The long isoform of PRLR promotes tumor progression by regulating CDK6 through MAPK signal pathway in SHH medulloblastoma

Medulloblastoma (MB) is the most common malignant brain tumors in children. Sonic Hedgehog (SHH) subgroup of MB accounts for about 25% of all MBs. SMO inhibitors are used for target therapy. However, drug resistance and toxicity occurred. New therapeutic targets are urgently needed to be developed. Here, through RNA-sequencing and Nanostring Assay analysis of primary MBs, we screened out prolactin receptor (PRLR) as a gene with higher expression level in SHH-MB compared with other subgroups of the tumor. Long isoform of PRLR (PRLR-LF) played a pivotal role in promoting SHH-MB tumor invasion, enhancing the proliferation and colony formation ability. KEGG analysis showed that PRLR-LF expression has close relationship with p53 signal pathway in SHH-MB cells. High expression of CDK6 downstream of the p53 pathway was observed to have a high correlation with PRLR expression, indicating a poor prognosis of the tumor. In addition, PRLR was demonstrated to promote cell proliferation by regulating CDK6 through Ras-MAPK signal pathway in vitro . Synthesized recombinant Δ1-11-G129R-PRL, a competitive inhibitor of PRLR, interfered PRL-PRLR binding, could inhibit the regulation to CDK6, and could and inhibit the proliferative ability of SHH-MB tumor cells. In conclusion, we unveiled PRLR promoted SHH-MB tumor progression through signaling pathway besides the canonical SHH pathway. PRLR inhibitor shed light on a potential therapeutic value for SHH-MB patients.