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Peer-reviewedCC BY 4.0Frontiers in Pharmacology

Extrachromosomal circular DNA drives focal amplification of AGAP2-AS1 to promote cutaneous tumorigenesis

  • Jin Zhang1,2
  • Zeying Liu1
  • Jinzhi Zhao1
  • Xun Liu1
  • Zhiying Liu2
  • Huiting Xue3
  • Tingting Lin1
  • Limin Zhu1
  1. 1Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital
  2. 2Department of Ophthalmology, The First Hospital of Hohhot
  3. 3Tumor Multimodal Digital and Intelligent Precision Diagnosis Engineering Research Center, School of Basic Medical Sciences, Inner Mongolia Medical University
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Abstract

Background: Extrachromosomal circular DNA (eccDNA) represents a pervasive structural continuum of genomic instability that drives intratumoral heterogeneity; the topography of the eccDNA-encoded non-coding transcriptome remains obscure in ultraviolet (UV)-driven malignancies.

Methods: We profiled eccDNA from Basal Cell Carcinoma, Inverted Follicular Keratosis, Merkel Cell Carcinoma, and matched adjacent normal tissues using Circle-Seq. Structural data were integrated with the eccDNA Gene Analyzer (ECGA) and The Cancer Genome Atlas (TCGA) clinical cohorts. In vitro siRNA-mediated knockdown assays were used to determine the oncogenic functionality of identified lncRNAs.

Results: Circle-Seq revealed genome-wide remodeling of circular DNA with focal hyper-amplification, GC-rich compositional biases, and recurrent hotspots on chromosomes 9, 16, and 20. Integrative screening identified AGAP2-AS1 as a clinically significant, copy-number-associated lncRNA, whose expression correlated with cellular responses to UV radiation and oxidative stress. Depletion of AGAP2-AS1 impaired tumor cell proliferation, migration, and invasion in vitro.

Conclusion: The eccDNA landscape serves as a reservoir of functional non-coding elements; focal amplification of AGAP2-AS1 contributes to malignant progression and stress adaptation in cutaneous neoplasia.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026extrachromosomal,
  title = {{Extrachromosomal circular DNA drives focal amplification of AGAP2-AS1 to promote cutaneous tumorigenesis}},
  author = {Jin Zhang and Zeying Liu and Jinzhi Zhao and Xun Liu and Zhiying Liu and Huiting Xue and Tingting Lin and Limin Zhu},
  journal = {Frontiers in Pharmacology},
  year = {2026},
  month = oct,
  doi = {10.3389/fphar.2026.1906797},
  url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1906797/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Extrachromosomal circular DNA drives focal amplification of AGAP2-AS1 to promote cutaneous tumorigenesis
AU  - Jin Zhang
AU  - Zeying Liu
AU  - Jinzhi Zhao
AU  - Xun Liu
AU  - Zhiying Liu
AU  - Huiting Xue
AU  - Tingting Lin
AU  - Limin Zhu
PY  - 2026
DA  - 2026/10/14
JO  - Frontiers in Pharmacology
DO  - 10.3389/fphar.2026.1906797
UR  - https://www.frontiersin.org/articles/10.3389/fphar.2026.1906797/full
AB  - Background: Extrachromosomal circular DNA (eccDNA) represents a pervasive structural continuum of genomic instability that drives intratumoral heterogeneity; the topography of the eccDNA-encoded non-coding transcriptome remains obscure in ultraviolet (UV)-driven malignancies.  Methods: We profiled eccDNA from Basal Cell Carcinoma, Inverted Follicular Keratosis, Merkel Cell Carcinoma, and matched adjacent normal tissues using Circle-Seq. Structural data were integrated with the eccDNA Gene Analyzer (ECGA) and The Cancer Genome Atlas (TCGA) clinical cohorts. In vitro siRNA-mediated knockdown assays were used to determine the oncogenic functionality of identified lncRNAs.  Results: Circle-Seq revealed genome-wide remodeling of circular DNA with focal hyper-amplification, GC-rich compositional biases, and recurrent hotspots on chromosomes 9, 16, and 20. Integrative screening identified AGAP2-AS1 as a clinically significant, copy-number-associated lncRNA, whose expression correlated with cellular responses to UV radiation and oxidative stress. Depletion of AGAP2-AS1 impaired tumor cell proliferation, migration, and invasion in vitro.  Conclusion: The eccDNA landscape serves as a reservoir of functional non-coding elements; focal amplification of AGAP2-AS1 contributes to malignant progression and stress adaptation in cutaneous neoplasia.
SN  - 1663-9812
ER  -