Open AccessUnfavorable neuroblastoma prognostic factor NLRR 2 inhibits cell differentiation by transcriptional induction through JNK pathway
Author(s) -
Sheikh Afzal,
Takatori Atsushi,
Hossain Md Shamim,
Hasan Md Kamrul,
Tagawa Masatoshi,
Nagase Hiroki,
Nakagawara Akira
Publication year - 2016
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13003
Subject(s) - gene knockdown , downregulation and upregulation , cell growth , biology , activator (genetics) , cellular differentiation , retinoic acid , neuroblastoma , gene expression , microbiology and biotechnology , regulation of gene expression , transcription factor , gene , cancer research , c jun , cell culture , genetics
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 .