Work

HHLA2-KCTD12 axis: a potential mechanism regulating the biological functions of laryngeal squamous cell carcinoma

Year: 2026

Type: article

Abstract: Background: Accumulating evidence suggests that aberrant HHLA2 expression is closely implicated not only in tumorigenesis, disease progression, and metastatic spread, but also in the intricate modulation of the tumor immune microenvironment. Nevertheless, the biological functions of HHLA2 and the molecular mechanisms underlying its action in laryngeal squamous cell carcinoma (LSCC) remain unexplored. Materials and methods: assays, including CCK-8-based proliferation analysis, wound-healing (scratch) assays, and invasion assays. Transcriptomic sequencing integrated with public database mining was subsequently performed to identify key target genes potentially governed by HHLA2 in regulating LSCC biological behavior. Furthermore, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) pathway analyses were conducted to delineate the signaling networks and molecular pathways through which HHLA2 might exert its regulatory effects in LSCC. Results: HHLA2 expression was significantly elevated in LSCC tumor tissues, and associated with poor prognosis in patients. Functional experiments revealed that suppression of HHLA2 leads to marked inhibition of LSCC cell proliferation, migration, and invasion, underscoring its essential role in sustaining malignant phenotypes. Mechanistically, we identified potassium channel tetrameric domain 12 (KCTD12) as a pivotal target of HHLA2 in mediating these oncogenic processes. Importantly, forced overexpression of KCTD12 effectively counterbalanced the inhibitory effects induced by HHLA2 depletion, thereby restoring proliferative, migratory, and invasive potential to LSCC cells. Furthermore, pathway enrichment analyses indicated that the TNF-NF-κB signalling pathway might serve as a key conduit through which HHLA2 orchestrated both tumor cell functions and immune regulatory mechanisms. The HHLA2-KCTD12 axis may regulate the phenotype of LSCC cells and reshape the tumor immune microenvironment through the TNF-NF-κB signaling pathway. Conclusions: HHLA2 enhanced the proliferative, migratory, and invasive capacities of LSCC cells and might contribute to immune microenvironment remodeling via modulation of TNF-NF-κB signaling through the HHLA2-KCTD12 axis.

Source: Frontiers in Oncology

DOI: 10.3389/fonc.2026.1898263

Authors: Yue Yu, Jianqiang You, Xiaoye Wang, Haixiang Xue, Haijun Chen, Wenjing Li

Institution: Soochow University

Language: English

Topic: Head and Neck Cancer Studies

Subfield: Otorhinolaryngology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801