HIF-1/2α: The Silent Architects of Adenoid Cystic Carcinoma-A Systematic Review and Meta-Analysis

Adenoid cystic carcinoma (AdCC) is a rare, aggressive salivary gland malignancy with a poor prognosis due to metastasis and local recurrence. Although hypoxia-inducible factors-1/2α (HIF-1/2α) play crucial roles in AdCC, their pleiotropic effects remain poorly understood. This systematic review and meta-analysis evaluates the impact of HIF-1/2α in AdCC progression.

A comprehensive literature search was conducted across PubMed, Scopus, EMBASE, and Web of Science to identify studies examining HIF-1/2α in AdCC. Study quality was assessed using the modified Newcastle-Ottawa scale, and meta-analyses were performed using IBM SPSS Statistics (Version 29).

Sixteen studies met inclusion criteria, with 10 studies encompassing 650 AdCC cases included in the meta-analysis. Positive HIF-1/2α expression was reported in 77.4% of AdCC cases (95% CI: 0.630-0.919, p < 0.001) and was significantly correlated with tumor size (OR: 0.38, 95% CI: 0.16-0.89, p = 0.03), advanced stage (OR: 2.86, 95% CI: 1.74-4.71, p < 0.001), and distant metastasis (OR: 1.82, 95% CI: 1.02-3.25, p = 0.04). Human studies demonstrated significantly increased HIF-1/2α protein and mRNA expression in AdCC cases compared to control groups. Solid-type AdCC exhibited predominantly higher nuclear HIF-1α expression than cribriform and tubular subtypes. Additionally, in cell culture models, the hypoxia-induced upregulation of these factors increased the expression of VEGF (20-fold), BNIP3 (6-fold), and NID1, promoting angiogenesis, epithelial-mesenchymal transition, autophagy, and invasiveness.

HIF-1/2α emerge as a pivotal drivers of AdCC progression, serving dual roles as prognostic biomarker and therapeutic target, necessitating further clinical investigation through multicenter validation studies.