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Zinc finger protein 695 facilitates the proliferation of colorectal cancer cells through activation of the NEK2 and PI3K/Akt/mTOR signaling pathways

  • Authors:
    • Xiaowei Li
    • Xubin Li
    • Jing Wang
    • Mei Xue
    • Mengqiao Zhang
    • Junfang Shuai
    • Jie Zhang
    • Danyang Ding
    • Ye Wang
    • Shiyang Hou
    • Xiaoqian Chi
    • Haiying Sun
    • Qiang Gao
    • Chunbo Kang

  • View Affiliations

  • Published online on: July 16, 2025     https://doi.org/10.3892/or.2025.8949
  • Article Number: 116

  • Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Colorectal cancer (CRC) is the third most common malignant tumor and the second leading cause of cancer‑related deaths worldwide. Identifying driver genes in CRC development may provide clinical benefits for patients. Zinc finger protein 695 (ZNF695) is a nuclear protein with transcriptional regulatory activity, which has been implicated in tumor progression; however, the role of ZNF695 in CRC is unclear. The clinical relevance of ZNF695 and NIMA‑related kinase 2 (NEK2) in patients with CRC was analyzed based on The Cancer Genome Atlas database. Knockdown was performed by transfecting the cells with small interfering RNAs, whereas overexpression was induced by infecting the cells with a lentivirus. In addition, cell Counting Kit‑8, colony formation, cell cycle and apoptosis assays were carried out to assess the role of ZNF695 and NEK2 in CRC. Chromatin immunoprecipitation‑quantitative PCR (qPCR) and dual luciferase reporter assays were used to examine the transcriptional regulation of ZNF695 on the NEK2 gene. Reverse transcription‑qPCR and western blotting were applied to assess mRNA and protein abundance, respectively. The present study aimed to investigate the clinical relevance, contribution and downstream effects of ZNF695 in CRC. The results revealed that ZNF695 was upregulated in CRC tissues compared with that in non‑cancer tissues. CRC cells also expressed higher ZNF695 expression than normal cells. In vitro, knockdown of ZNF695 suppressed the proliferation of HCT‑8 cells; conversely, overexpression of ZNF695 promoted the malignancy of HT‑29 cells. Moreover, ZNF695 accelerated cell cycle progression and inhibited apoptosis in CRC cells. Mechanistically, it was revealed that ZNF695 upregulated the expression of NEK2 at both the mRNA and protein levels. Luciferase reporter assay demonstrated that ZNF695 enhanced the transcriptional activity of the NEK2 promoter. Furthermore, knockdown of NEK2 reversed the oncogenic function of ZNF695. Additionally, ZNF695 activated the PI3K/Akt/mTOR signaling pathway in CRC cells. Inhibition of this pathway with rapamycin resulted in higher cytotoxicity to CRC cells with ZNF695 overexpression, suggesting that elevated ZNF695 levels may increase the sensitivity of CRC cells to rapamycin. In summary, the current study identified ZNF695 as a tumor‑promoting protein in CRC through activation of the NEK2 and PI3K/Akt/mTOR signaling pathways. Targeting the NEK2 and PI3K/Akt/mTOR signaling pathways may therefore be a promising strategy for the treatment of patients with CRC and high ZNF695 expression.
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October-2025
Volume 54 Issue 4

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Li X, Li X, Wang J, Xue M, Zhang M, Shuai J, Zhang J, Ding D, Wang Y, Hou S, Hou S, et al: Zinc finger protein 695 facilitates the proliferation of colorectal cancer cells through activation of the NEK2 and PI3K/Akt/mTOR signaling pathways. Oncol Rep 54: 116, 2025.
APA
Li, X., Li, X., Wang, J., Xue, M., Zhang, M., Shuai, J. ... Kang, C. (2025). Zinc finger protein 695 facilitates the proliferation of colorectal cancer cells through activation of the NEK2 and PI3K/Akt/mTOR signaling pathways. Oncology Reports, 54, 116. https://doi.org/10.3892/or.2025.8949
MLA
Li, X., Li, X., Wang, J., Xue, M., Zhang, M., Shuai, J., Zhang, J., Ding, D., Wang, Y., Hou, S., Chi, X., Sun, H., Gao, Q., Kang, C."Zinc finger protein 695 facilitates the proliferation of colorectal cancer cells through activation of the NEK2 and PI3K/Akt/mTOR signaling pathways". Oncology Reports 54.4 (2025): 116.
Chicago
Li, X., Li, X., Wang, J., Xue, M., Zhang, M., Shuai, J., Zhang, J., Ding, D., Wang, Y., Hou, S., Chi, X., Sun, H., Gao, Q., Kang, C."Zinc finger protein 695 facilitates the proliferation of colorectal cancer cells through activation of the NEK2 and PI3K/Akt/mTOR signaling pathways". Oncology Reports 54, no. 4 (2025): 116. https://doi.org/10.3892/or.2025.8949