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E2F2 enhances the chemoresistance of pancreatic cancer to gemcitabine by regulating the cell cycle and upregulating the expression of RRM2

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Abstract

Both pro-oncogenic and anti-oncogenic effects of E2F2 have been revealed in different malignancies. However, the precise role of E2F2 in pancreatic cancer, in particular in relation to therapeutic intervention with gemcitabine, remains unclear. In this study, the effect of E2F2 on the proliferation and cell cycle modulation of pancreatic cancer cells, and whether E2F2 plays a role in the treatment of pancreatic cancer cells by gemcitabine, were investigated. The expression of E2F2 in pancreatic cancer was assessed by various methods including bioinformatics prediction, Western blotting, and real-time PCR. The effect of E2F2 on the proliferation and cell cycling of pancreatic cancer cells was analyzed by tissue culture and flow cytometry. In addition, the effect of E2F2 on the intervention of pancreatic cancer by gemcitabine was investigated using both in vitro and in vivo approaches. The expression of E2F2 was found to be significantly increased in pancreatic cancer tissues and cell lines. The pathogenic capacity of E2F2 lied in the fact that this transcription factor promoted the transformation of pancreatic cancer cell cycle from G1-phase to S-phase, thus enhancing the proliferation of pancreatic cancer cells. Furthermore, the expression of E2F2 was increased in pancreatic cancer cells in the presence of gemcitabine, and the augmented expression of E2F2 upregulated the gemcitabine resistance-related gene RRM2 and its downstream signaling molecule deoxycytidine kinase (DCK). The resistance of pancreatic cancer cells to gemcitabine was confirmed using both in vitro and in vivo models. In this study, E2F2 has been demonstrated for the first time to play a pro-oncogenic role in pancreatic cancer by promoting the transition of the cell cycle from G1-phase to S-phase and, therefore, enhancing the proliferation of pancreatic cancer cells. E2F2 has also been demonstrated to enhance the chemotherapy resistance of pancreatic cancer cells to gemcitabine by upregulating the expression of RRM2 and DCK that is downstream of RRM2.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was supported by a grant from the National Natural Science Foundation of China (81960429) and Guizhou Province Science and Technology Projects ([2018]5779-31).

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Author notes

  1. Qianfan Liu, Chunzhuo Song and Junjun Li contribute equally to this work.

Authors and Affiliations

  1. Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, Guizhou, People’s Republic of China

    Qianfan Liu, Chunzhuo Song, Junjun Li, Meng Liu, Liyue FU, Jiuliang Jiang & Haitao Zhu

  2. Department of General Surgery, Northern Jiangsu People’s Hospital, Yangzhou, 225000, Jiangsu Province, People’s Republic of China

    Qianfan Liu

  3. Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research On Common Chronic Diseases, Guiyang, 550001, Guizhou, People’s Republic of China

    Zhirui Zeng

  4. Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People’s Republic of China

    Chunzhuo Song

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  1. Qianfan Liu
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by CS, JL and HZ. The first draft of the manuscript was written by QL and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Haitao Zhu.

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The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Guizhou Medical University.

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Informed consent was obtained from all individual participants included in the study. The authors affirm that human research participants provided informed consent for publication of the images in the figure (Fig. 1E, F).

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Liu, Q., Song, C., Li, J. et al. E2F2 enhances the chemoresistance of pancreatic cancer to gemcitabine by regulating the cell cycle and upregulating the expression of RRM2. Med Oncol 39, 124 (2022). https://doi.org/10.1007/s12032-022-01715-x

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