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

Junxiao Liu1,2, Huayi Feng3, Zhuang Xiong1

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

Oncogene
|August 23, 2025
PubMed

Insights

Leucine-rich repeat LGI family member 3 (LGI3) drives aggressive TFE3-rearranged renal cell carcinoma (TFE3-RCC) by stabilizing GEMIN6, which promotes Aurora B kinase. Targeting LGI3, GEMIN6, or AURKB may offer new therapies for TFE3-RCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • TFE3-rearranged renal cell carcinoma (TFE3-RCC) is aggressive with poor prognosis.
  • The molecular drivers of TFE3-RCC tumorigenesis are not fully understood.

Purpose of the Study:

  • To identify downstream targets of the TFE3 fusion protein in TFE3-RCC.
  • To elucidate the mechanism of LGI3 in TFE3-RCC progression.
  • To evaluate therapeutic strategies targeting the LGI3 pathway.

Main Methods:

  • Luciferase reporter assays to confirm TFE3 binding to the LGI3 promoter.
  • Cell proliferation, migration, and invasion assays.
  • Western blotting and ubiquitination assays to study protein interactions.
  • Organoid and cell line drug sensitivity assays.

Main Results:

  • LGI3 is a direct transcriptional target of the TFE3 fusion protein.
  • LGI3 promotes TFE3-RCC cell proliferation, migration, and invasion.
  • LGI3 stabilizes GEMIN6 by inhibiting its ubiquitination, leading to increased Aurora B kinase (AURKB) mRNA maturation.
  • LGI3, GEMIN6, and AURKB are upregulated in human TFE3-RCC tissues.
  • Drugs targeting GEMIN6 or AURKB inhibited TFE3-RCC growth in vitro and in organoids.

Conclusions:

  • LGI3 is a key oncogenic driver in TFE3-RCC, acting via the LGI3-GEMIN6-AURKB axis.
  • This pathway represents a novel therapeutic vulnerability in TFE3-RCC.
  • Targeting GEMIN6 or AURKB shows promise for TFE3-RCC treatment.

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