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RNA 结合蛋白 IGF2BP2 的减少下调 NT5DC2,后者通过调节 p53 信号通路抑制弥漫性大 B 细胞淋巴瘤细胞的增殖,并诱导细胞周期停滞和细胞凋亡。

Decreased RNA‑binding protein IGF2BP2 downregulates NT5DC2, which suppresses cell proliferation, and induces cell cycle arrest and apoptosis in diffuse large B‑cell lymphoma cells by regulating the p53 signaling pathway.

机构信息

School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang 154007, P.R. China.

School of Clinical Medicine, Jiamusi University, Jiamusi, Heilongjiang 154007, P.R. China.

出版信息

Mol Med Rep. 2022 Sep;26(3). doi: 10.3892/mmr.2022.12802. Epub 2022 Jul 27.

Abstract

Diffuse large B‑cell lymphoma (DLBCL) remains difficult to treat clinically due to its highly aggressive characteristics. Insulin‑like growth factor 2 mRNA‑binding protein 2 (IGF2BP2) and 5'‑nucleotidase domain‑containing 2 (NT5DC2) have been suggested as potential regulators in numerous types of cancer. The present study aimed to determine whether downregulation of IGF2BP2 and NT5DC2 suppresses cell proliferation, and induces cell cycle arrest and apoptosis in DLBCL cells by regulating the p53 signaling pathway. The expression levels of IGF2BP2 and NT5DC2 in DLBCL cells were determined by reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analysis. Transfection of cells with IGF2BP2 overexpressing plasmids and NT5DC2 interference plasmids was performed, and the efficacy of transfection was confirmed by RT‑qPCR and western blot analysis. The viability, proliferation, cell cycle progression and apoptosis of DLBCL cells were analyzed by Cell Counting Kit‑8 assay, 5‑bromo‑2‑deoxyuridine staining and flow cytometry. RNA pull‑down and immunoprecipitation assays were used to verify the binding of IGF2BP2 and NT5DC2. The expression levels of apoptosis, cell cycle and p53 pathway‑associated proteins were determined by western blotting. The results revealed that NT5DC2 expression was increased in DLBCL cell lines and was the highest in OCI‑Ly7 cells. IGF2BP2 expression was also increased in OCI‑Ly7 cells and IGF2BP2 bound to NT5DC2. Knockdown of NT5DC2 suppressed cell viability and proliferation, induced cell cycle arrest and promoted apoptosis in DLBCL cells, which was reversed by upregulation of IGF2BP2. In addition, knockdown of NT5DC2 increased the expression of p53 and p21, but suppressed the expression of proliferating cell nuclear antigen, CDK4 and cyclin D1; these effects were reversed by upregulation of IGF2BP2. In conclusion, knockdown of NT5DC2 suppressed cell viability and proliferation, induced cell cycle arrest and promoted apoptosis in DLBCL cells by regulating the p53 signaling pathway and these effects were reversed by upregulation of IGF2BP2.

摘要

弥漫性大 B 细胞淋巴瘤(DLBCL)由于其高度侵袭性的特征,临床上仍难以治疗。胰岛素样生长因子 2 mRNA 结合蛋白 2(IGF2BP2)和 5'-核苷酸酶结构域包含蛋白 2(NT5DC2)已被认为是多种类型癌症的潜在调节剂。本研究旨在通过调节 p53 信号通路,确定下调 IGF2BP2 和 NT5DC2 是否抑制 DLBCL 细胞的增殖,并诱导细胞周期停滞和细胞凋亡。通过逆转录定量 PCR(RT-qPCR)和 Western blot 分析检测 DLBCL 细胞中 IGF2BP2 和 NT5DC2 的表达水平。用 IGF2BP2 过表达质粒和 NT5DC2 干扰质粒转染细胞,并通过 RT-qPCR 和 Western blot 分析确认转染效率。通过细胞计数试剂盒-8 检测、5-溴-2-脱氧尿苷染色和流式细胞术分析 DLBCL 细胞的活力、增殖、细胞周期进程和凋亡。RNA 下拉和免疫沉淀实验用于验证 IGF2BP2 和 NT5DC2 的结合。通过 Western blot 测定凋亡、细胞周期和 p53 通路相关蛋白的表达水平。结果显示,NT5DC2 在 DLBCL 细胞系中表达增加,在 OCI-Ly7 细胞中表达最高。IGF2BP2 在 OCI-Ly7 细胞中也表达增加,IGF2BP2 与 NT5DC2 结合。NT5DC2 敲低抑制 DLBCL 细胞活力和增殖,诱导细胞周期停滞并促进细胞凋亡,上调 IGF2BP2 可逆转上述作用。此外,NT5DC2 敲低增加了 p53 和 p21 的表达,但抑制了增殖细胞核抗原、CDK4 和 cyclin D1 的表达;上调 IGF2BP2 可逆转这些作用。综上所述,下调 NT5DC2 通过调节 p53 信号通路抑制 DLBCL 细胞的活力和增殖,诱导细胞周期停滞并促进细胞凋亡,上调 IGF2BP2 可逆转上述作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/801b/9366151/80c89b76b1f7/mmr-26-03-12802-g00.jpg

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