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Mechanistic investigation of TRIB3-mediated growth, metastasis and ferroptosis in renal cell carcinoma
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DOI：10.1007/s13577-026-01424-x.png)
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Abstract
En 中文
Renal cell carcinoma (RCC) is a common and highly lethal malignancy. Tribbles pseudokinase 3 (TRIB3) has been reported to exert oncogenic roles in the pathogenesis of multiple tumors; nevertheless, the detailed mechanisms through which TRIB3 drives RCC development remain largely undefined. In this study, qPCR and Western blot were used to quantify the levels of TRIB3, STIP1 homology and U-box containing protein 1 (STUB1), and activating transcription factor 2 (ATF2). Cell proliferation, invasion, stemness, and angiogenic capacity were assessed by MTT assay, flow cytometry, Transwell invasion assay, sphere-formation assay, and tube-formation assay, respectively. The interaction between TRIB3 and STUB1 was examined by co-immunoprecipitation (Co-IP), and the relationship between TRIB3 and ATF2 was verified using dual-luciferase reporter assays. A xenograft model was employed to evaluate the tumorigenic potential of RCC cells upon STUB1 overexpression. The study found that TRIB3 expression was markedly elevated in RCC. Knockdown of TRIB3 profoundly inhibited cell proliferation, invasion, migration, and stem-like properties, while simultaneously inducing apoptosis and promoting ferroptosis. TRIB3 physically interacted with STUB1 and was poly-ubiquitinated and degraded by this E3 ligase; consequently, STUB1 overexpression suppressed RCC progression both in vitro and in vivo by targeting TRIB3. Conversely, ATF2 transcriptionally activated TRIB3 expression, and enforced TRIB3 expression partially rescued the inhibitory effects of ATF2 knockdown in RCC cells. Collectively, these findings demonstrate that TRIB3 drives RCC progression; STUB1 curbs RCC by degrading TRIB3, whereas ATF2 promotes RCC via transcriptional activation of TRIB3. Thus, modulating TRIB3 expression may offer a novel therapeutic strategy for RCC.
Keywords:
Renal cell carcinoma
Tribbles pseudokinase 3
STIP1 homology and u-box containing protein 1
Activating transcription factor 2
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