{
  "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.\n\nMaterials and methods: HHLA2 expression was systematically assessed in LSCC tumor specimens and matched adjacent tissues using multiplex immunofluorescence (mIHC). The functional consequences of HHLA2 silencing in LSCC cells were evaluated through a series of in vitro 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.\n\nResults: 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.\n\nConclusions: 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Otorhinolaryngology Head and Neck Surgery, the Third Affiliated Hospital of Soochow University (Changzhou First People’s Hospital)"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yue Yu"
    },
    {
      "affs": [
        0
      ],
      "name": "Jianqiang You"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaoye Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Haixiang Xue"
    },
    {
      "affs": [
        0
      ],
      "name": "Haijun Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "Wenjing Li"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4zvn4pwmsj5f3.bib",
  "cited_by": 0,
  "doi": "10.3389/fonc.2026.1898263",
  "fulltext_url": "https://europepmc.org/articles/PMC13687375",
  "id": "4zvn4pwmsj5f3",
  "issns": [
    "2234-943X"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fonc.2026.1898263/full",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2733|Head and Neck Cancer Studies"
    ]
  ],
  "openalex": "W7221002067",
  "pdf_url": "https://europepmc.org/articles/PMC13687375?pdf=render",
  "pmcid": "PMC13687375",
  "pmid": "42923022",
  "published": "2026-10-08",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/4zvn4pwmsj5f3.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:13Z",
      "native_id": "10.3389/fonc.2026.1898263",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fonc.2026.1898263/full"
    },
    {
      "first_seen": "2026-10-30T12:20:33Z",
      "native_id": "MED:42923022",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42923022"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "issn:2234-943X",
      "subfield": "oncology"
    }
  ],
  "title": "HHLA2-KCTD12 axis: a potential mechanism regulating the biological functions of laryngeal squamous cell carcinoma",
  "title_text": "HHLA2-KCTD12 axis: a potential mechanism regulating the biological functions of laryngeal squamous cell carcinoma",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:33Z",
  "url": "https://research.draconitic.com/paper/4zvn4pwmsj5f3",
  "venue": "Frontiers in Oncology",
  "versions": []
}