Esophageal squamous cell carcinoma (ESCC) represents a significant global health burden characterized by a high mortality rate, primarily due to uncontrolled tumor proliferation and the prevalence of distant metastases at the time of diagnosis. Despite significant advances, there remains a critical need to identify the underlying molecular mechanisms to establish new therapeutic approaches.

A recent study published in Genes & Diseases by researchers from the Fourth Military Medical University, 94719 Military Hospital, and Xi’an Medical University, identifies high-mobility group box 3 (HMGB3), a non-histone nuclear protein, as a critical driver of malignancy in ESCC.

HMGB3 expression was found to be significantly elevated in ESCC tissues and cell lines, with higher levels correlating with poor clinical outcomes and aggressive tumor behavior. Functional analyses demonstrated that HMGB3 enhances cell proliferation, migration, and invasion, while its silencing suppresses these malignant phenotypes and the formation of lung metastatic nodules, establishing it as a critical oncogenic effector in ESCC.

Mechanistically, TGIF2 acts as an upstream transcriptional activator by directly binding to the -1138 bp to -894 bp region of the HMGB3 promoter, thereby driving its overexpression. This regulatory interaction positions TGIF2 as a key initiator of the oncogenic cascade, which is further augmented by EGFR signaling; EGF-mediated phosphorylation of TGIF2 leads to increased HMGB3 protein levels—a process that can be effectively blocked by the EGFR inhibitor gefitinib.

Elevated HMGB3, in turn, interacts with Toll-like receptor 3 (TLR3) at key residues including GLU-576, THR-710, and VAL-720, forming a functional complex that activates downstream signaling pathways. This interaction promotes the activation of NF-κB signaling, evidenced by increased phosphorylation and nuclear translocation of p65, which then binds to and transcriptionally activates the promoters of both TGF-β and TLR3. This molecular cascade establishes a positive feedback loop that ensures sustained TGF-β production and signaling, which is indispensable for the proliferation and metastasis observed in ESCC.

In addition to protein-protein interactions, ATAC-seq analysis suggests that HMGB3 also regulates the TGF-β pathway by altering chromatin accessibility at the sites of several pathway components, including TGF-β receptors and SMAD proteins, highlighting a multifaceted regulatory role. The study further elucidates that the oncogenic effects of the TGIF2-HMGB3 axis are mediated through the activation of the Smad-dependent TGF-β signaling pathway. The coordinated activation of TLR3/NF-κB and TGF-β/Smad pathways integrates inflammatory and developmental signaling networks, collectively driving tumor progression and metastatic dissemination.

The clinical relevance of this axis was validated in an independent patient cohort, where the co-expression of TGIF2, HMGB3, and TGF-β was found to be a strong indicator of a poor prognosis; multivariate Cox regression analysis identified each as an independent prognostic risk factor. Furthermore, the use of patient-derived organoid models confirmed that depleting TGIF2 or HMGB3 significantly suppresses tumor growth, highlighting them as potential therapeutic targets.

The authors acknowledge certain limitations, including the unresolved molecular complexity of how HMGB3 modulates TGF-β signaling through both chromatin remodeling and protein interactions. Additionally, the specific impact of the TGIF2/HMGB3/TGF-β axis on the tumor microenvironment remains unclear and requires further investigation. Finally, the clinical significance and prognostic value of this axis necessitate validation in larger patient cohorts and expanded single-cell sequencing datasets to develop personalized therapeutic strategies.
In conclusion, this study is the first to identify the TGIF2/HMGB3/TLR3/TGF-β axis as a pivotal regulatory network and prognostic indicator in ESCC, and inhibiting this pathway—through strategies such as the use of the TGF-β-neutralizing antibody 1D11 or NF-κB inhibitors like BAY 11-7082—may offer a promising approach for clinical intervention in patients with ESCC.

Reference

Title of the original paper: TGIF2-mediated HMGB3 overexpression promotes esophageal squamous cell carcinoma proliferation and metastasis through TLR3/TGF-β signaling

Journal : Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101987

Funding Information:
National Natural Science Foundation of China (No. 82073210, 82372693, 82303427)
National Clinical Research Center for Digestive Diseases (China) (No. 2015BAI13B07)
Shaanxi Provincial Outstanding Youth Fund (China) (No. 2024JC-JCQN-77)
Fund for Scientific and Technological Innovation Team of Shaanxi Innovation Capability Support Plan (China) (No. 2023-CX-TD-67)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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