Exosomal hsa-piR1089 promotes proliferation and migration in neuroblastoma via targeting KEAP1

Neuroblastoma (NB) is a sympathetic nervous system tumor and one of the most common pediatric, extra-cranial, solid tumors, especially in early childhood. Its expression is heterogeneous and shows a unique clinical and prognostic feature. Due to its insidious onset, most diagnoses are accompanied by metastasis, making patient prognoses extremely poor. Novel biomarkers are urgently needed for easy diagnosis, metastasis detection, and investigation of potential mechanisms regulating NB tumor progression. Recent research highlights that circulating tumor markers could be used to diagnose and monitor prognosis in various tumors. Among them, exosomal genetic material has attracted much attention because of its tumor-secreted specificity and unique mechanism of action. In this study, we used next-generation sequencing to study PIWI-interacting RNAs (piRNAs) in exosomes derived from NB patient plasma. We found higher human piRNA 1089 (hsa-piR-1089) levels in exosomes from NB patients than from normal controls. Our receiver operating characteristic (ROC) curve analyses showed that hsa-piR-1089 had high diagnostic sensitivity and specificity. We also found that high hsa-piR-1089 expression in NB tumor tissues was associated with a high-risk Children's Oncology Group classification and metastasis. Our in vitro experiments showed that exosomal hsa-piR-1089 promoted NB cell proliferation and migration by inhibiting Kelch-like ECH-associated protein 1 (KEAP1) expression. Moreover, low KEAP1 expression was associated with NB progression in clinical samples. In conclusion, our data indicate that blood-borne exosomal hsa-piR-1089 is a diagnostic marker for NB and assessing metastasis. Our study provides a quick, simple, and noninvasive diagnostic method for NB and contributes to developing new treatment strategies.