This study first comprehensively reveals the expression patterns and clinical prognostic value of HPGD in esophageal squamous cell carcinoma (ESCC). It identifies that HPGD suppresses tumor progression through LXA4-ERK1/2-U2AF2-TFRC axis activation of ferroptosis and autrophagy mechanisms, providing novel molecular insights and potential therapeutic targets for ESCC targeted treatments.
Literature Overview
The article "HPGD suppresses esophageal squamous cell carcinoma through LXA4-ERK1/2-U2AF2-TFRC axis-induced ferroptosis and autophagy" published in Molecular Cancer investigates HPGD expression levels, clinical correlations, and molecular mechanisms in ESCC. Findings demonstrate significant HPGD downregulation in ESCC tissues, correlating with poor tumor differentiation and patient prognosis. HPGD promotes LXA4 degradation, inhibits ERK1/2 signaling, enhances RNA-binding protein U2AF2 interaction with the TFRC promoter, upregulates TFRC expression, increases intracellular iron levels, and thereby induces ferroptosis and autophagy to suppress tumor progression. This mechanism establishes a new molecular target for ESCC therapy.
Background Knowledge
Esophageal squamous cell carcinoma (ESCC) represents a globally prevalent malignancy with particularly high incidence in China. Due to challenges in early diagnosis, most patients present at middle-to-late stages, resulting in poor overall survival. As a key enzyme in the lipoxygenase metabolic pathway, HPGD has demonstrated tumor-suppressive effects in gastric and colorectal cancers, though its role in ESCC remains undefined. Ferroptosis, an iron-dependent programmed cell death mechanism linked to lipid peroxidation accumulation, interacts with autophagy's dual functions. The transferrin receptor (TFRC), critical for iron uptake regulation, requires precise expression control for ferroptosis induction. This study employs RNA-seq, Western blotting, flow cytometry, and dual-luciferase reporter assays to elucidate the HPGD-U2AF2-TFRC signaling axis in ESCC. The research not only clarifies HPGD's tumor-suppressive functions in ESCC but also provides theoretical foundations for developing targeted therapeutics against this pathway.
Research Methods and Experiments
The research team initially performed transcriptomic sequencing on paired tumor-normal tissues from ESCC patients, identifying HPGD as a significantly downregulated gene. They subsequently validated HPGD expression and its correlation with patient prognosis in two independent clinical cohorts. Functional impacts were assessed through in vitro experiments involving HPGD overexpression in ESCC cells, including proliferation, migration, invasion, and apoptosis assays. Further investigations combined transcriptomic sequencing, lipid peroxidation detection, flow cytometry for autophagy analysis, with biotin pull-down assays, mass spectrometry, and chromatin immunoprecipitation (ChIP) experiments. The study demonstrated that HPGD inhibits ERK1/2 signaling, promotes U2AF2 binding to the TFRC promoter region, upregulates TFRC expression, and thereby triggers ferroptosis and autophagy. In vivo validation used nude mouse xenograft models to confirm HPGD's tumor-suppressive effects, supported by ROS, GPX4, and GSH measurements verifying ferroptosis pathway involvement.
Key Conclusions and Perspectives
Research Significance and Prospects
This study systematically defines HPGD's tumor-suppressive mechanisms in ESCC and establishes its potential as a prognostic biomarker and therapeutic target. Future research should focus on developing HPGD small molecule activators or TFRC-targeted gene therapies for improved ESCC treatment options. Moreover, U2AF2's newly identified transcriptional regulatory function in TFRC expression expands understanding of RNA-binding proteins' roles in cancer biology, offering fresh perspectives for oncological research.
Conclusion
This study provides the first systematic analysis of HPGD expression patterns and clinical significance in esophageal squamous cell carcinoma (ESCC). HPGD demonstrates significant downregulation in tumor tissues, correlating with poor differentiation and adverse prognosis. Molecular investigations reveal HPGD suppresses ESCC progression through LXA4-ERK1/2-U2AF2-TFRC axis regulation of ferroptosis and autophagy. HPGD overexpression increases U2AF2 promoter binding to TFRC, elevates TFRC expression, promotes iron accumulation and lipid peroxidation, and activates ferroptosis. Elevated ROS levels simultaneously trigger autophagy through AMPK/mTOR pathways, creating a positive feedback loop that further suppresses tumor growth. In vivo experiments confirm HPGD's tumor-suppressive effects. These findings expand understanding of HPGD's functions in cancer biology and identify U2AF2's novel transcriptional regulatory role, providing theoretical foundations for future targeted therapies. The results suggest HPGD and TFRC could serve as potential prognostic markers and therapeutic targets, offering critical insights for precision medicine and drug development in ESCC treatment.
