Abstract
MicroRNA-874 (miR-874) is downregulated in several human cancers and has been suggested to be a tumor suppressor gene. However, the molecular mechanism of miR-874 downregulation in breast cancer has not been well elucidated. Here we aimed to study the aberrant hyper-methylation of CpG sites with the utility of miR-874 downreregulation in breast cancer and evaluate the clinical function of miR-874 as a prognostic marker. The miR-874 expressions in cells and tissues of two breast cancer lines were measured by real-time PCR. The DNA methylation status of the miR-874 promoter region in 19 pairs of breast cancer and adjacent normal samples was analyzed with Sequenom EpiTYPER MassArray. To evaluate whether miR-874 is a potential prognostic marker in breast cancer, we also explored the clinical long-time follow-up records from The Cancer Genome Atlas (TCGA). We found miR-874 expression was downregulated in 47 pairs of breast cancer tissues. Moreover, univariate and multivariate analysis revealed miR-874 expression may be a prognostic biomarker of overall survival in breast cancer patients. Preconditioning with 5-Aza-CdR in two cell lines elevated miR-874 expressions. The data from Sequenom EpiTYPER MassArray showed that DNA methylation of the promoter region of miR-874 was upregulated and accompanied by decreased miR-874 expression, which was further confirmed by TCGA. After comprehensive considerations, we think miR-874, which might be served as a prognostic biomarker, is mediated by DNA methylation.
Highlights
Breast cancer is one of the most commonly diagnosed cancers and a major cause of cancer-related death in women worldwide [1]
The miR-874 expressions are downregulated in breast cancer tissues compared with paranormal tissues from an external breast cancer cohort in The Cancer Genome Atlas (TCGA) (Figure 1B), indicating that miR-874 is significantly down-regulated in breast cancer (P < 0.01)
We find miR-874 expression is associated with pathological differentiation, tumor/ node/metastasis (TNM) staging and lymph node metastasis in breast cancer tissues
Summary
Breast cancer is one of the most commonly diagnosed cancers and a major cause of cancer-related death in women worldwide [1]. The existing screening techniques and treatment methods (including neoadjuvant chemotherapy, surgical methods, cytotoxic chemotherapy, radiotherapy, and targeting agents against hormone receptors and HER-2) have still low prognostic values for breast cancer [2, 3]. It is important to identify more reliable prognostic markers that are effective in prevention and treatment of breast cancer. MicroRNAs (miRNAs) are short highly-conserved small non-coding RNA molecules of 19 to 25 nucleotides that regulate post-transcriptional gene expressions. MiRNAs play important roles in gene expression regulation and control diverse physiological and pathological processes. MiRNAs are involved in regulating various bioprocesses, including apoptosis, proliferation, cell differentiation, metabolism, signal transduction and carcinogenesis [7, 8] MiRNAs play important roles in gene expression regulation and control diverse physiological and pathological processes. miRNAs are involved in regulating various bioprocesses, including apoptosis, proliferation, cell differentiation, metabolism, signal transduction and carcinogenesis [7, 8]
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