed cell death protein 1 and programmed death‑ligand 1 progressively increased with advancing stages of liver disease. IFN‑γ emerged as a protective factor against HCC [odds ratio (OR)=0.991; 95% CI, 0.984‑0.997], while IL‑22 was identified as a risk factor (OR=1.020, 95% CI, 1.004‑1.036). The combined evaluation of IFN‑γ and IL‑22 demonstrated superior diagnostic accuracy [area under the curve (AUC)=0.863; 95% CI, 0.755‑0.971] compared with AFP alone (AUC=0.644; 95% CI, 0.483‑0.804). The combination of IFN‑γ and IL‑22 exhibited enhanced diagnostic performance compared with AFP alone in predicting and detecting early‑stage HCC, suggesting its potential utility as a novel biomarker panel for HCC screening.
View Figures

Figure 1

Serum expression profiles of immune
checkpoint proteins in healthy donors and patients with CHB, LC,
and HCC. (A) Tim-3 expression levels across study groups. (B) PD-L1
expression profiles among different cohorts. (C) PD-1 concentration
variations in the study populations. *P<0.05. CHB,
chronic hepatitis B; LC, liver cirrhosis; HCC, hepatocellular
carcinoma; Tim-3, T-cell immunoglobulin and mucin domain-containing
protein 3; PD-L1, programmed death-ligand 1; PD-1, programmed cell
death protein 1.

Figure 2

Serum cytokine expression profiles in
healthy donors and patients with CHB, LC, and HCC. (A-H)
Quantitative analysis of eight distinct cytokine expression
profiles: (A) IL-1β, (B) IFN-γ, (C) IL-22, (D) IL-4, (E) IL-9, (F)
IL-13, (G) IL-6 and (H) IL-10. (I) PI3K expression levels across
study groups. *P<0.05 and **P<0.01.
CHB, chronic hepatitis B; LC, liver cirrhosis; HCC, hepatocellular
carcinoma; IL-, interleukin; IFN-γ, interferon-γ; PI3K,
phosphatidylinositol 3-kinase.

Figure 3

Comparative diagnostic performance of
IFN-γ, IL-22, and AFP in HCC detection. ROC curve analysis
comparing the diagnostic efficacy of IFN-γ, IL-22, and AFP in
patients with HCC. IFN-γ, interferon-γ; IL-22, interleukin-22; AFP,
α-fetoprotein.
View References

1 

European Association For The Study Of The Liver and European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol. 56:908–943. 2012.PubMed/NCBI View Article : Google Scholar

2 

Greten TF, Wang XW and Korangy F: Current concepts of immune based treatments for patients with HCC: From basic science to novel treatment approaches. Gut. 64:842–848. 2015.PubMed/NCBI View Article : Google Scholar

3 

Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 12:252–264. 2012.PubMed/NCBI View Article : Google Scholar

4 

Yan W, Liu X, Ma H, Zhang H, Song X, Gao L, Liang X and Ma C: Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages. Gut. 64:1593–1604. 2015.PubMed/NCBI View Article : Google Scholar

5 

Sarin SK, Kumar M, Eslam M, George J, Al Mahtab M, Akbar SMF, Jia J, Tian Q, Aggarwal R, Muljono DH, et al: Liver diseases in the Asia-Pacific region: A lancet gastroenterology & hepatology commission. Lancet Gastroenterol Hepatol. 5:167–228. 2020.PubMed/NCBI View Article : Google Scholar

6 

Shiha G, Sarin SK, Ibrahim AE, Omata M, Kumar A, Lesmana LA, Leung N, Tozun N, Hamid S, Jafri W, et al: Liver fibrosis: Consensus recommendations of the Asian Pacific association for the study of the liver (APASL). Hepatol Int. 3:323–333. 2009.PubMed/NCBI View Article : Google Scholar

7 

Tewari D, Patni P and Bishayee A, Sah AN and Bishayee A: Natural products targeting the PI3K-Akt-mTOR signaling pathway in cancer: A novel therapeutic strategy. Semin Cancer Biol. 80:1–17. 2022.PubMed/NCBI View Article : Google Scholar

8 

Kim DH, Yoon JH, Choi MH, Lee CH, Kang TW, Kim HA, Ku YM, Lee JM, Kim SH, Kim KA, et al: Comparison of non-contrast abbreviated MRI and ultrasound as surveillance modalities for HCC. J Hepatol. 81:461–470. 2024.PubMed/NCBI View Article : Google Scholar

9 

Wang Z, Qin H, Liu S, Sheng J and Zhang X: Precision diagnosis of hepatocellular carcinoma. Chin Med J (Engl). 136:1155–1165. 2023.PubMed/NCBI View Article : Google Scholar

10 

Ringelhan M, Pfister D, O'Connor T, Pikarsky E and Heikenwalder M: The immunology of hepatocellular carcinoma. Nat Immunol. 19:222–232. 2018.PubMed/NCBI View Article : Google Scholar

11 

Elsegood CL, Tirnitz-Parker JE, Olynyk JK and Yeoh GC: Immune checkpoint inhibition: Prospects for prevention and therapy of hepatocellular carcinoma. Clin Transl Immunology. 6(e161)2017.PubMed/NCBI View Article : Google Scholar

12 

Shrestha R, Prithviraj P, Anaka M, Bridle KR, Crawford DHG, Dhungel B, Steel JC and Jayachandran A: Monitoring immune checkpoint regulators as predictive biomarkers in hepatocellular carcinoma. Front Oncol. 8(269)2018.PubMed/NCBI View Article : Google Scholar

13 

Yun J, Yu G, Hu P, Chao Y, Li X, Chen X, Wei Q and Wang J: PD-1 expression is elevated in monocytes from hepatocellular carcinoma patients and contributes to CD8 T cell suppression. Immunol Res. 68:436–444. 2020.PubMed/NCBI View Article : Google Scholar

14 

Wang Q, Sun P, Huang H, Zhang Q, Sun X, Wang Z and Pu C: GPC3 in liver cancer exosomes: Dual regulation of growth in normal and hepatocellular carcinoma cells through the Wnt/β-catenin signaling pathway. Bull Biomed Sci. 1:67–76. 2023.

15 

Liaw YF and Chu CM: Hepatitis B virus infection. Lancet. 373:582–592. 2009.PubMed/NCBI View Article : Google Scholar

16 

Lavanchy D: Worldwide epidemiology of HBV infection, disease burden, and vaccine prevention. J Clin Virol. 34 (Suppl 1):S1–S3. 2005.PubMed/NCBI View Article : Google Scholar

17 

Perz JF, Armstrong GL, Farrington LA, Hutin YJ and Bell BP: The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 45:529–538. 2006.PubMed/NCBI View Article : Google Scholar

18 

Yin J, Xie J, Liu S, Zhang H, Han L, Lu W, Shen Q, Xu G, Dong H, Shen J, et al: Association between the various mutations in viral core promoter region to different stages of hepatitis B, ranging of asymptomatic carrier state to hepatocellular carcinoma. Am J Gastroenterol. 106:81–92. 2011.PubMed/NCBI View Article : Google Scholar

19 

Li P, Du Q, Cao Z, Guo Z, Evankovich J, Yan W, Chang Y, Shao L, Stolz DB, Tsung A and Geller DA: Interferon-γ induces autophagy with growth inhibition and cell death in human hepatocellular carcinoma (HCC) cells through interferon-regulatory factor-1 (IRF-1). Cancer Lett. 314:213–222. 2012.PubMed/NCBI View Article : Google Scholar

20 

Li J, Zeng M, Yan K, Yang Y, Li H and Xu X: IL-17 promotes hepatocellular carcinoma through inhibiting apoptosis induced by IFN-γ. Biochem Biophys Res Commun. 522:525–531. 2020.PubMed/NCBI View Article : Google Scholar

21 

Yu X, Lang B, Chen X, Tian Y, Qian S, Zhang Z, Fu Y, Xu J, Han X, Ding H and Jiang Y: The inhibitory receptor Tim-3 fails to suppress IFN-γ production via the NFAT pathway in NK-cell, unlike that in CD4+ T cells. BMC Immunol. 22(25)2021.PubMed/NCBI View Article : Google Scholar

22 

Wu Y, Min J, Ge C, Shu J, Tian D, Yuan Y and Zhou D: Interleukin 22 in liver injury, inflammation and cancer. Int J Biol Sci. 16:2405–2413. 2020.PubMed/NCBI View Article : Google Scholar

23 

Shabgah AG, Navashenaq JG, Shabgah OG, Mohammadi H and Sahebkar A: Interleukin-22 in human inflammatory diseases and viral infections. Autoimmun Rev. 16:1209–1218. 2017.PubMed/NCBI View Article : Google Scholar

24 

Saalim M, Resham S, Manzoor S, Ahmad H, Bangash TA, Latif A and Jaleel S: IL-22 in hepatocyte's survival of Pakistani patients with end stage liver disease: An insight into IL 22 mediated hepato-regenerative pathway. Mol Biol Rep. 46:1127–1138. 2019.PubMed/NCBI View Article : Google Scholar

25 

Saalim M, Resham S, Manzoor S, Ahmad H, Jaleel S, Ashraf J, Imran M and Naseem S: IL-22: A promising candidate to inhibit viral-induced liver disease progression and hepatocellular carcinoma. Tumour Biol. 37:105–114. 2016.PubMed/NCBI View Article : Google Scholar

26 

Lu Y, Wu Z, Peng Q, Ma L, Zhang X, Zhao J, Qin X and Li S: Role of IL-4 gene polymorphisms in HBV-related hepatocellular carcinoma in a Chinese population. PLoS One. 9(e110061)2014.PubMed/NCBI View Article : Google Scholar

27 

Wan J, Wu Y, Ji X, Huang L, Cai W, Su Z, Wang S and Xu H: IL-9 and IL-9-producing cells in tumor immunity. Cell Commun Signal. 18(50)2020.PubMed/NCBI View Article : Google Scholar

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Huang H, Sun X, Zhang Q, Liu C, Cao X, Zhang D, Wang G and Pu C: Combined serum IFN‑&gamma; and IL‑22 levels as predictive biomarkers for hepatocellular carcinoma risk: A clinical investigation. Biomed Rep 23: 149, 2025.
APA
Huang, H., Sun, X., Zhang, Q., Liu, C., Cao, X., Zhang, D. ... Pu, C. (2025). Combined serum IFN‑&gamma; and IL‑22 levels as predictive biomarkers for hepatocellular carcinoma risk: A clinical investigation. Biomedical Reports, 23, 149. https://doi.org/10.3892/br.2025.2027
MLA
Huang, H., Sun, X., Zhang, Q., Liu, C., Cao, X., Zhang, D., Wang, G., Pu, C."Combined serum IFN‑&gamma; and IL‑22 levels as predictive biomarkers for hepatocellular carcinoma risk: A clinical investigation". Biomedical Reports 23.3 (2025): 149.
Chicago
Huang, H., Sun, X., Zhang, Q., Liu, C., Cao, X., Zhang, D., Wang, G., Pu, C."Combined serum IFN‑&gamma; and IL‑22 levels as predictive biomarkers for hepatocellular carcinoma risk: A clinical investigation". Biomedical Reports 23, no. 3 (2025): 149. https://doi.org/10.3892/br.2025.2027
Copy and paste a formatted citation
x
Spandidos Publications style
Huang H, Sun X, Zhang Q, Liu C, Cao X, Zhang D, Wang G and Pu C: Combined serum IFN‑&gamma; and IL‑22 levels as predictive biomarkers for hepatocellular carcinoma risk: A clinical investigation. Biomed Rep 23: 149, 2025.
APA
Huang, H., Sun, X., Zhang, Q., Liu, C., Cao, X., Zhang, D. ... Pu, C. (2025). Combined serum IFN‑&gamma; and IL‑22 levels as predictive biomarkers for hepatocellular carcinoma risk: A clinical investigation. Biomedical Reports, 23, 149. https://doi.org/10.3892/br.2025.2027
MLA
Huang, H., Sun, X., Zhang, Q., Liu, C., Cao, X., Zhang, D., Wang, G., Pu, C."Combined serum IFN‑&gamma; and IL‑22 levels as predictive biomarkers for hepatocellular carcinoma risk: A clinical investigation". Biomedical Reports 23.3 (2025): 149.
Chicago
Huang, H., Sun, X., Zhang, Q., Liu, C., Cao, X., Zhang, D., Wang, G., Pu, C."Combined serum IFN‑&gamma; and IL‑22 levels as predictive biomarkers for hepatocellular carcinoma risk: A clinical investigation". Biomedical Reports 23, no. 3 (2025): 149. https://doi.org/10.3892/br.2025.2027
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team