Lower expression of miR-218 in human breast cancer is associated with lymph node metastases, higher grades, and poorer prognosis

Abstract

Breast cancer is considered as the most prevalent malignancy in women worldwide. Despite emergence of several prognosticators for better management of patients, there are still limitations for their clinical application due to the complexity of breast tumors, and therefore, new biomarkers for better prognosis of clinical outcomes would be of the great essence. MicroRNAs are highly conserved small non-coding regulatory RNAs involved in post-transcriptional regulating of gene expression during different cellular mechanisms. Accumulating studies suggest that miR-218 plays a multifunctional role in various cancer types and different stages. Here, to address prognostic significance of miR-218 in breast cancer, we investigate the expression profile of miR-218 and B-cell-specific Moloney murine leukemia virus integration site 1 ( BMI1) gene, as one of the putative targets of miR-218, in 33 paired breast tumors and their adjacent normal tissues with respect to the clinicopathological features of patients using quantitative real-time polymerase chain reaction. The correlation of both miR-218 and BMI1 gene expression with overall survival of breast cancer patients was also examined recruiting OncoLNC data portal. Finally, to better understand biological function of miR-218 in breast cancer, we performed in silico Gene Ontology and signaling pathway enrichment analysis on miR-218 targetome. According to our data, significant elevation of the expression of miR-218 and downregulation of BMI1 were observed in clinical breast cancer specimens compared with normal tissues ( p < 0.0001). The lower expression of miR-218 was associated with lymph node metastases, higher grades, and poorer prognosis (logrank p = 0.00988), whereas no significant difference in overall survival was observed between patients with higher and lower expression of BMI1 (logrank p = 0.254). These findings suggest that miR-218 expression profiling might be clinically applicable as a prognostic biomarker in breast cancer. In addition, our in silico enrichment analyses revealed that the association of miR-218 expression with breast cancer prognosis might be through its involvement in endocytosis and gap junction biological pathways.

Prognostic impact of micro-rna expression in breast cancer: systematic review

“…In contrast, hypoexpressed microRNAs may act as tumor suppressors, as long as they suppress the expression of oncogenes 8 . Tumor suppressor miRNAs included miRNA-339-5p 19 , miRNA-206 18 , miRNA-204 20 , miRNA-127 16 , miRNA-200b 21,25 , miRNA-15a 26 , miRNA-29b 12 , miRNA-124 13 , miRNA-129-5p 17 , miRNA-199-5p 4 and miRNA-218 6 , and the hypoexpression of most of these was associated with the presence of lymph node metastasis.…”

“…Flowchart of the study selection process. 13 , miRNA-127 16 , miRNA-129-5p 17 , miRNA-199b-5p 4 , microRNA-206 18 , miRNA-218 6 and miRNA-339-5p 19 associated with the presence of lymph node metastasis ( Table 2).…”

“…The hyperexpression of miRNA-21 10 , miRNA-301a 11 and miRNA-711 5 was associated with poorer prognosis (lower overall survival) in six studies, while miRNA-127 16 and miRNA-339-5p 19 hyperexpression were associated with better prognosis (greater overall survival) in two studies. On the other hand, the hypoexpression of miRNA-15a 26 , miRNA-29b 12 , miRNA-124 13 , miRNA-129-5p 17 , miRNA-199b-5p 4 , miRNA-200b 21,25 , miRNA-204 20 , miRNA-20 18 and miRNA-218 6 was associated to the worst prognosis in nine studies, and miRNA-210 24 hypoexpression was associated with better prognosis in a single study (Table 2).…”

“…The miRNAs can be studied in tumor tissues and biological fluids, such as serum or plasma. Differences in the expression of certain miRNAs in breast carcinoma tissues compared to normal tissues have been described in several studies and suggest that miRNAs may be promising biomarkers, useful for early detection and prognosis of breast cancer [4][5][6]14 .…”

“…It is, therefore, necessary to identify new biomarkers for it, in order to better predict the clinical outcomes, as well as to establish the most appropriate treatment for each patient. Recent researches have explored the possibility of using microRNAs (miRNAs) as diagnostic and/or prognostic biomarkers, since these molecules are implicated in the progression of breast cancer [4][5][6] .…”