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TSPAN15 enhances EMT-mediated metastasis of HCC by promoting autophagy through BTRC-mediated PDCD4 degradation.

Zicheng Shao,Q-Y Hao,Jie Chen,Yuhua Lu

Published 2025 in Molecular Immunology

ABSTRACT

BACKGROUND Cumulative evidence shows that Tetraspanin 15 (TSPAN15) shows a high degree of consistency in a variety of tumor characteristics, which has attracted extensive attention from researchers. We used TSPAN15 as a starting point to explore the role and mechanism of TSPAN15 in in hepatocellular carcinoma (HCC). METHODS Using database analysis, recombinant plasmid transfection technology, transwell, autophagic flux analysis and western blotting, the effects of TSPAN15 on autophagy, invasion, epithelial-mesenchymal transition (EMT) of HCC cells, and tumor growth and metastasis were elucidated after silencing TSPAN15 in HCC cells. The effect of TSPAN15 on tumor growth was detected by using xenograft model of nude mice. RESULTS Based on the online database and immunohistochemistry analysis, it was found that the mRNA and protein expression of TSPAN15 in HCC tissues was significantly higher than that in normal liver tissues or adjacent non-cancerous tissues. High expression of TSPAN15 was an independent risk factor for poor prognosis in TCGA-LIHC patients. TSPAN15 silencing inhibited HCC autophagy and autophagy-induced migration, invasion and EMT as well as tumor growth and metastasis. Mechanistically, TSPAN15 contributed to programmed cell death 4 (PDCD4) proteasomal degradation through physical interaction with beta-transducin repeat containing (BTRC), thus activing autophagy. Rescue experiments revealed that PDCD4 effectively inhibited TSPAN15-induced autophagy, migration, invasion and EMT. CONCLUSION Abnormally expressed TSPAN15 promotes the degradation of tumor suppressor gene PDCD4 through ubiquitination, thereby promoting autophagy and autophagy-mediated EMT and metastasis of HCC cells, demonstrating the importance of TSPAN15 in the molecular etiology of HCC and its potential therapeutic value.

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