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Reciprocal FGF19-GLI2 signaling induces epithelial-to-mesenchymal transition to promote lung squamous cell carcinoma metastasis

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Abstract

Purpose

Metastatic lung squamous cell carcinoma (LUSC) is one of the most common causes of cancer death worldwide. As yet, however, the molecular mechanism underlying LUSC metastasis remains elusive. In this study, we report a novel mechanism involving signaling interactions between FGF19 and GLI2 that could drive the progression of LUSC.

Methods

The expression of FGF19 in human LUSC samples was assessed by immunohistochemistry. The concentration of FGF19 in serum samples was assessed by ELISA. RNA sequencing, scratch wound-healing, trans-well, GO analysis, GSEA, luciferase reporter, Western blotting, immunofluorescence and immunohistochemistry assays, as well as an animal model were used to investigate the molecular mechanism underlying FGF19 driven LUSC progression. The therapeutic effect of a GLI2 inhibitor was determined using both in vitro cellular and in vivo animal experiments.

Results

We found that FGF19, a member of the fibroblast growth factor family, plays a crucial role in the invasion and metastasis of LUSC, and identified GLI2 as an important downstream effector of FGF19 involved in metastasis. Surprisingly, we found that FGF19 and GLI2 could reciprocally induce the expression of each other, and form a positive feedback loop to promote LUSC cell invasion and metastasis. These findings were corroborated by an association between a poor prognosis of LUSC patients and FGF19/GLI2 co-expression. In addition, we found that the GLI inhibitor GANT61 could effectively reduce FGF19-mediated LUSC invasion and metastasis.

Conclusion

Our data suggest that FGF19 may serve as a novel biomarker for predicting metastatic LUSC. Intervening with the FGF19-GLI2 feedback loop may be a strategy for the treatment of FGF19-driven LUSC metastasis.

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Data availability

The RNA-seq data generated in this study are available in GEO under accession number GSE207588. Other data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

The authors thank to all those who financed the study.

Funding

This work was supported by grants from the Science and Technology Commission of Shanghai Municipality (21ZR1433100), the State Key Laboratory of Oncogenes and Related Genes (KF2122) and SJTU funding (YG2022ZD016).

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Author notes

  1. Yanshuang Zhang and Tingyu Wu contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, 200030, Shanghai, China

    Yanshuang Zhang, Tingyu Wu, Zhuo Chen, Jiachen Chen & Weiliang Xia

  2. Department of Medical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, 1954 Huashan Road, 200030, Shanghai, China

    Yuting Wang & Shun Lu

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  1. Yanshuang Zhang
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Contributions

Conception and design: Y.Z. and W.X.; Data acquisition and analysis: Y.Z., T.W., Y.W., Z.C., J.C. and W.X.; writing and original draft preparation: Y.Z., T.W. and W.X.; critical review and editing: Y.Z., T.W. and W.X.; studies related to clinical samples: Y.W., S.L.; supervision: W.X.; funding acquisition: W.X. All authors have seen and approved the final draft of the manuscript before submission. The work reported has been performed by the authors, unless clearly specified in the text.

Corresponding author

Correspondence to Weiliang Xia.

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Ethics approval and consent to participate

This work was approved by the Research Ethics Committee of the School of Biomedical Engineering, Shanghai Jiao Tong University (Shanghai, China). All patients were informed of the study and consented to the use of samples for research purposes. All animal experiments were performed following the regulations and internal biosafety and bioethics guidelines of the Research Ethics Committee of the School of Biomedical Engineering, Shanghai Jiao Tong University (Shanghai, China).

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Zhang, Y., Wu, T., Wang, Y. et al. Reciprocal FGF19-GLI2 signaling induces epithelial-to-mesenchymal transition to promote lung squamous cell carcinoma metastasis. Cell Oncol. 46, 437–450 (2023). https://doi.org/10.1007/s13402-022-00760-y

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