Study on the role of MYCN in retinoblastoma by inhibiting p53 and activating wnt/βcatenin/Fra-1 signaling pathway by reducing DKK3

作者全名："Chen, Xinke; Ouyang, Lijuan; Ke, Ning; Pi, Lianhong; Zhou, Xiyuan"

作者地址："[Chen, Xinke; Ouyang, Lijuan; Ke, Ning; Pi, Lianhong] Chongqing Med Univ, Minist Educ, Childrens Hosp, Natl Clin Res Ctr Child Hlth & Disorders,Dept Opht, Chongqing, Peoples R China; [Zhou, Xiyuan] Chongqing Med Univ, Affiliated Hosp 2, Chongqing Eye Inst, Chongqing Key Lab Ophthalmol, Chongqing, Peoples R China"

通信作者："Zhou, XY (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, 76 Linjiang Rd, Chongqing 400010, Peoples R China."

来源：DRUG DEVELOPMENT RESEARCH

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001270802900001

JCR分区：Q1

影响因子：3.8

年份：2024

卷号：85

期号：5

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结束页：　

文献类型：Article

关键词：DKK3; malignant progression; MYCN; retinoblastoma; wnt/beta catenin/Fra-1

摘要："Retinoblastoma (RB) is a pediatric malignancy, typically diagnosed at birth or during early childhood. The pathogenesis of RB is marked by the amplification of the Basic Helix-Loop-Helix (BHLH) Transcription Factor MYCN, which serves as a transcriptional regulator capable of binding to Dickkopf 3 (DKK3). However, the precise role of DKK3 in the malignant progression of RB cells caused by MYCN remains elusive. In the present study, the expression of MYCN was either overexpressed or interfered in RB cells. Subsequently, the expression level of DKK3 was assessed through quantitative real-time polymerase chain reaction and western blot analysis. Cell proliferation was evaluated using the Cell Counting Kit-8 assay and 5-ethynyl-2 '-deoxyuridine staining, while cell cycle progression and apoptosis were analyzed by flow cytometry and western blot analysis, respectively. Additionally, the expression of proteins involved in the Wnt/beta-catenin/Fra-1/p53 signaling pathway was evaluated via western blot analysis. To gain further insights, Wnt agonists and the P53 inhibitor PFT-alpha were introduced into exploration. The current investigation revealed a negative correlation between the expression levels of MYCN and DKK3 in RB cells. Additionally, DKK3 overexpression inhibited cell proliferation, promoted cell apoptosis, and arrested cell cycle in RB cells with high expression of MYCN. Moreover, enhanced DKK3 expression inhibited proliferation, promoted cell cycle arrest and apoptosis of RB cells by modulating the wnt/beta catenin/Fra-1/p53 signaling pathway. Furthermore, in vivo experiments revealed that overexpression of DKK3 inhibits the growth of RB tumors. Collectively, our findings elucidate that MYCN stimulates the Wnt/beta-catenin/Fra-1 pathway by suppressing DKK3 expression, ultimately suppressing p53 activity and contributing to malignant progression of RB."

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