Xanthine dehydrogenase as a prognostic biomarker related to tumor immunology in hepatocellular carcinoma

Our plain-English summary of Xanthine dehydrogenase as a prognostic biomarker related to tumor immunology in hepatocellular carcinoma, by Z. Lin, Y.Z. Xie, M.C. Zhao, et al (Cancer Cell International, 2021).

The study

• Authors: Z. Lin, Y.Z. Xie, M.C. Zhao, P.P. Hou, J. Tang, G.L. Chen
• Journal: Cancer Cell International
• Published: 2021;21(1):475
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Xanthine dehydrogenase (XDH) is a critical enzyme involved in the oxidative metabolism of purines, pterin and aldehydes and a central component of the innate immune system. However, the prognostic value of XDH in predicting tumor-infiltrating lymphocyte abundance, the immune response, and survival in different cancers, including hepatocellular carcinoma (HCC), is still unclear.

Methods: XDH expression was analyzed in multiple databases, including Oncomine, the Tumor Immune Estimation Resource (TIMER), the Kaplan-Meier plotter database, the Gene Expression Profiling Interactive Analysis (GEPIA) database, and The Cancer Genome Atlas (TCGA). XDH-associated transcriptional profiles were detected with an mRNA array, and the levels of infiltrating immune cells were validated by immunohistochemistry (IHC) of HCC tissues. A predictive signature containing multiple XDH-associated immune genes was established using the Cox regression model.

Results: Decreased XDH mRNA expression was detected in human cancers originating from the liver, bladder, breast, colon, bile duct, kidney, and hematolymphoid system. The prognostic potential of XDH mRNA expression was also significant in certain other cancers, including HCC, breast cancer, kidney or bladder carcinoma, gastric cancer, mesothelioma, lung cancer, and ovarian cancer. In HCC, a low XDH mRNA level predicted poorer overall survival, disease-specific survival, disease-free survival, and progression-free survival. The prognostic value of XDH was independent of the clinical features of HCC patients. Indeed, XDH expression in HCC activated several immune-related pathways, including the T cell receptor, PI3K-AKT, and MAPK signaling pathways, which induced a cytotoxic immune response. Importantly, the microenvironment of XDHhigh HCC tumors contained abundant infiltrating CD8 + T cells but not exhausted T cells. A risk prediction signature based on multiple XDH-associated immune genes was revealed as an independent predictor in the TCGA liver cancer cohort.

Conclusion: These findings suggest that XDH is a valuable prognostic biomarker in HCC and other cancers and indicate that it may function in tumor immunology. Loss of XDH expression may be an immune evasion mechanism for HCC.

© 2021. The Author(s).

In plain English

This study examined the gene xanthine dehydrogenase (XDH) in liver cancer (hepatocellular carcinoma, HCC). It did not study asbestos. Its own analyses used alcohol use and hepatitis virus infection only to group patients for survival comparisons. The authors analyzed public cancer databases, increased XDH expression in an HCC cell line, and stained HCC tissue samples. In Kaplan–Meier plotter data, HCC patients with high XDH mRNA had longer overall survival than those with low levels (hazard ratio 0.55, 95% confidence interval 0.38 to 0.78). In the GEPIA database, high XDH mRNA was linked to worse overall and disease-free survival in mesothelioma. The main text gave no numbers for this and did not name the mesothelioma type. In HCC tissue, XDH levels were correlated with the number of CD8+ immune cells (r = 0.6354). A 20-gene risk score independently predicted survival in a liver cancer cohort (hazard ratio 1.35, 95% CI 1.26–1.4). The authors concluded that XDH is a potential independent prognostic biomarker for HCC. They noted that the work relied mainly on public databases and that sample sizes for some tumor types, including HCC, were too small for a solid conclusion.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Bioinformatics analysis of public cancer gene-expression databases, combined with a cell-line experiment (RNA array and western blot) and immunohistochemistry of HCC tissue samples
• Who was studied: Public database cancer cohorts. These included the Kaplan–Meier plotter HCC cohorts (n = 364, 316, 370 and 362 for the different survival measures) and the TCGA liver cancer cohort. The study also used the MHCC-97H HCC cell line and HCC tissue samples from Fudan University (number of patients not stated in the main text).
• Exposure: No asbestos exposure was studied. The factor examined was XDH gene (mRNA) expression in tumors. In the study's own analyses, alcohol consumption and viral hepatitis were used only to define patient subgroups in the survival analyses.
• Main results:
  • In the Kaplan–Meier plotter HCC data, patients with high XDH mRNA had longer overall survival than patients with low XDH mRNA (HR 0.55, 95% CI 0.38 to 0.78, P = 0.00072)
  • In the GEPIA analysis, high XDH mRNA expression was correlated with worse overall survival and disease-free survival in mesothelioma (MESO). No numbers or mesothelioma site were given in the main text.
  • In HCC tissue stained by immunohistochemistry, XDH expression was positively correlated with infiltration of CD8+ immune cells (r = 0.6354, p = 0.0025)
  • In the TCGA liver cancer cohort, the 20-gene XDH-associated immune risk score was an independent predictor of prognosis after adjusting for sex, age and stage (HR = 1.35, 95% CI = 1.26–1.4, p < 0.001)
• The authors' conclusion: The authors concluded that XDH is a potential independent prognostic biomarker for HCC and may play a role in HCC tumor immunology through an immune evasion mechanism
• Limitations the authors state:
  • The study relied mainly on public database data. Further laboratory or animal experiments are needed to confirm the proposed immune evasion mechanism.
  • The sample size for some tumor types, including HCC, was too small to form a solid conclusion

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Carcinoma, Immunohistochemistry, Stomach Cancer, Mesothelioma, Lung Cancer, Ovarian Cancer, Overall Survival.

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