Perinucleolar Compartment (PNC) Prevalence as an Independent Prognostic Factor in Pediatric Ewing Sarcoma: A Multi-Institutional Study

Abstract

The perinucleolar compartment (PNC) is a small nuclear body that plays important role in tumorigenesis. PNC prevalence correlates with poor prognosis and cancer metastasis. Its expression in pediatric Ewing sarcoma (EWS) has not previously been documented. In this study, we analyzed 40 EWS tumor cases from Caucasian and Hispanic patients for PNC prevalence by immunohistochemical detection of polypyrimidine tract binding protein and correlated the prevalence with dysregulated microRNA profiles. EWS cases showed staining ranging from 0 to 100%, which were categorized as diffuse (≥77%, n = 9, high PNC) or not diffuse (<77%, n = 31) for low PNC. High PNC prevalence was significantly higher in Hispanic patients from the US (n = 6, p = 0.017) and in patients who relapsed with metastatic disease (n = 4; p = 0.011). High PNC was associated with significantly shorter disease-free survival and early recurrence compared to those with low PNC. Using NanoString digital profiling, high PNC tumors revealed upregulation of eight and downregulation of 18 microRNAs. Of these, miR-320d and miR-29c-3p had the most significant differential expression in tumors with high PNC. In conclusion, this is the first study that demonstrates the presence of PNC in EWS, reflecting its utility as a predictive biomarker associated with tumor metastasis, specific microRNA profile, Hispanic ethnic origin, and poor prognosis.

RAVER1 hinders lethal EMT and modulates miR/RISC activity by the control of alternative splicing

“…The original identification of RAVER1 revealed its association and co-localization with PTBPs in perinucleolar compartments ( Supplementary Figure S3A ) ( 17 ). Independent studies suggested elevated frequency of PNCs in progressed, metastatic malignancies ( 22 , 23 ). Accordingly, it was tempting to speculate that RAVER1’s role in tumor cell proliferation is associated with its potentially PTBP-dependent modulation of PNC homeostasis.…”

“…In s.c. LUAD (A549) xenograft mouse models, the loss of RAVER1 even reduced tumor growth, indicating that RAVER1 serves a rather pro-oncogenic role in lung and presumably other cancers. PTBPs and RAVER1 associate and co-localize in perinucleolar compartments (PNCs, ( 17 )), which were proposed to be enhanced in progressed malignancies ( 22 , 23 ). Thus, it was tempting to speculate that RAVER1 modulates tumor cell fate in a PNC-dependent manner.…”