{
  "abstract": "Gallbladder cancer (GBC) is an aggressive digestive malignancy with poor prognosis and frequent treatment resistance. Aberrant receptor tyrosine kinase (RTK) signaling is common in GBC and supports use of RTK inhibitors (RTKis) such as sunitinib, yet clinical responses remain limited and the mechanisms driving resistance are unclear. In this study, we utilized patient-derived xenograft (PDX) models of GBC and conducted RNA microarray profiling alongside whole-exome sequencing to identify differentially expressed long non-coding RNAs (lncRNAs) and gene mutations associated with sunitinib resistance. Our findings reveal a novel resistance mechanism whereby TP53 loss impairs its binding to the transcription factor SP1, resulting in SP1-mediated transcriptional activation of the lncRNA ARHGEF7-AS2. Upregulation of ARHGEF7-AS2 functions as a competing endogenous RNA (ceRNA) that sequesters miR-326, thereby relieving repression of its target gene AXL and activating the downstream AKT signaling cascade. This regulatory axis promotes resistance to sunitinib in GBC cells. Importantly, inhibition of ARHGEF7-AS2 or pharmacological blockade of the AXL/AKT pathway restored sunitinib sensitivity, underscoring the therapeutic potential of targeting this pathway. Collectively, our study identifies a previously unrecognized TP53/ARHGEF7-AS2/miR-326/AXL signaling axis that contributes to sunitinib resistance in GBC, providing new mechanistic insights and potential avenues for therapeutic intervention in advanced disease.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China",
    "Department of Systems Biology, Beckman Research Institute, City of Hope, Monrovia, CA 91016, USA",
    "Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China",
    "The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China",
    "Department of Pathology, Mount Sinai West/Morningside Hospitals, New York, NY 10025, USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Linhua Yang"
    },
    {
      "affs": [
        1
      ],
      "name": "Ming Zhan"
    },
    {
      "affs": [
        2
      ],
      "name": "Ruifeng Yang"
    },
    {
      "affs": [
        3
      ],
      "name": "Miaomiao Guo"
    },
    {
      "affs": [
        0
      ],
      "name": "Min He"
    },
    {
      "affs": [
        0
      ],
      "name": "Yixiang Gu"
    },
    {
      "affs": [
        0
      ],
      "name": "Yang Zhang"
    },
    {
      "affs": [
        1
      ],
      "name": "Zhilian Jia"
    },
    {
      "affs": [
        1
      ],
      "name": "Xiaohua Huang"
    },
    {
      "affs": [
        4
      ],
      "name": "Bingyu Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Hui Wang"
    },
    {
      "affs": [
        3
      ],
      "name": "Ruimeng Yang"
    },
    {
      "affs": [
        0
      ],
      "name": "Yingbin Liu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/byjyh6pkknc5f.bib",
  "cited_by": 0,
  "doi": "10.1016/j.apsb.2026.08.019",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13729714/?tool=EBI",
  "id": "byjyh6pkknc5f",
  "issns": [
    "2211-3835",
    "2211-3843"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC13729714",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Article"
    ],
    [
      "openalex",
      "2746|Cholangiocarcinoma and Gallbladder Cancer Studies"
    ]
  ],
  "openalex": "W7204165981",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13729714/pdf/?tool=EBI",
  "pmcid": "PMC13729714",
  "pmid": "42979428",
  "published": "2026-08-25",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/byjyh6pkknc5f.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T15:20:47Z",
      "native_id": "PMC:PMC13729714",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13729714"
    },
    {
      "first_seen": "2026-11-07T12:22:28Z",
      "native_id": "PMC13729714",
      "source": "pmc",
      "url": "https://doi.org/10.1016/j.apsb.2026.08.019"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2746|Cholangiocarcinoma and Gallbladder Cancer Studies",
      "subfield": "surgery"
    }
  ],
  "title": "TP53 mutation promotes sunitinib resistance in gallbladder cancer via the ARHGEF7-AS2/miR-326/AXL pathway",
  "title_text": "TP53 mutation promotes sunitinib resistance in gallbladder cancer via the ARHGEF7-AS2/miR-326/AXL pathway",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:22:28Z",
  "url": "https://research.draconitic.com/paper/byjyh6pkknc5f",
  "venue": "Acta pharmaceutica Sinica. B",
  "versions": []
}