Immune-related gene risk model establishment and role of key gene FUCA1 in malignant pleural mesothelioma

Our plain-English summary of Immune-related gene risk model establishment and role of key gene FUCA1 in malignant pleural mesothelioma, by L. Shi, D. Yuan, F. Zhu, et al (Frontiers in Pharmacology, 2025).

The study

• Authors: L. Shi, D. Yuan, F. Zhu, Y. He, R. Zuo, L. Chen, Y. Luo, Y. Wang, D. Huang, P. Chen, H. Guo
• Journal: Frontiers in Pharmacology
• Published: 2025;16:1577232
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare type of tumor closely associated with asbestos exposure. Increasing evidence shows that high immuno-heterogeneity reduces the therapeutic efficacy of MPM. At present, good biomarkers to screen immunodominant populations and predict the efficacy of immunotherapy are lacking.

Methods: In this study, expression data from TCGA, GSE2459, GSE51024, and GSE29354 were integrated for model construction. An eight-gene risk score model (FLI1, IL32, FUCA1, CCR2, PSMB10, CCL5, WT1, and KRT5) was constructed using CIBERSORT, weighted gene co-expression network analysis, Cox regression analysis, differentially expressed gene analysis, and protein-protein interaction network. The K-M survival analysis was used to evaluate the prediction ability of the risk score model. The TIDE database and Oncology Drug Sensitivity Genomics database were used to assess the predictive power of risk score models for treatment. In addition, the expression of the key gene in para-carcinoma tissue and MPM samples were detected by Immunohistochemistry. Patient clinical information was employed to evaluate the relationship between key genes and patient survival. Finally, the biological functions of the key gene were examined by in vitro and in vivo experiments.

Results: The score model was used to divide patients with MPM into low- and high-risk groups. The high-risk group was characterized by a survival disadvantage, and they were less sensitive to immunotherapy. Clinical data suggest that FUCA1, which is a key gene in the model, is an independent risk factor for predicting the prognosis of patients with MPM. A series of experiments demonstrated that FUCA1 expression was negatively correlated with the proliferation, invasion and migration abilities of MPM cells. Further studies revealed that FUCA1 inhibited epithelial-mesenchymal transition in MPM cells by regulating the PI3K-AKT signaling pathway.

Conclusion: The risk score model provides a new perspective for screening potential populations to benefit from immunotherapy and predicting their survival. FUCA1 may be a potential prognostic biomarker and promising therapeutic target for patients with MPM.

Copyright © 2025 Shi, Yuan, Zhu, He, Zuo, Chen, Luo, Wang, Huang, Chen and Guo.

In plain English

This laboratory and computer-based study examined immune-related genes in malignant pleural mesothelioma (MPM). It did not measure anyone's asbestos exposure. The authors pooled gene-expression data on 289 samples from public databases and built a risk score from eight genes. The high-risk group (n = 70) had significantly lower survival than the low-risk group (n = 102), p less than 0.0001. There were no immunotherapy data on mesothelioma patients, so the authors used lung cancer and advanced urothelial carcinoma cohorts instead. On that indirect basis, the low-risk group was predicted to respond more often (43% vs 30%). In tumor samples from 34 MPM patients at one hospital in Tianjin, China, low FUCA1 expression went with worse prognosis. FUCA1 expression, distant metastasis and TNM stage were independent risk factors. In two mesothelioma cell lines, more FUCA1 went with less cell growth, invasion and migration, which the authors linked to the PI3K-AKT pathway. In mice (5 per group), tumors grown from cells with extra FUCA1 were smaller. The authors concluded that FUCA1 may be a potential prognostic biomarker and therapeutic target. They noted that their sample size was relatively small.

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: Original research combining analysis of public gene-expression databases (building a risk score model), a retrospective study of hospital tumor samples, cell-line experiments and a mouse xenograft experiment
• Who was studied: 289 MPM transcriptome samples from TCGA (86) and GEO datasets GSE2459 (54), GSE51024 (96) and GSE29354 (53). 172 patients were scored in the risk model. Tumor samples came from 34 MPM patients at Tianjin Medical University Cancer Institute and Hospital, China, from January 2013 to July 2021. The study also used the cell lines NCI-H2452 and NCI-H2052 and female BALB/c nude mice.
• Exposure: No asbestos exposure was studied or measured. Asbestos is mentioned only as background. The study examined expression of eight genes (FLI1, IL32, FUCA1, CCR2, PSMB10, CCL5, WT1, KRT5), with a focus on FUCA1.
• Main results:
  • Survival in the high-risk group (n = 70) was significantly lower than in the low-risk group (n = 102), with p less than 0.0001.
  • Using a non-small cell lung cancer immunotherapy cohort to predict indirectly, the low-risk MPM group had a higher predicted response rate to immunotherapy: 43% vs 30% for the high-risk group.
  • In an atezolizumab-treated advanced urothelial carcinoma cohort (IMvigor210), the low-risk group had a higher proportion of objective response: 42% vs 26%.
  • Predicted drug sensitivity (IC50) was higher in the high-risk group for all four chemotherapy drugs. The difference was statistically significant only for cisplatin and etoposide.
  • In the 34 Tianjin hospital patients, distant metastasis, TNM stage and FUCA1 expression were independent risk factors for prognosis. Low FUCA1 expression went with poorer prognosis.
  • In the MPM cell lines, cells with FUCA1 knocked down grew more, and cells with extra FUCA1 grew less.
  • In the MPM cell lines NCI-H2452 and NCI-H2052, FUCA1 knockdown promoted cell invasion and migration, and extra FUCA1 suppressed them.
  • In nude mice (n = 5 per group) injected with NCI-H2052 cells, tumors were smaller in the FUCA1-overexpression group than in the vector control group.
  • In cell experiments, FUCA1 was found to regulate epithelial-mesenchymal transition through the PI3K-AKT signaling pathway.
• The authors' conclusion: The authors concluded that the risk score model offers a new perspective for screening patients who may benefit from immunotherapy and for predicting survival. They concluded that FUCA1 may be a potential prognostic biomarker and promising therapeutic target for patients with MPM.
• Limitations the authors state:
  • Immunotherapy predictions relied on cohorts of patients with non-small cell lung cancer and urothelial carcinoma, because there were no immunotherapy data on MPM patients.
  • The sample size was relatively small, and the findings may not apply to all patients with MPM.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Asbestos Exposure, Biomarker, Immunotherapy, Carcinoma, Immunohistochemistry, Prognosis.

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