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E2F Transcription Factor 1 Activates FKBP Prolyl Isomerase 4 to Promote Angiogenesis in Cervical Squamous Cell Carcinoma Via the PI3K/AKT Signaling Pathway

  • Reproductive Biology: Original Article
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Abstract

Angiogenesis, namely the formation of blood vessels, is crucial for tumor growth, metastasis and development. E2F transcription factor 1 (E2F1) has been linked to tumorigenesis in several human cancers. This work examines the role of E2F1 and its downstream targets in angiogenesis in cervical squamous cell carcinoma (CSCC). E2F1 was predicted as a candidate oncogene in CSCC using a GSE63514 dataset. Increased E2F1 expression was detected in CSCC tumor samples and cell lines by RT-qPCR, immunohistochemistry, and western blot assays. E2F1 downregulation reduced the angiogenesis activity of HUVECs and the invasiveness of CSCC cells. In vivo, E2F1 knockdown also reduced the xenograft tumor growth and promoted tumor necrosis in mice. FKBP prolyl isomerase 4 (FKBP4) was identified as a target of E2F1. E2F1 bound to FKBP4 promoter for transcriptional activation. Further upregulation of FKBP4 blocked the tumor-suppressive role of E2F1 silencing. FKBP4 was enriched in the PI3K/AKT signaling. In cells and xenograft tumors, the E2F1/FKBP4 axis promoted PI3K and AKT phosphorylation. Activation of the PI3K/AKT signaling restored the angiogenesis activity in cells blocked by E2F1 silencing. In summary, this work demonstrates that E2F1 promotes FKBP4 transcription to activate the PI3K/AKT pathway, which augments the angiogenesis and invasiveness of CSCC.

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Data Availability

The datasets generated and/or analyzed during the current study are not publicly available due research design but are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Dalian Medical University, No. 467, Zhongshan Road, Shahekou District, Dalian, 116023, Liaoning, People’s Republic of China

    Jiazhen Huang & Ying Zhao

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  1. Jiazhen Huang
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  2. Ying Zhao
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Contributions

JZH contribute to study concepts, study design, experimental studies, manuscript preparation, and editing; YZ contribute to experimental studies, manuscript preparation, and editing. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ying Zhao.

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Ethics Approval

This research got the approval of the Ethics Committee of the Second Affiliated Hospital of Dalian Medical University and abided by the Declaration of Helsinki. Signed informed consent was received from each participant. The use of animals was approved by the Animal Ethics Committee of the Second Affiliated Hospital of Dalian Medical University. All procedures were performed adhering to the tenets of the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85–23, revised 1996).

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The authors declare no competing interests.

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Huang, J., Zhao, Y. E2F Transcription Factor 1 Activates FKBP Prolyl Isomerase 4 to Promote Angiogenesis in Cervical Squamous Cell Carcinoma Via the PI3K/AKT Signaling Pathway. Reprod. Sci. 30, 1229–1240 (2023). https://doi.org/10.1007/s43032-022-01034-6

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  • DOI: https://doi.org/10.1007/s43032-022-01034-6

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