Identification of CAPG as a potential prognostic biomarker associated with immune cell infiltration and ferroptosis in uterine corpus endometrial carcinoma

Front Endocrinol (Lausanne). 2024 Nov 12:15:1452219. doi: 10.3389/fendo.2024.1452219. eCollection 2024.

Abstract

Introduction: Capping actin protein, gelsolin-like (CAPG) is a potential therapeutic target in various cancers. However, the potential immunotherapeutic effects and prognostic value of CAPG in uterine corpus endometrial carcinoma (UCEC) remain unclear.

Methods: The characterization, methylation effects, prognostic value, targeted miRNAs of CAPG, and the correlation of CAPG with immune cell infiltration and ferroptosis in UCEC were investigated using multiple public databases and online tools. Furtherly, we explored the potential physiological function of CAPG using EdU and Transwell migration assays, identified the cell localization and expression of CAPG and GPX4 by immunofluorescence, and detected the intracellular Fe2+ levels using a FerroOrange fluorescent probe in Ishikawa cells. Additionally, the OncoPredict package was used to analyze the potential chemotherapeutic drugs for UCEC.

Results: CAPG showed generally high expression in tumor group. The overall survival rate of the high-risk group was significantly lower than that of the low-risk group. Enrichment analysis indicated that CAPG is involved in immune-related pathways and is closely associated with the tumor microenvironment. CAPG expression levels were affected by abnormal DNA methylation and/or targeted miRNAs, infiltration levels and marker genes of various immune cells, thereby impacting immune response, ferroptosis, and patient prognosis. Ferroptosis analysis indicated that ALOX5 and VLDLR were the top CAPG-related ferroptosis markers; glutathione metabolism levels in tumor group were generally high, and decitabine was a ferroptosis inducer. CAPG-siRNA suppressed the cell proliferation and invasion, and markedly elevated the expression levels of immune-related genes IL8, TNF, TLR4 and the intracellular Fe2+ levels. CAPG co-located with GPX4 in nucleus and co-regulated ferroptosis and metabolism in Ishikawa cells. Moreover, four chemotherapy drugs showed better sensitivity to UCEC patients in the low-risk cohort.

Conclusions: CAPG may serve as a potential biomarker of UCEC owing to its role in modulating the immune response and ferroptosis, providing novel perspectives for combined immunotherapy of UCEC.

Keywords: CAPG; biomarker; ferroptosis; immune status; uterine corpus endometrial carcinoma.

MeSH terms

  • Biomarkers, Tumor* / genetics
  • Biomarkers, Tumor* / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA Methylation
  • Endometrial Neoplasms* / immunology
  • Endometrial Neoplasms* / metabolism
  • Endometrial Neoplasms* / pathology
  • Female
  • Ferroptosis*
  • Gelsolin / genetics
  • Gelsolin / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Phospholipid Hydroperoxide Glutathione Peroxidase / genetics
  • Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism
  • Prognosis
  • Tumor Microenvironment / immunology

Substances

  • Biomarkers, Tumor
  • Gelsolin
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • MicroRNAs

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Doctoral Research Start-up Foundation of Xinxiang Medical University (No. 505477), Natural Science Foundation of Shanghai (No. 22ZR1456200) and National Natural Science Foundation of China (No. 82171655).