Hsa-miR-221-3p promotes proliferation
and migration in HER2-positive breast cancer cells by targeting LASS2 and MBD2
Xiying Shao1,2,3*, Yabing Zheng1,2,3*, Yuan Huang1,2,3, Guangliang Li1,2,3, Weibin Zou1,2,3 and Lei Shi1,2,3
1Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, 2Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences and 3Department of Breast Medical Oncology, Zhejiang Cancer Hospital, Zhejiang, PR China.
*These authors contributed equally to this work
Corresponding Author: Yabing Zheng, Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences. No. 1, Banshan east Rd., Gongshu District, Hangzhou City, Zhejiang 310022, PR China. e-mail: zhengyb@zjcc.org.cn
Summary. Background. Human epidermal growth factor receptor (HER2)-positive breast cancers account for nearly 20% of all breast cancer cases and microRNAs (miRNAs) play crucial roles in disease progression. The study was aimed to explore the role of miR-221-3p in HER2-positive breast cancer.
Methods. Differentially expressed miRNAs were identified by high-throughput sequencing. Quantitative real-time PCR was used to evaluate mRNA levels of corresponding genes. CKK8 and transwell assays were performed to evaluate cell viability and migration. The translation binding was assessed by luciferase assay.
Results. Hsa-miR-221-3p was highly upregulated in HER2-positive breast cancer samples, particularly in patients with advanced or metastatic disease, as compared to healthy controls. miR-221-3p upregulation using mimics promoted cell proliferation and migration in HER2-positive cell lines, whereas miR-221-3p suppression had the opposite effect. Additionally, miR-221-3p mimics reduced the expression levels of LASS2 and MBD2 in HER2-positive breast cancer cells; conversely, miR-221-3p inhibition upregulated LASS2 and MBD2. miR-221-3p inhibited the translation of LASS2 and MBD2 by directly binding to their 3'-untranslated regions. Forced expression of LASS2 and MBD2 significantly attenuated the ability of miR-221-3p mimics to enhance cell growth and migration in HER2-positive but not in HER2-negative breast cancer cells. In HER-2-positive breast cancer patients, the levels of miR-221-3p were negatively correlated with the mRNA levels of LASS2 and MBD2.
Conclusions. Upregulation of hsa-miR-221-3 in HER2-positive breast cancer contributes to cancer cell proliferation and migration by directly targeting the tumor suppressors LASS2 and MBD2. Therefore, the hsa-miR-221-3 may serve as a promising and actionable therapeutic target in HER2-positive breast cancer. Histol Histopathol 37, 1099-1112 (2022)
Key words: HER2-positive breast cancer, Hsa-miR-221, LASS2, MBD2, Proliferation and migration
DOI: 10.14670/HH-18-483
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©The Author(s) 2022. Open Access. This article is licensed under a Creative Commons CC-BY International License. |
