AURKA promotes malignant properties of neuroblastoma and is downregulated by the PP2A pathway

The role of Aurora kinase A (AURKA) in malignant transformation of sympathoadrenergic progenitors (SAPs), the cells of origin of neuroblastoma (NB), and in progression and maintenance of NB is incompletely understood. MYCN is amplified in a subset of high-risk NB cases with poor prognosis. CDKN2A, which encodes the tumor suppressors p16INK4A and p14ARF, is deleted or silenced in a subset of NB. PPP2R4 (also known as PTPA) is a key activator of the phosphatase PP2A known to suppress NB. We show that AURKA and MYCN expression decreases postnatally in murine adrenal glands, suggesting that their expression may contribute to the maintenance of SAPs. In mouse embryonic fibroblasts (MEFs), used in place of difficult-to-isolate SAPs, AURKA contributed to transformation only when MYCN was overexpressed and INK4A/ARF was depleted. In transgenic mice expressing human AURKA (hAURKA) in adrenal glands, hAURKA mRNA was present but protein was undetectable, likely due to AURKAs short half-life, possibly limiting its role in initial transformation of SAPs. However, AURKA cooperated with MYCN to promote progression of established human SH-EP NB cells lacking INK4A/ARF. In addition, AURKA expression increased during NB progression in TH-MYCN mice and correlated with poor prognosis in human NB, supporting a role for AURKA in disease progression and maintenance. CDKN2A and PPP2R4 mRNA levels also rose during NB progression in TH-MYCN mice, possibly reflecting inadequate tumor-suppressive responses. Bayesian analysis of TH-MYCN expression data supported a role for PPP2R4 in inhibiting NB maintenance. Knockout of PPP2R4 in KELLY NB cells, along with reduced mePPP2CA, the catalytic subunit of PP2A, increased AURKA protein levels, indicating that PP2A regulates AURKA abundance. Together, these findings indicate that AURKA promotes malignant properties of NB and is decreased by the PP2A pathway in NB cells