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LGI3 promotes the progression of TFE3-rearranged renal cell carcinoma through GEMIN6/AURKB axis

Oncogene volume 44, pages 3729–3740 (2025)Cite this article

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Abstract

Transcription factor binding to IGHM enhancer 3-rearranged renal cell carcinoma (TFE3-RCC) is characterized by its aggressive nature, limited treatment options, and poor prognosis. However, the downstream targets of TFE3 fusion protein responsible for its tumorigenesis and progression remain unclear. Here, we demonstrated that leucine-rich repeat LGI family member 3 (LGI3) is a direct target of TFE3 fusion protein. TFE3 fusion protein can bind to the promoter of LGI3 and then activate its transcription. Importantly, LGI3 contributes to the proliferation, migration, and invasion of TFE3-RCC. Mechanistically, LGI3 interacts with gem nuclear organelle-associated protein 6 (GEMIN6) and inhibits its degradation via decreasing its ubiquitination. GEMIN6 upregulation promotes the mRNA maturation of Aurora B kinase (AURKB), thereby promoting the progression of TFE3-RCC. Importantly, drugs targeting GEMIN6 or AURKB significantly suppressed the growth of TFE3-RCC cells and organoids. In human TFE3-RCC tissues, LGI3 is highly expressed and positively correlated with GEMIN6 and AURKB. Overall, we revealed a novel mechanism underlying the progression of TFE3-RCC and provided potential new therapeutic targets.

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Fig. 1: LGI3 is highly expressed in TFE3-RCC.
Fig. 2: LGI3 is a direct target of TFE3.
Fig. 3: LGI3 mediating the function of TFE3 promotes the progression of TFE3-RCC.
Fig. 4: LGI3 enhances the stability of GEMIN6.
Fig. 5: LGI3 promotes the progression of TFE3-RCC via the GEMIN6/AURKB axis.
Fig. 6: Targeting GEMIN6 and AURKB inhibit the growth of TFE301-1 cells and TFE3-RCC organoids.
Fig. 7: GEMIN6 and AURKB are highly expressed and positively correlated with LGI3 in TFE3-RCC.

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Data availability

The TCGA data was downloaded from the Genomics Data Commons portal of the National Cancer Institute(https://portal.gdc.cancer.gov/). Data of the West China Hospital was downloaded from the GEO with the identifier GSE167573. Data of Dana-Farber Cancer Institute was downloaded from the GEO with the identifier GSE188885. The transcriptome sequencing data is available via NCBI (https://www.ncbi.nlm.nih.gov/sra/PRJNA1241189). The LC-MS data is available via ProteomeXchange with the identifier PXD061623.

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Acknowledgements

This work was supported by the PLA General Hospital-Third Medical Center Discipline Innovation and Development Special Fund Project (2024BJ-04), Capital’s Funds for Health Improvement and Research (No. 2024-1-5042), PLA General Hospital Youth Independent Innovation Science Fund Growth Project (22QNCZ029).

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Author notes

  1. These authors contributed equally: Junxiao Liu, Huayi Feng, Zhuang Xiong.

Authors and Affiliations

  1. Department of Urology, The Third Medical Center, Chinese PLA General Hospital, Beijing, China

    Junxiao Liu, Zhuang Xiong, Shouqing Cao, Tianwei Cai, Wenjie Wei, Wen Tao, Xu Zhang, Xin Ma & Xiubin Li

  2. Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Junxiao Liu

  3. Department of Urology, General Hospital of Central Theater Command, Wuhuan, China

    Huayi Feng

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Contributions

Xu Zhang, Xin Ma, and Xiubin Li conceived and designed the study. Junxiao Liu, Xin Ma, and Xiubin Li participated in the experiment design. Junxiao Liu, Huayi Feng and Zhuang Xiong performed the experiments. Junxiao Liu, Huayi Feng and Zhuang Xiong wrote the manuscript. Shouqing Cao, Tianwei Cai, Wenjie Wei, and Wen Tao contributed to analyze and supervise the results of this study. Xiubin Li and Xin Ma revised the manuscript. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Xu Zhang, Xin Ma or Xiubin Li.

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The authors declare no competing interests.

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Human tissues were collected at the Department of Urology of Chinese PLA General Hospital in accordance with the protocol approved by The Ethics Committee of the Chinese PLA General Hospital. Written informed consent was obtained from all participants before sample collection. All ethical regulations relevant to human research participants were followed.

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Liu, J., Feng, H., Xiong, Z. et al. LGI3 promotes the progression of TFE3-rearranged renal cell carcinoma through GEMIN6/AURKB axis. Oncogene 44, 3729–3740 (2025). https://doi.org/10.1038/s41388-025-03553-3

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