The PTTG1-TRIM59 Protein Complex Promotes Proliferation and Metastasis of Pediatric Neuroblastoma by Stabilizing STAT3 Phosphorylation Status

Abstract

Background: Neuroblastoma, originating from neural crest, presents a challenging pediatric malignancy. The pituitary tumor-transforming gene 1 (PTTG1) is a recently discovered oncogene implicated in various cancers. This study aimed to elucidate the impact of the PTTG1-tripartite motif 59 (TRIM59) protein complex on the proliferation and metastasis of pediatric neuroblastoma by modulating the phosphorylation status of signal transducer and activator of transcription 3 (STAT3). Methods: Utilizing SK-N-AS and SK-N-BE cell lines, we conducted in vitro experiments with gene expression regulation via cell transfection. Migration and invasion capabilities were assessed through matrix gel invasion, wound healing assays, cell activity detection via Cell Counting Kit-8 (CCK-8), and Kaplan-Meier survival analysis. PTTG1 expression in cancer tissue was determined via immunohistochemical techniques. Western blot and co-immunoprecipitation (co-IP) assays were employed to identify PTTG1/STAT3/phosphorylated (p)-STAT3/Bcl-2-associated X (Bax)/B-cell lymphoma-2 (Bcl-2)/TRIM59 expression and interaction. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was used to detect the expression levels of PTTG1/Bax/Bcl-2/E-Cadherin/Vimentin/Twist1/Twist2/Snai1/Slug/Zinc finger E-box binding homeobox 1 (ZEB1)/ZEB2. Results: PTTG1 knockdown inhibited neuroblastoma cell proliferation, migration, and invasion while promoting apoptosis. It also suppressed STAT3 phosphorylation and epithelial-mesenchymal transition (EMT). Patients exhibiting low PTTG1 expression (p < 0.05) had a significantly better prognosis. qRT-PCR analysis revealed increased expression (p < 0.05) of proapoptotic factors (Bax/E-cadherin) and STAT3-related transcription factors (Bax/Bcl-2/E-cadherin/Vimentin) upon PPTG1 knockdown. Notably, our findings demonstrate the role of the PTTG1-TRIM59 complex in facilitating neuroblastoma progression through the STAT3 pathway. Conclusion: The PTTG1-TRIM59 complex and STAT3 represent potential therapeutic targets for pediatric neuroblastoma. Our findings underscore the pivotal role of the PTTG1-TRIM59 complex in stabilizing STAT3 phosphorylation and promoting neuroblastoma growth and metastasis.