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RXRA is a direct target gene of miR‐506‐3p that regulates oncogene MYCN expression and cell differentiation in neuroblastoma
Author(s) -
Shelton Spencer Dewayne,
Zhao Zhenze,
Du Liqin
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.804.16
Subject(s) - neuroblastoma , cancer research , biology , retinoic acid , oncogene , retinoid x receptor , microrna , cancer , gene , transcription factor , genetics , cell culture , cell cycle , nuclear receptor
Neuroblastoma is an aggressive childhood cancer that arises from neural precursor cells that fail to differentiate. In 20% of high‐risk neuroblastoma cases oncogene MYCN is overexpressed. We previously identified that miR‐506‐3p is a strong repressor of MYCN expression as well as an inducer of neuroblastoma differentiation. However, the 3'UTR of MYCN mRNA lacks the target site of miR‐506‐3p, suggesting that miR‐506‐3p regulates MYCN expression through an indirect pathway. Combining gene expression array data and informatics analyses, we identified 11 candidate genes that are direct targets of miR‐506‐3p and potentially regulate MYCN expression. The candidate genes were silenced and screened for decreased MYCN expression and increased neuroblastoma neurite outgrowth – the morphological differentiation marker of neuroblastoma cells. Interestingly, retinoid X receptor alpha ( RXRA ) was the only gene to exhibit significant downregulation of MYCN expression and induced the most dramatic neurite outgrowth. We then examined the RXRA protein expression during retinoic acid treatment and demonstrated that RXRA protein level is significantly downregulated in retinoic acid treated cells. Upon investigation of neuroblastoma patient databases, we found that high risk and MYCN amplified patients that exhibited higher RXRA mRNA levels had lower overall and relapse free survival statistics. Altogether, these results suggest that RXRA functions as an oncogene through promoting MYCN expression and repressing cellular differentiation in neuroblastoma. Further investigation is ongoing to elucidate the molecular pathways that mediate the oncogenic function of RXRA in neuroblastoma cells. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .