{
  "abstract": "Background and objectives\n\nOsteosarcoma (OS) is an aggressive bone cancer with a poor prognosis, especially in metastatic cases. The tumor microenvironment (TME), particularly tumor-associated macrophages (TAMs), plays a crucial role in its progression. This study aimed to investigate the role and mechanism of the tripartite motif-containing 65 (TRIM65), B-cell translocation gene 3 (BTG3), hypoxia-inducible factor 1α (HIF-1α; TRIM65-BTG3-HIF-1α) signaling axis in regulating TAMs and angiogenesis in OS.Methods\n\nBioinformatic analysis of The Cancer Genome Atlas (TCGA) and TARGET-OS datasets identified M2 macrophage-related genes. Clinical OS samples were analyzed via immunohistochemistry (IHC), immunofluorescence (IF), messenger ribonucleic acid (mRNA) sequencing, and data-independent acquisition (DIA) quantitative proteomics. In vitro functional assays (cell counting kit-8 [CCK-8], colony formation, transwell migration/invasion, tube formation) and in vivo subcutaneous xenograft models in nude mice were performed using OS cell lines (U-2 OS [U2OS], sarcoma osteogenics [SAOS], human OS (HOS), 143B) and the human fetal osteoblast (hFOB) normal osteoblast line. Macrophage polarization was induced from Tohoku Hospital pediatrics-1 (THP-1) cells. Molecular interactions were assessed by co-immunoprecipitation (Co-IP), ubiquitination assays, and luciferase reporter assays.Results\n\nHigh infiltration of M2 macrophages correlated with poor patient prognosis. BTG3 was identified as a key M2-related gene exhibiting a \"transcriptional upregulation with translational downregulation\" pattern in OS. TRIM65, an E3 ubiquitin ligase upregulated in OS, directly interacted with and promoted the ubiquitin-mediated degradation of the BTG3 protein. Knockdown of TRIM65 inhibited OS cell proliferation, migration, invasion in vitro, and tumor growth in vivo. BTG3 acted as a negative regulator of HIF-1α transcriptional activity. Loss of BTG3 led to HIF-1α activation, which in turn promoted M2 polarization and enhanced migration of macrophages. Furthermore, conditioned medium from BTG3-deficient cells significantly promoted endothelial cell migration and tube formation, indicating enhanced angiogenesis. This pro-angiogenic effect was dependent on HIF-1α activation.Conclusions\n\nWe delineate a novel TRIM65-BTG3-HIF-1α signaling axis in OS. TRIM65 degrades BTG3, leading to HIF-1α activation, which drives M2 macrophage polarization and angiogenesis, ultimately fostering tumor progression. Targeting this axis may offer a promising therapeutic strategy for OS.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China.",
    "Department of Orthopedics, Anhui Public Health Clinical Center, Hefei, Anhui Province, China.",
    "Clinical College of Anhui Medical University, Anhui Medical University, Hefei, Anhui Province, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Hao Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Rui Yang"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhongxuan Wu"
    },
    {
      "affs": [
        0
      ],
      "name": "Mian Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Longze Xiao"
    },
    {
      "affs": [
        0
      ],
      "name": "Yukang Que"
    },
    {
      "affs": [
        0
      ],
      "name": "Peng He"
    },
    {
      "affs": [
        0
      ],
      "name": "Qiming Ma"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Tangbing Xu"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Chi Zhang",
      "orcid": "0009-0003-1840-4679"
    },
    {
      "affs": [
        0
      ],
      "name": "Shenglin Xu",
      "orcid": "0009-0002-5619-6594"
    },
    {
      "affs": [
        0
      ],
      "name": "Yong Hu",
      "orcid": "0000-0003-0638-3279"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/34a6c25nbvszc.bib",
  "cited_by": 0,
  "doi": "10.1515/jtim-2026-0075",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13726653/?tool=EBI",
  "id": "34a6c25nbvszc",
  "issns": [
    "2450-131X",
    "2224-4018"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC13726653",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Article"
    ],
    [
      "openalex",
      "2403|Immune cells in cancer"
    ]
  ],
  "openalex": "W7223326679",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13726653/pdf/?tool=EBI",
  "pmcid": "PMC13726653",
  "pmid": "42974522",
  "published": "2026-10-23",
  "publisher": "De Gruyter",
  "ris": "https://research.draconitic.com/paper/34a6c25nbvszc.ris",
  "sources": [
    {
      "first_seen": "2026-11-03T15:20:51Z",
      "native_id": "PMC:PMC13726653",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13726653"
    },
    {
      "first_seen": "2026-11-04T15:20:48Z",
      "native_id": "MED:42974522",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42974522"
    },
    {
      "first_seen": "2026-11-05T12:22:57Z",
      "native_id": "PMC13726653",
      "source": "pmc",
      "url": "https://doi.org/10.1515/jtim-2026-0075"
    }
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Immune cells in cancer",
      "subfield": "immunology"
    }
  ],
  "title": "TRIM65-BTG3-HIF-1α axis drives osteosarcoma progression via M2 macrophage polarization and angiogenesis",
  "title_text": "TRIM65-BTG3-HIF-1α axis drives osteosarcoma progression via M2 macrophage polarization and angiogenesis",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:22:33Z",
  "url": "https://research.draconitic.com/paper/34a6c25nbvszc",
  "venue": "Journal of translational internal medicine",
  "versions": []
}