HMMR has oncoprotein-like properties in neuroblastoma cells and high HMMR expression has independent prognostic...

Neuroblastoma (NB) is a devastating childhood cancer where most tumours have no clear oncogenic driver. We aimed to define whether HMMR, an oncogene-like protein in several cancers, harbors similar potential in neuroblastoma cells. HMMR is a hyaluronic acid (HA) receptor and a mitotic microtubule regulator. We show that high HMMR expression does not correlate well with MYCN driver expression and moreover statistically HMMR is an independent prognostic indicator of poor survival in NB patients. In cultured KELLY neuroblastoma cells, removal of the HMMR protein suppresses proliferation, motility and clonogenic capacity, while xenografts of HMMR-deficient cells imparted longer animal survival compared to wild type cells. Loss of motility in culture was compensated by addition of exogenous HA, suggesting that HMMR signaling is at least partly under HA control. Through an unbiased phosphoproteomic analysis, we also found that signaling downstream of MAPK1/2 was disrupted after loss of HMMR. In addition, RPS6 and p70S6 kinase were hypophosphorylated, while the DNA damage response (DDR) proteins such as CHK2 and TP53BP1 were significantly hyperphosphorylated. We thus provide, for the first time, evidence that HMMR does have oncoprotein-like properties in neuroblastoma cells and that HMMR expression has potential as a prognostic marker. Moreover, initial biochemical analyses highlight a potential influence for HMMR in MTOR and DDR pathway regulation.