Abstract
BackgroundmiR-133a-3p has been recently discovered to be down-regulated in various human malignancies, including breast cancer, and reduced miR-133a-3p levels have been significantly associated with breast cancer cell growth and invasion. However, the regulatory mechanisms leading to abnormal expression of miR-133a-3p in breast cancer remain obscure.MethodsqRT-PCR was applied to detect the expression of miR-133a-3p in breast cancer tissues and cell lines. Bisulfite sequencing was used to detect the degree of methylation of the miR-133a-3p promoter. The effects of miR-133a-3p on breast cancer in vitro were examined by cell proliferation assay, transwell assay, flow cytometry, and western blotting. Bioinformatic analysis, dual-luciferase assay and RIP assay were employed to identify the interaction between miR-133a-3p and MAML1. A xenograft model was used to show the metastasis of breast cancer cells.ResultsWe confirmed that miR-133a-3p was silenced by DNA hypermethylation in breast cancer cell lines and tissues, which predicted poor prognosis in breast cancer patients, and reducing miR-133a-3p expression led to a significant increase in the migration, invasion, proliferation, and stemness of breast cancer cells in vitro. Mastermind-like transcriptional coactivator 1 (MAML1) was confirmed to be a target of miR-133a-3p involved in regulating breast cancer metastasis both in vitro and in vivo. Moreover, a series of investigations indicated that MAML1 initiated a positive feedback loop, which could up-regulate DNA methyltransferase 3A (DNMT3A) to promote hypermethylation of the miR-133a-3p promoter.ConclusionTaken together, our findings revealed a novel miR-133a-3p/MAML1/DNMT3A positive feedback loop in breast cancer cells, which may become a potential therapeutic target for breast cancer.
Highlights
MiR-133a-3p has been recently discovered to be down-regulated in various human malignancies, including breast cancer, and reduced miR-133a-3p levels have been significantly associated with breast cancer cell growth and invasion
Results miR-133a-3p is down-regulated in breast cancer tissues and cells By searching the starBase public database, we first determined whether miR-133a-3p had a specific expression profile in breast cancer
We found that miR-133a-3p levels were down-regulated in most (15/17) of the common cancer tissues compared to their normal counterparts, and remarkably lower in 1085 breast cancer tissues compared to 104 normal breast tissues from the TCGA database (Fig. 1a)
Summary
MiR-133a-3p has been recently discovered to be down-regulated in various human malignancies, including breast cancer, and reduced miR-133a-3p levels have been significantly associated with breast cancer cell growth and invasion. The regulatory mechanisms leading to abnormal expression of miR-133a-3p in breast cancer remain obscure. Down-regulation of miR-133a3p has been found to be associated with disease progression and poor prognosis in breast cancer patients, and the underlying mechanisms have been investigated. MiR-133a-3p suppresses tumor cell invasion and migration by targeting Fascin (FSCN1) [6] and regulates the cell cycle and proliferation of breast cancer cells by targeting epidermal growth factor receptor (EGFR) [7]. The regulatory mechanisms leading to abnormal expression of miR133a-3p in breast cancer still need to be studied
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