Upregulation of GSTP1 mediated by chimeric TFE3 promotes TFE3-tRCC progression by targeting JNK signaling pathway.

BACKGROUND

TFE3-translocation renal cell carcinoma (TFE3-tRCC), a distinct subtype of kidney cancer characterized by Xp11.2 translocations, involving TFE3 fusion with various partner genes, lacks effective treatments and prognostic biomarkers for advanced stages. This study aimed to unravel the pathogenic mechanisms and uncover novel therapeutic targets.

METHODS

The transcriptional characterization of TFE3-tRCC was conducted by RNA sequencing on 14 untreated primary TFE3-tRCC patients. The relative mRNA and protein levels were detected using qRT-PCR and Western blot, respectively. The location of ASPL-TFE3 fusion protein was analyzed by immunofluorescence. MTT and colony formation assays were used to detect cell proliferation. Annexin V/PI staining was used to evaluate cell apoptosis. Transwell assays were used to evaluate in vitro cell migration and invasion.

RESULTS

In TFE3-tRCC patients, GSTP1 expression was upregulated. ASPL-TFE3 cell models revealed that the ASPL-TFE3 fusion protein translocates to the nucleus, contributing to tumorigenesis. Notably, GSTP1 was transcriptionally activated by chimeric TFE3. Treatment with GSTP1-targeting siRNA or the GSTP1 inhibitor Ezatiostat effectively inhibited tumor growth and induced apoptosis in TFE3-tRCC cells. Furthermore, GSTP1 was found to drive TFE3-tRCC progression via modulation of the JNK signaling pathway.

CONCLUSION

Upregulation of GSTP1 mediated by chimeric TFE3 promotes TFE3-tRCC progression by targeting JNK signaling pathway, which underscore the potential of GSTP1 as a promising therapeutic target for TFE3-tRCC.