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The novel human gene family encoding neuronal leucine rich repeat ( NLRR ) proteins were identified as prognostic markers from our previous screening of primary neuroblastoma ( NB )  cDNA  libraries. Of the  NLRR  gene family members,  NLRR 1 and  NLRR 3 are associated with the regulation of cellular proliferation and differentiation, respectively. However, the functional regulation and clinical significance of  NLRR 2 in  NB  remain unclear. Here, we evaluated the differential expression of   NLRR 2,  where high expressions of   NLRR 2  were significantly associated with a poor prognosis of  NB  ( P  = 0.0009), in 78  NBs . Enforced expression of   NLRR 2  in  NB  cells enhanced cellular proliferation and induced resistance to retinoic acid ( RA )‐mediated cell growth inhibition. In contrast, knockdown of   NLRR 2  exhibited growth inhibition effects and enhanced  RA ‐induced cell differentiation in  NB  cells. After  RA  treatment,  NLRR 2 expression was increased and correlated with the upregulation of c‐Jun, a member of the activator protein‐1 ( AP ‐1) family in  NB  cells. Moreover, the expressions of  NLRR 2 and c‐Jun were suppressed by treatment with a  JNK  inhibitor, which ameliorated the promoter activity of the   NLRR 2  gene while knockdown of c‐Jun reduced   NLRR 2  expression. We then searched  AP ‐1 binding consensus in the   NLRR 2  promoter region and confirmed c‐Jun recruitment at a consensus. Conclusively,   NLRR 2  must be an inducible gene regulated by the  JNK  pathway to enhance cell survival and inhibit  NB  cell differentiation. Therefore,  NLRR 2 should have an important role in  NB  aggressiveness and be a potential therapeutic target for the treatment of  RA  resistant and aggressive  NB .

Unfavorable neuroblastoma prognostic factor NLRR 2 inhibits cell differentiation by transcriptional induction through JNK pathway