Open AccessHypoxia‐inhibited miR‐338‐3p suppresses breast cancer progression by directly targeting ZEB2
Author(s) -
He Juanjuan,
Wang Jing,
Li Songchao,
Li Teng,
Chen Kunlun,
Zhang Shaojin
Publication year - 2020
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14589
Subject(s) - gene knockdown , microrna , gene silencing , cancer research , pi3k/akt/mtor pathway , chromatin immunoprecipitation , downregulation and upregulation , biology , cell growth , epithelial–mesenchymal transition , protein kinase b , hypoxia (environmental) , cell migration , hif1a , signal transduction , microbiology and biotechnology , cell culture , chemistry , angiogenesis , gene expression , genetics , gene , promoter , organic chemistry , oxygen
Hypoxia plays an essential role in the development of various cancers. The biological function and underlying mechanism of microRNA‐338‐3p (miR‐338‐3p) under hypoxia remain unclarified in breast cancer (BC). Herein, we performed bioinformatics, gain and loss of function of miR‐338‐3p, a luciferase reporter assay, and chromatin immunoprecipitation (ChIP) in vitro and in a tumor xenograft model. We also explored the potential signaling pathways of miR‐338‐3p in BC. We detected the expression levels and prognostic significance of miR‐338‐3p in BC by qRT‐PCR and in situ hybridization. MiR‐338‐3p was lowly expressed in BC tissues and cell lines, and BC patients with underexpression of miR‐338‐3p tend to have a dismal overall survival. Functional experiments showed that miR‐338‐3p overexpression inhibited BC cell proliferation, invasion, migration, and epithelial‐mesenchymal transition (EMT) process, whereas miR‐338‐3p silencing abolished these biological behaviors. Zinc finger E‐box‐binding homeobox 2 (ZEB2) was validated as a direct target of miR‐338‐3p. ZEB2 overexpression promoted while ZEB2 knockdown abolished the promoted effects of miR‐338‐3p knockdown on cell biological behaviors through the NF‐ĸB and PI3K/Akt signal pathways. HIF1A can transcriptionally downregulate miR‐338‐3p under hypoxia. In total, miR‐338‐3p counteracts hypoxia‐induced BC cells growth, migration, invasion, and EMT via the ZEB2 and NF‐ĸB/PI3K signal pathways, implicating miR‐338‐3p may be a promising target to treat patients with BC.