Screening of miRNAs associated with lymph node metastasis in Her-2-positive breast cancer and their relationship with prognosis

Her-2 阳性乳腺癌淋巴结转移相关的miRNA 的 筛选及其与患者预后关系的研究

Abstract

The aim of this study was to identify some biomarkers for predicting lymph node metastasis and prognosis of human epidermal growth factor receptor 2 (Her-2)-positive breast cancer (BC). We analyzed correlations between microRNAs (miRNAs) and the prognosis of patients with BC based on data collected from The Cancer Genome Atlas (TCGA) database. The expression levels of miR-455, miR-143, and miR-99a were measured in clinical samples of Her-2-positive BC patients with different degrees of lymph node metastasis. We investigated the impacts of overexpressed miR-455 on the proliferation and invasiveness of MDA-MB-453 cells and measured its effects on the expression of long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of miR-455 was significantly and positively correlated to the prognosis and overall survival (OS) of the BC (P=0.028), according to TCGA information. The expression level of miR-455 was positively correlated with OS and relapse-free survival (RFS) of patients with Her-2- positive BC, and was negatively correlated with the number of metastatic lymph nodes (P 0.05). Transwell assay suggested that MDA-MB-453 cells became much less invasive (P 0.01) after being transfected with miR-455 mimics. During the qRT-PCR, the expression level of MALAT1 declined significantly after transfection (P 0.01). Overexpressed miR-455 significantly inhibited the proliferation and migration of MDA-MB-453 cells and the expression of MALAT1. We conclude that miR-455 may be a useful potential biomarker for forecasting lymph node metastasis and the prognosis of Her-2-positive BC patients. miR-455 may play an important role in lymph node metastasis of BC by interacting with MALAT1.

概要

目的:寻找一种或多种能预测人类表皮生长因子受体2(Her-2)阳性乳腺癌患者是否发生淋巴结转移及其预后的分子标志物。

创新点: 本研究发现,miR-455 与Her-2 阳性乳腺癌转移 相关,可能是一个预测Her-2 阳性乳腺癌患者淋 巴结转移和预后的分子标志物。miR-455 可以通 过与长链非编码RNA 人肺腺癌转移相关转录本 1(MALAT1)的相互作用,在乳腺癌的淋巴结转 移过程中发挥重要功能。 方法:通过下载肿瘤基因组图谱(TCGA)数据库中与 乳腺癌相关的微小RNA(miRNA)测序数据, 筛选与乳腺癌淋巴结转移相关的miRNA,进一步 分析这些miRNA 与乳腺癌患者预后的相关性。 同时,用实时荧光定量聚合酶链反应(qRT-PCR) 方法检测这些miRNA 在不同程度淋巴结转移的 Her-2 阳性乳腺癌患者组织中的表达水平,及其 与预后的相关性。通过细胞学实验研究过表达 miR-455 对Her-2 阳性乳腺癌细胞系MDAMB- 453 增殖和侵袭能力的影响,并用qRT-PCR 检测过表达miR-455 对MALAT1 表达的影响。

结论 miR-455 可能是Her-2 阳性乳腺癌患者淋巴结转 移和预后的潜在预测因子

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En-qi QIAO participated in writing and revising this paper. Xi-ping ZHANG conceived the idea and wrote this paper. Hong-jian YANG participated in revising the paper. All authors have read and approved the final manuscript and, therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.

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Correspondence to Xi-ping Zhang.

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En-qi QIAO, Hong-jian YANG, and Xi-ping ZHANG declare that they have no conflict of interest. The approval of the Ethics Committee of Zhejiang Cancer Hospital (Hangzhou, China) was secured for our reported research, and all authors abided by the relevant rules of the Ethics Committee when this study proceeded. The Ethics Committee of Zhejiang Cancer Hospital approved publication of this paper. The research involving human subjects, human material, and human data was performed in accordance with the Declaration of Helsinki 2008 (5) and was approved by an appropriate ethics committee of Zhejiang Cancer Hospital, Hangzhou, China.

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Project supported by the Foundation for Key Platform Technological Project of Zhejiang Medical Science and Hygiene (No. 2016ZDB003), China

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Qiao, E., Yang, H. & Zhang, X. Screening of miRNAs associated with lymph node metastasis in Her-2-positive breast cancer and their relationship with prognosis. J. Zhejiang Univ. Sci. B 21, 495–508 (2020). https://doi.org/10.1631/jzus.B1900584

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关键词

  • 乳腺癌
  • 人表皮生长因子受体2(Her-2)
  • 淋巴结转移
  • 微小RNA(miRNA)
  • 人肺腺癌转移 相关转录本1(MALAT1)