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Extracellular vesicle-carried GTF2I from mesenchymal stem cells promotes the expression of tumor-suppressive FAT1 and inhibits stemness maintenance in thyroid carcinoma

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Abstract

Through bioinformatics predictions, we identified that GTF2I and FAT1 were downregulated in thyroid carcinoma (TC). Further, Pearson’s correlation coefficient revealed a positive correlation between GTF2I expression and FAT1 expression. Therefore, we selected them for this present study, where the effects of bone marrow mesenchymal stem cell-derived EVs (BMSDs-EVs) enriched with GTF2I were evaluated on the epithelial–to–mesenchymal transition (EMT) and stemness maintenance in TC. The under-expression of GTF2I and FAT1 was validated in TC cell lines. Ectopically expressed GTF2I and FAT1 were found to augment malignant phenotypes of TC cells, EMT, and stemness maintenance. Mechanistic studies revealed that GTF2I bound to the promoter region of FAT1 and consequently upregulated its expression. MSC-EVs could shuttle GTF2I into TPC-1 cells, where GTF2I inhibited TC malignant phenotypes, EMT, and stemness maintenance by increasing the expression of FAT1 and facilitating the FAT1-mediated CDK4/FOXM1 downregulation. In vivo experiments confirmed that silencing of GTF2I accelerated tumor growth in nude mice. Taken together, our work suggests that GTF2I transferred by MSC-EVs confer antioncogenic effects through the FAT1/CDK4/FOXM1 axis and may be used as a promising biomarker for TC treatment.

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Acknowledgements

This work was supported by Shanghai Shenkang Hospital Development Center (No. SHDC12019X38).

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  1. Co-first authors.

Authors and Affiliations

  1. Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Jie Shao, Baorui Tao, Zihao Cai & Jinhong Chen

  2. Department of Pathology, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Wenjuan Wang & Haixia Li

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  1. Jie Shao
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  2. Wenjuan Wang
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  4. Zihao Cai
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Correspondence to Jinhong Chen.

Ethics declarations

Conflicts of interest Jie Shao, Wenjuan Wang, Baorui Tao, Zihao Cai, Haixia Li, and Jinhong Chen declare that they have no competing interests.

The study was conducted under the approval of the Ethics Committee of Huashan Hospital, Fudan University (Ethical code: 2019-031). The current study was approved by the Animal Ethics Committee of Huashan Hospital, Fudan University (Ethical code: 2019 JS-102) and performed according to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.

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Supplementary material, approximately 331 KB.

Table S1

shRNA sequences

Table S2

Primer sequences for reverse transcription quantitative polymerase chain reaction

Supplementary material, approximately 1.36 MB.

Table S4

Binding site of GTF2I and FAT1 promoter

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Shao, J., Wang, W., Tao, B. et al. Extracellular vesicle-carried GTF2I from mesenchymal stem cells promotes the expression of tumor-suppressive FAT1 and inhibits stemness maintenance in thyroid carcinoma. Front. Med. 17, 1186–1203 (2023). https://doi.org/10.1007/s11684-023-0999-5

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