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Increased SPRY1 expression activates NF-κB signaling and promotes pancreatic cancer progression by recruiting neutrophils and macrophages through CXCL12-CXCR4 axis

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Abstract

Purpose

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high mortality rate, in which about 90% of patients harbor somatic oncogenic point mutations in KRAS. SPRY family genes have been recognized as crucial negative regulators of Ras/Raf/ERK signaling. Here, we investigate the expression and role of SPRY proteins in PDAC.

Methods

Expression of SPRY genes in human and mice PDAC was analyzed using The Cancer Genome Atlas and Gene Expression Omnibus datasets, and by immunohistochemistry analysis. Gain-of-function, loss-of-function of Spry1 and orthotopic xenograft model were adopted to investigate the function of Spry1 in mice PDAC. Bioinformatics analysis, transwell and flowcytometry analysis were used to identify the effects of SPRY1 on immune cells. Co-immunoprecipitation and K-ras4B G12V overexpression were used to identify molecular mechanism.

Results

SPRY1 expression was remarkably increased in PDAC tissues and positively associated with poor prognosis of PDAC patients. SPRY1 knockdown suppressed tumor growth in mice. SPRY1 was found to promote CXCL12 expression and facilitate neutrophil and macrophage infiltration via CXCL12-CXCR4 axis. Pharmacological inhibition of CXCL12-CXCR4 largely abrogated the oncogenic functions of SPRY1 by suppressing neutrophil and macrophage infiltration. Mechanistically, SPRY1 interacted with ubiquitin carboxy-terminal hydrolase L1 to induce activation of nuclear factor κB signaling and ultimately increase CXCL12 expression. Moreover, SPRY1 transcription was dependent on KRAS mutation and was mediated by MAPK-ERK signaling.

Conclusion

High expression of SPRY1 can function as an oncogene in PDAC by promoting cancer-associated inflammation. Targeting SPRY1 might be an important approach for designing new strategy of tumor therapy.

Highlights

The expression of SPRY1 is increased during malignant transformation and predicts a poor prognosis in PDAC.

SPRY1 promotes neutrophil and macrophage recruitment via CXCL12-CXCR4 axis.

SPRY1 modulates CXCL12 expression through promoting nuclear factor κB signaling activation via interaction with ubiquitin carboxy-terminal hydrolase L1.

SPRY1 transcription is dependent on KRAS mutation and mediated by MAPK-ERK signaling in PDAC.

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Data availability

The data are available within the Article, Supplementary Information, or available from the authors upon request. Source data are provided with this paper.

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Acknowledgments

We thank Prof. Xiongjun Wang for technical support.

Funding

This study was supported by the National Natural Science Foundation of China (No. 31801212 to LY). Beijing Natural Science Foundation (No. 5232003 to LW).

Author information

Author notes

  1. Tiezhu Shi, Xiao Li and Jiahao Zheng contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People’s Republic of China

    Linli Yao

  2. School of Life Sciences, Guangzhou University, 230 Wai Huan Xi Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, People’s Republic of China

    Tiezhu Shi

  3. Department of Obstetrics and Gynecology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, People’s Republic of China

    Xiao Li

  4. Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, People’s Republic of China

    Jiahao Zheng, Zonghao Duan & Jianyu Yang

  5. School of Biosciences, Faculty of Health and Medical Sciences, Taylor’s University. No. 1, Jalan Taylor’s, Subang Jaya, Selangor, 47500, Malaysia

    Yin Yin Ooi

  6. Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, People’s Republic of China

    Yan Gao, Qi Wang & Lulu Wang

  7. Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Capital Medical University, Beijing, 100069, People’s Republic of China

    Yan Gao & Lulu Wang

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  1. Tiezhu Shi
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Contributions

LY, JY and LW conceived the project; LY and JY designed experiments, interpreted data in the manuscript and wrote the manuscript; LW performed bioinformatics analyses, data analysis and wrote the manuscript; XL, JZ, LY and TS performed cell and animal experiments; JY provided clinical specimens and made clinical pathology evaluations; XL, JZ and ZD performed western blotting analysis and IHC analysis; OYY, YG and QW reviewed the manuscript and discussed the data. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jianyu Yang, Lulu Wang or Linli Yao.

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Ethical approval

All procedures related to patients were carried out in accordance with International Ethical Guidelines for Biomedical Research Involving Human Subjects (CIOMS). The study was approved by the Research Ethics Committee of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University. All the mouse experiments were approved by the Research Ethics Committee of Shanghai Jiao Tong University.

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Shi, T., Li, X., Zheng, J. et al. Increased SPRY1 expression activates NF-κB signaling and promotes pancreatic cancer progression by recruiting neutrophils and macrophages through CXCL12-CXCR4 axis. Cell Oncol. 46, 969–985 (2023). https://doi.org/10.1007/s13402-023-00791-z

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