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Human papillomavirus16 E7 enhances cell stemness by regulating the APC2/SPIN4/β-catenin axis in cervical cancer
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  • Published: 24 February 2026

Human papillomavirus16 E7 enhances cell stemness by regulating the APC2/SPIN4/β-catenin axis in cervical cancer

  • Tao Shen1,2 na1,
  • Yuejiang Ma1,2 na1,
  • Tingting Wu1,2 na1,
  • Zhu Cao1,2,
  • Peng Yi  ORCID: orcid.org/0009-0000-1832-17833,
  • Xiufeng Huang  ORCID: orcid.org/0000-0002-0861-40451,2 &
  • …
  • Shizhou Yang  ORCID: orcid.org/0009-0005-5682-218X1,2 

Oncogenesis , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Cancer stem cells
  • Cervical cancer

Abstract

High-risk human papillomavirus (HPV) is a causal factor in cervical cancer, driving the cancer’s initiation and progression. Although cancer stem cells (CSCs) have been implicated in maintaining the stemness and malignancy of cervical cancer cells, the underlying mechanisms are not yet fully understood. In this study, we modulated gene expression in Caski and SiHa cervical cancer cells using siRNA and overexpression approaches. Functional assays, including MTT, transwell, RT-qPCR, western blotting, immunohistochemistry, luciferase reporter, immunofluorescence, and sphere formation, were performed to evaluate target gene expression. Additionally, transcriptome sequencing was used to analyze the impact of silencing HPV16 E7 on SiHa cells, and a xenograft model was assessed for in vivo effects. Our transcriptome sequencing reveals substantial changes in gene expression profiles upon HPV16 E7 silencing in cervical cancer. Notably, we identified APC2 as a key downstream target transcriptionally activated by HPV16 E7 through the transcription factor E2F1, and its elevated expression is associated with poor prognosis in cervical cancer. Surprisingly, APC2 exhibits oncogeneic properties in cervical cancer by activating the Wnt/β-catenin pathway, and its overexpression reverses the inhibitory effects of HPV16 E7 silencing on malignancy and CSC properties. Additionally, SPIN4 is identified as a pivotal downstream target of the HPV16 E7/APC2 axis, positively modulating cervical cancer progression. Our study reveals a novel HPV16 E7-APC2-SPIN4 axis as a key driver of cervical cancer. In this pathway, APC2 unexpectedly functions as an oncogene by activating the Wnt/β-catenin signaling to promote tumorigenesis and CSC properties.

Data availability

All data generated or analyzed during this study are shown within this article. Sequence of the putative E2F1 binding site in the APC2 promoter and its mutant (APC2 MUT) are provided in Supplementary Data 1. The graphical abstract was created with BioRender.com. Additional information or other data are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the Natural Science Foundation of Zhejiang Province (Nos. ZCLQN25H0401, LQ20H160054, and LQ20H160049), and the Quzhou Municipal Bureau of Science and Technology of Zhejiang Province (Nos. 2021Y012 and 2021Y002).

Author information

Author notes

  1. These authors contributed equally: Tao Shen, Yuejiang Ma, Tingting Wu.

Authors and Affiliations

  1. Department of Gynecology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Tao Shen, Yuejiang Ma, Tingting Wu, Zhu Cao, Xiufeng Huang & Shizhou Yang

  2. Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Hangzhou, Zhejiang, China

    Tao Shen, Yuejiang Ma, Tingting Wu, Zhu Cao, Xiufeng Huang & Shizhou Yang

  3. Center of Reproductive Medicine, the Quzhou Affiliated Hospital of Wenzhou Medical University (Quzhou People’s Hospital), Quzhou, Zhejiang, China

    Peng Yi

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Contributions

TS, YM, and TW: Conceptualization; data curation; investigation; methodology; writing—original draft. ZC: Performed experiments; analysed data. PY, XH, and SY: Conceptualization; investigation; methodology; writing—review and editing.

Corresponding authors

Correspondence to Peng Yi, Xiufeng Huang or Shizhou Yang.

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Competing interests

The authors declare no competing interests.

Ethical approval

The animal experiments in this study were conducted following the ARRIVE guidelines and the “Guiding Principles in the Care and Use of Animals” (China) and approved by the Laboratory Animal Welfare & Ethics Committee of Women’s Hospital, School of Medicine, Zhejiang University (Approval Number: AE 20250009). The clinical samples of CC tumors and normal cervical tissue were collected from patients with informed consent and ethical guidelines approved by the Ethics Committee of Women’s Hospital, School of Medicine, Zhejiang University (Approval number: IRB-20230172-R).

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Supplementary information

Supplementary Data 1

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Shen, T., Ma, Y., Wu, T. et al. Human papillomavirus16 E7 enhances cell stemness by regulating the APC2/SPIN4/β-catenin axis in cervical cancer. Oncogenesis (2026). https://doi.org/10.1038/s41389-026-00602-8

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  • Received: 05 June 2025

  • Revised: 27 November 2025

  • Accepted: 12 February 2026

  • Published: 24 February 2026

  • DOI: https://doi.org/10.1038/s41389-026-00602-8

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