The Multiomics Landscape of Plasma-Derived Small Extracellular Vesicles during the Development of HPV<sup>+</sup> Cervical Cancer
The transition from HPV infection to cervical cancer (CC) remains unclear, especially concerning small extracellular vesicles (sEVs). We analyzed plasma-sEVs from HPV-negative individuals (HPVN-sEVs), HPV-positive individuals (HPVP-sEVs), and HPV-positive CC patients (HPVC-sEVs) via proteomics (n = 5/5/9) and transcriptomics (n = 3/3/4). Multiomics revealed HPVP-sEVs harbor antiviral and pro-inflammatory signals early in infection, whereas HPVC-sEVs shift toward immunosuppression to sustain persistent infection. Specifically, IFITM2─an antiviral gene─was markedly enriched in HPVP-sEVs versus HPVN-sEVs (<i>P</i> < 0.001) and HPVC-sEVs (<i>P</i> = 0.014). Both HPVP-sEVs (<i>P</i> = 0.004) and HPVC-sEVs (<i>P</i> < 0.001) suppressed M2 macrophages, with HPVC-sEVs further reducing IL-6 (HPVN-sEVs, <i>P</i> = 0.005; HPVP-sEVs, <i>P</i> = 0.015). Notably, IFITM2 mRNA and protein levels in plasma-sEVs distinguished HPVP from HPVC patients, showing superior diagnostic accuracy (AUC = 0.833 and 0.822, respectively) over CA-125. These findings underscore sEVs' dynamic role in HPV-driven carcinogenesis and their potential as noninvasive biomarkers for CC diagnosis.
Authors
- Yuanyuan Lu (ORCID: https://orcid.org/0000-0003-0194-8074)
- Bingjia Yu
- Bo Ding (ORCID: https://orcid.org/0000-0002-5577-7015)
- Yun Zheng
- Haohan Liu (ORCID: https://orcid.org/0000-0003-0750-9304)
- Xing Zhang (ORCID: https://orcid.org/0000-0002-1892-1380)
- Cong Zhang (ORCID: https://orcid.org/0000-0002-3058-070X)
- Yan Zhang (ORCID: https://orcid.org/0000-0002-6296-3588)
- Qigang Dai (ORCID: https://orcid.org/0000-0003-0716-1264)
- Xiuting Li (ORCID: https://orcid.org/0000-0002-3364-8191)
- Xin Ding (ORCID: https://orcid.org/0009-0002-8576-5776)
- Guiyuan Zhang (ORCID: https://orcid.org/0000-0002-4737-7505)
- Shizhi Wang (ORCID: https://orcid.org/0000-0002-6083-6753)
- Hua Jin (ORCID: https://orcid.org/0000-0002-1988-8009)
- Wenjing Yan (ORCID: https://orcid.org/0000-0001-6534-8276)
- Hao Zhang (ORCID: https://orcid.org/0009-0006-9483-834X)
Institutions
- Shihezi University (CN)
- Weifang Medical University (CN)
- Management and Science University (MY)
- Nanjing General Hospital of Nanjing Military Command (CN)
- Jiangsu Vocational College of Medicine (CN)
- Second Hospital of Shandong University (CN)
- Nantong Tumor Hospital (CN)
- Zhongda Hospital Southeast University (CN)
- Jiangsu Provincial Center for Disease Control and Prevention (CN)
- Faculty of Public Health (GB)
- Zhongshan Hospital (CN)
- Jinling Institute of Technology (CN)
- Indiana University School of Medicine
- Southeast University (CN)
- Nanjing Medical University (CN)
- Nanjing University (CN)
Publication Details
- Journal
- Journal of Proteome Research
- Published
- 2025-08-20
- DOI
- https://doi.org/10.1021/acs.jproteome.5c00304
- Citations
- 1
- Primary Topic
- Extracellular vesicles in disease
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Jiangsu Province
- Nanjing University
- Graduate Research and Innovation Projects of Jiangsu Province