2021 대한암예방학회 오색심포지엄 초록 예시

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Anti-cancer Stem Cell Effect of β-carotene through Regulating Retinoic Acid Receptor in Neuroblastoma

Yoo-Sun Kim1, Eunju Kim1, Yoon Jung Park1, Yuri Kim1

1Department of Nutritional Science and Food Management, Ewha Womans University, Seoul 03760, Republic of Korea

Backgrounds: Neuroblastoma (NB) is childhood malignancy that retains characteristics of ancer stem cells (CSCs). Targeting the CSCs is one of the therapeutic strategies proposed to achieve complete remission of NB. β-carotene (BC), an active precursor of retinoids, is a well-known antioxidant reported to possess anti-CSCs effects. Here, we investigated the involvement of retinoic acid receptors (RARs) in the anti-CSCs effects of BC.

Methods: Two human NB cell lines, SK-N-BE(2)C and SH-SY5Y were used. To examine the effects of  BC on the expression level of delta-like 1 homologue (DLK1) and RARs, real time PCR analysis and western blot assay were performed. To determine the functional role of RARβ in DLK1 regulation, the putative binding site for RARβ in the DLK1 promoter was identified using the ALLGEN PROMO database. The RARβ binding to RARE within the DLK1 promoter was examined by ChIP assay. Colony and sphere forming assays were performed in RARβ silenced NB cells to evaluate the role of BC-mediated RARβ in regulating the self-renewing capacity of NB cells.

Results: BC down-regulates DLK1 gene expression, a bona fide marker of CSCs, by up-regulating RARβ expression among three RAR isoforms in both NB cell lines. ChIP assay indicated that RARβ bound directly to a RARE sequence (TGACCCTC) in the DLK1 promoter, and the binding was dramatically enhanced in responses to BC treatment. The knock-down of RARβ up-regulated DLK1 gene expression and increased the self-renewal capacity of NB cells, which was suppressed by BC.

Conclusions: This study provided evidence that the therapeutic anti-CSC effects of BC depend on RARβ and its ability to interact with and down-regulate the stem cell marker, DLK1.

Key words : β-carotene, neuroblastoma, cancer stem cells, retinoic acid receptors, retinoic acid response elements

2021 대한암예방학회 오색심포지엄 초록

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