Oesophageal squamous cell carcinoma (ESCC) represents a significant global health burden characterised by a high mortality rate, primarily due to uncontrolled tumour 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 tumour behaviour.

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 signalling; 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 signalling pathways.

This interaction promotes the activation of NF-κB signalling, 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 signalling, 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 signalling pathway.

The coordinated activation of TLR3/NF-κB and TGF-β/Smad pathways integrates inflammatory and developmental signalling networks, collectively driving tumour 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 tumour growth, highlighting them as potential therapeutic targets.

The authors acknowledge certain limitations, including the unresolved molecular complexity of how HMGB3 modulates TGF-β signalling through both chromatin remodelling and protein interactions.

Additionally, the specific impact of the TGIF2/HMGB3/TGF-β axis on the tumour 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 personalised 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-neutralising antibody 1D11 or NF-κB inhibitors like BAY 11-7082—may offer a promising approach for clinical intervention in patients with ESCC.

Source: Compuscript Ltd