DNA 甲基转移酶 3B 通过下调 microRNA-432-5p 表达进而上调 CCND2 促进结直肠癌的发生。

Reduced expression of microRNA-432-5p by DNA methyltransferase 3B leads to development of colorectal cancer through upregulation of CCND2.

机构信息

Department of Colorectal & Anal Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, PR China.

Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130021, Jilin, PR China.

出版信息

Exp Cell Res. 2022 Jan 1;410(1):112936. doi: 10.1016/j.yexcr.2021.112936. Epub 2021 Nov 19.

DOI:10.1016/j.yexcr.2021.112936

PMID:34801563

Abstract

BACKGROUND

The tumor suppressive function of microRNA-432-5p (miR-432-5p) has been reported in several human malignances. This study aimed to probe the expression profile and role of miR-432-5p in colorectal cancer (CRC) and the molecular mechanism.

METHODS

Differentially expressed miRNAs between CRC and healthy samples were screened using a miRNA expression dataset GSE136020. The related molecules were identified by integrated bioinformatic analyses. A murine model of primary CRC was established and xenograft tumors were induced in mice. Altered expression of DNMT3B, miR-432-5p and cyclin D2 (CCND2) were introduced in CRC cells to determine their roles in the development of CRC.

RESULTS

miR-432-5p was downregulated in CRC according to the GSE136020 dataset. CCND2 mRNA was confirmed as a target of miR-432-5p. miR-432-5p was downregulated, whereas CCND2 was abundantly expressed in CRC tissues and cells. DNA methyltransferase 3B (DNMT3B) induced DNA methylation at the CpG island of miR-432-5p to inhibit its expression. miR-432-5p mimic significantly suppressed tumorigenesis of primary CRC in mice. Downregulation of DNMT3B weakened viability, invasiveness, blocked the cell cycle progression of CRC cells in vitro, and inhibited xenograft tumor growth and metastasis in nude mice. However, additional downregulation of miR-432-5p or upregulation of CCND2 restored the malignant behaviors of CRC cells.

CONCLUSION

This study showed that DNMT3B induced DNA methylation and downregulation of miR-432-5p to promote development of CRC by upregulating CCND2.

摘要

背景

miR-432-5p（miR-432-5p）在几种人类恶性肿瘤中具有肿瘤抑制功能。本研究旨在探讨 miR-432-5p 在结直肠癌（CRC）中的表达谱和作用及其分子机制。

方法

使用 miRNA 表达数据集 GSE136020 筛选 CRC 与健康样本之间差异表达的 miRNA。通过整合生物信息学分析鉴定相关分子。建立原发性 CRC 小鼠模型，并在小鼠中诱导异种移植肿瘤。在 CRC 细胞中引入 DNMT3B、miR-432-5p 和 cyclin D2（CCND2）的改变表达，以确定它们在 CRC 发展中的作用。

结果

根据 GSE136020 数据集，miR-432-5p 在 CRC 中下调。CCND2 mRNA 被确认为 miR-432-5p 的靶标。miR-432-5p 下调，而 CCND2 在 CRC 组织和细胞中大量表达。DNA 甲基转移酶 3B（DNMT3B）诱导 miR-432-5p 的 CpG 岛甲基化，抑制其表达。miR-432-5p 模拟物可显著抑制小鼠原发性 CRC 的肿瘤发生。DNMT3B 的下调减弱了 CRC 细胞的活力和侵袭性，阻止了细胞周期的进展，并抑制了裸鼠异种移植肿瘤的生长和转移。然而，miR-432-5p 的进一步下调或 CCND2 的上调恢复了 CRC 细胞的恶性行为。