RNA binding proteins in the pathogenesis of pediatric cancer

RNA binding proteins (RBPs) are regulators of RNA metabolism and influence protein expression in various physiologic and pathologic conditions through regulation of RNA splicing, stability and translation. Several studies have demonstrated that RBPs play a role in cancer development through dysregulation of RNA-RBP interaction and disruption of RPB expression. One such protein, the polypyrimidine tract binding protein (PTB) is a member of the heterogeneous nuclear ribonucleoproteins (hnRNP) family and functions as suppressor of splicing and an activator of protein translation. Its accumulation in the perinucleolar compartment (PNC) promotes cancer progression and metastasis. Its expression in various adult cancers has been identified to correlate with tumor metastatic potential and patients’ prognosis.  PTB expression has not yet been studied in pediatric malignancies.

Retrospective clinical information was collected on 65 patients <22 years of age with osteosarcoma (OS), Ewing’s sarcoma (ES), or rhabdomyosarcoma (RMS) over a 10- year period. Formalin-fixed paraffin-embedded slides of primary or metastatic tumor samples were immunostained with SH54, a monoclonal antibody that specifically recognizes PTB that is highly concentrated in the PNC. Scoring for PTB staining was determined by estimating the percentage of cells showing positive staining.  Statistical analysis was performed to demonstrate any association between PTB prevalence and demographic characteristics of patients and tumor types. 

PTB expression differs by tumor type with osteosarcoma (mean 58.3%, n=13) having higher prevalence than ES (mean 40.9% n=26) and RMS (37.7%, n=36) and the difference was statistically significant (p=0.0569 and p=0.0297 respectively). Bone tumors (ES and OS) had higher expression rate at metastatic biopsies compared to primary tumor biopsies (99% CI: 0.2865187 – 52.60305, p= 0.0031). PTB expression in rhabdomyosarcoma was higher in embryonal than alveolar RMS. In ES, PTB overexpression was associated with significantly shorter disease-free survival and early recurrence compared to those with tumors with low expression. PTB expression is not affected by patient’s age or gender.

Studying PTB highlights its role in the pathogenesis of pediatric cancer. Targeting PTB by inhibitory therapy results in important potential clinical applications in pediatric cancer. Further studies are needed to determine its prevalence in other pediatric tumors and its relationship to prognosis.