Metadherin: A pivotal oncogene and therapeutic target in head and neck cancer-a systematic review

Abstract

Purpose

Metadherin (MTDH) is frequently overexpressed across human malignancies, yet its roles in head and neck cancer (HNC) remain incompletely characterized. This systematic review evaluates the biological functions, molecular mechanisms, and clinical relevance of MTDH in HNC.

Methods

A systematic literature search was conducted across four electronic databases (PubMed, Embase, Scopus, and Web of Science) in accordance with PRISMA 2020 guidelines.

Results

Thirty-three studies met inclusion criteria. MTDH was consistently overexpressed across HNC subtypes and associated with advanced clinicopathological features and poor prognosis. Functional studies demonstrated that elevated MTDH promotes migration, invasion, metastasis, epithelial-mesenchymal transition (EMT), proliferation, angiogenesis, and chemoresistance. Mechanistically, MTDH activates NF-κB, PI3K/Akt, Wnt, and MAPK pathways and is post-transcriptionally regulated by nine miRNAs, with HNC-specific features including a CCL18-driven macrophage paracrine axis, MMP1-selective NF-κB effector activity, and a potential association with invasion front architecture as reflected by Worst Pattern of Invasion (WPOI). Clinically, MTDH modulates chemoresistance, ferroptosis-mediated radiosensitivity, and immune checkpoint expression.

Conclusion

This systematic review identifies MTDH as a multifaceted oncoprotein that plays a central role in HNC progression, metastasis, and therapeutic response, highlighting its potential as a prognostic biomarker and therapeutic target.