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CPSF4 promotes tumor-initiating phenotype by enhancing VEGF/NRP2/TAZ signaling in lung cancer

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Abstract

Lung cancer is the leading cause of malignant tumor-related deaths worldwide. The presence of tumor-initiating cells in lung cancer leads to tumor recurrence, metastasis, and resistance to conventional treatment. Cleavage and polyadenylation specificity factor 4 (CPSF4) activation in tumor cells contributes to the poor prognosis of lung cancer. However, the precise biological functions and molecular mechanisms of CPSF4 in the regulation of tumor-initiating cells remain unclear. We demonstrated that CPSF4 promotes tumor-initiating phenotype and confers chemoresistance to paclitaxel both in vitro and in vivo. Mechanistically, we showed that CPSF4 binds to the promoters of vascular endothelial growth factor (VEGF) and neuropilin-2 (NRP2) and activated their transcription. In addition, we showed that CPSF4/VEGF/NRP2-mediated tumor-initiating phenotype and chemoresistance through TAZ induction. Furthermore, analysis of clinical data revealed that lung cancer patients with high CPSF4 expression exhibit high expression levels of VEGF, NRP2, and TAZ and that expression of these proteins are positively correlated with poor prognosis. Importantly, selective inhibition of VEGF, NRP2, or TAZ markedly suppressed CPSF4-mediated tumor-initiating phenotype and chemoresistance. Our findings reveal the mechanism of CPSF4 modulating tumor-initiating phenotype and chemoresistance in lung cancer and indicate that the CPSF4-VEGF-NRP2-TAZ signaling pathway may be a prognosis marker and therapeutic target in lung cancer.

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Data availability

The datasets are available in the National Center of Biotechnology Information (NCBI) GEO (https://www.ncbi.nlm.nih.gov/geo/). Datasets GSE41271 and GSE37745 were used in the present study.

Abbreviations

CPSF4:

Cleavage and polyadenylation specificity factor 4

ChIP:

Chromatin immunoprecipitation

VEGF:

Vascular endothelial growth factor

NRP:

Neuropilin

TICs:

Tumor-initiating cells

PTX:

Paclitaxel

GEO:

Gene Expression Omnibus

GSEA:

Gene set enrichment analysis

PVDF:

Polyvinylidene difluoride

IHC:

Immunohistochemical

SD:

Standard deviation

COUP-TFII:

COUP transcription factor II

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Acknowledgements

We thank the members of FeiMeng Zheng’s, WuGuo Deng’s, and ShuSen Wang’s laboratory for their critical comments and technical support.

Funding

This work was supported by funds from the National Natural Science Foundation of China, China (81401905 to W.B.C.) and the National Natural Science Foundation of Guangdong, China (2017A030313489 to T.Q.).

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Author notes

  1. YingQiu Song and Kai Sun have contributed equally to this work.

Authors and Affiliations

  1. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    YingQiu Song, LinLi Shi, WangBing Chen & GuiLing Li

  2. Department of Medical Oncology, The Eastern Hospital, The First Affiliated Hospital, Sun Yat-Sen University, No.58, Zhong Shan Er Lu, Guangzhou, 510080, China

    FeiMeng Zheng

  3. Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei, China

    Kai Sun

  4. Department of Ultrasound, Wuhan No.1 Hospital, Wuhan, China

    LiLan Gong

  5. Department of Medical Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Tao Qin

  6. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China

    ShuSen Wang & WuGuo Deng

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  1. YingQiu Song
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Contributions

The work was done in collaboration with all authors. WBC, FMZ, and GLL contribute to the conception and design of this work and reviewed the manuscript. WBC, YQS, and KS analyzed the raw data. FMZ help analyze data and organize data. YQS and KS designed the experimental methods, completed the experiments, and wrote the manuscript. LLG and LLS provided technical support during completing the experiments. SSW, WGD, and TQ provided critical comments.

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Correspondence to WangBing Chen, FeiMeng Zheng or GuiLing Li.

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Song, Y., Sun, K., Gong, L. et al. CPSF4 promotes tumor-initiating phenotype by enhancing VEGF/NRP2/TAZ signaling in lung cancer. Med Oncol 40, 62 (2023). https://doi.org/10.1007/s12032-022-01919-1

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