MicroRNA-33b Suppresses Epithelial–Mesenchymal Transition Repressing the MYC–EZH2 Pathway in HER2+ Breast Carcinoma

Abstract

Downregulation of miR-33b has been documented in many types of cancers and is being involved in proliferation, migration, and epithelial-mesenchymal transition (EMT). Furthermore, the enhancer of zeste homolog 2-gene (EZH2) is a master regulator of controlling the stem cell differentiation and the cell proliferation processes. We aim to evaluate the implication of miR-33b in the EMT pathway in HER2+ breast cancer (BC) and to analyze the role of EZH2 in this process as well as the interaction between them. miR-33b is downregulated in HER2+ BC cells vs healthy controls, where EZH2 has an opposite expression in vitro and in patients' samples. The upregulation of miR-33b suppressed proliferation, induced apoptosis, reduced invasion, migration and regulated EMT by an increase of E-cadherin and a decrease of ß-catenin and vimentin. The silencing of EZH2 mimicked the impact of miR-33b overexpression. Furthermore, the inhibition of miR-33b induces cell proliferation, invasion, migration, EMT, and EZH2 expression in non-tumorigenic cells. Importantly, the Kaplan-Meier analysis showed a significant association between high miR-33b expression and better overall survival. These results suggest miR-33b as a suppressive miRNA that could inhibit tumor metastasis and invasion in HER2+ BC partly by impeding EMT through the repression of the MYC-EZH2 loop.

Epigenetic network of EZH2/SFRP1/Wnt in the epithelial-mesenchymal transition of laryngeal carcinoma cells

“…Our experiment showed that E-cadherin and Vimentin were increased while N-cadherin diminished in TU177 and Tu686 cells as a response to EZH2 downregulation, indicating that EZH2 downregulation inhibited the EMT of LGC. In consistence with our results, silencing EZH2 also repels the EMT in esophageal, lung, ovarian, and breast cancers [10,[25][26][27]. Taken together, we demonstrated that EZH2 downregulation inhibits the EMT of LGC cells.…”

The miR-4732-5p/XPR1 axis suppresses the invasion, metastasis, and epithelial–mesenchymal transition of lung adenocarcinoma via the PI3K/Akt/GSK3β/Snail pathway

“…Aberrant expressions of various miRNAs have been identified in different tumors, including colorectal cancer, gastric cancer, breast cancer, and NSCLC. [10][11][12][13] It has been well documented that miRNA can affect the invasion and metastasis of cancer through EMT. 14 In previous studies, we screened the miRNAs with low expression in LUAD through the TCGA database and verified in tissues and cells.…”

Flotillin-2 promotes cell proliferation via activating the c-Myc/BCAT1 axis by suppressing miR-33b-5p in nasopharyngeal carcinoma

“…We predicted the candidate miRNAs targeting c-Myc via ENCORI (The Encyclopedia of RNA Interactomes) database. miR-33b-5p, a tumor suppressor gene, which directly inhibits c-Myc in several cancers, was selected for validation [ 27 – 30 ]. Indeed, silenced FLOT2 upregulated the miR-33b-5p level in 5-8F cells, while FLOT2 overexpression downregulated miR-33b-5p expression in 6-10B cells ( Figure 5A ).…”