Dysregulation of miR-638 in Breast Cancer Patients and Bioinformatics Investigation of Its Target Genes in Apoptosis, Angiogenesis and Autophagy Pathways

Abstract

Background: Breast cancer, as the most frequent cancer diagnosed in women worldwide, is affected by different regulatory mechanisms and cellular processes such as microRNAs (miRNAs) and autophagy, which influence tumor cell progression. MiRNAs play a crucial role in cancer progression. Aberrant miRNA expression has been described in various human cancers. Growing evidence proposes that miRNAs have a considerable role in tumor development and may constitute robust biomarkers for cancer diagnosis and prognosis. Objectives: The aim of this study was to evaluate miRNA-638 (miR-638) expression level in breast cancer patients and its bioinformatics analysis. Methods: In this case-control study, miR-638 expression was examined in fresh breast tissues of 47 patients with breast cancer using real time polymerase chain reaction (PCR). Then the role of miR-638 in various signaling pathways was studied using Target Scan, the MicroRNA-Target Interactions (miRTarBase) database, miRWalk2.0 and the database for annotation, visualization and integrated discovery (DAVID). Results: The miR-638 expression level showed a significant decrease in breast cancer patients. Also, this miRNA might be involved in apoptosis, angiogenesis, and autophagy. Conclusions: According to the results, miR-638 can be used as a potential prognostic biomarker for cancer growth, and its low expression is thought to increase cancer progression by disrupting cell death and autophagy, which are considered as important pathways in breast cancer.

Regulation of autophagy by microRNAs in human breast cancer

“…This caused reduced autophagy but increased tumorigenesis and cancer aggressiveness [ 76 ] miR-224-5p Clinical sampling (metastatic breast cancer = 30, non-metastatic breast cancer = 35, normal control = 25); in vitro secondary cell lines (MDA-MB-231 and MCF-7) Introduction of miR-224-5p suppressed autophagy by reducing Smad4 expression (p < 0.05). High miR-224-5p level was found in metastatic breast cancer patients than normal control or patients with non-metastatic lesions [ 101 ] miR-486-5p In vitro secondary cell lines (MCF-7 and MDA-MB-231) Upregulation of miR-486-5p would downregulate PTEN expression (p < 0.05) and autophagy but enhanced AKT signaling pathway [ 56 ] Suppress autophagy but promote tumorigenesis miR-638 Case–control (breast cancer or normal control, each had 47 samples); bioinformatics target prediction Downregulation of miR-638 might be associated with good disease prognosis and slow disease prognosis by increasing autophagy activity [ 79 ] Suppress both autophagy and tumorigenesis Let-7a Un-reported In vitro secondary cell line (MDA-MB-231) Overexpression of Let-7a significantly (p < 0.05) increased apoptosis, reduced autophagy, and cell proliferation in vitro [ 102 ] miR-20a miR-20b Clinical sampling (breast cancer tissues and normal tissues = 19); in vitro secondary cell lines (MCF-7, MCF-10A and MDA-MB-231) Overexpression of miR-20a and miR-20b suppressed (p < 0.05) autophagy and tumorigenesis [ 72 ] miR-26b Clinical sampling (breast cancer tissues and normal tissues = 3); in vitro secondary cell line (MCF-7) Increased expression of miR-26b downregulated DRAM1 protein expression in breast cancer cell and this reduced autophagy and sensitized cancer cells to irradiation ...…”

“…Four miRNAs which were shown to enhance both autophagy and breast cancer progression include miR-23a [ 96 ], miR-23b-3p [ 35 ], miR-126 [ 86 ] and miR-638 [ 81 ]. Nine miRNAs were found to suppress autophagy but enhance breast cancer development and these miRNAs include miR-20a [ 74 ], miR-21 [ 75 ], miR-25 [ 68 ], miR-96-5p [ 83 ], miR-137 [ 99 ], miR-221 [ 76 ], miR-224-5p [ 101 ], miR-486-5p [ 56 ] and miR-638 [ 79 ]. One miRNA was shown to promote autophagy and suppress breast cancer tumerigenicity and this miRNA is miR-125b-5p [ 66 ].…”

“…Out of all these miRNAs, miR-20a was found to suppress both autophagy and tumorigenesis in a study [ 72 ] but in another study [ 74 ], miR-20a was said to promote cancer progression despite it suppressed cellular autophagy. Another miRNA which was shown to have different overall effects on autophagy regulation in breast cancer is miR-638, in which it was demonstrated to accelerate both autophagy and tumorigenesis in a study [ 81 ] but in another case–control study [ 79 ], miR-638 was shown to inhibit autophagy and promote breast cancer progression Upregulation; Downregulation…”

“…On the other hand, Beclin-1 expression was found to be negatively correlated to the expression of miR-20a [ 74 ], miR-21 [ 75 ] and miR-221 [ 76 ]. MiR-20a could also suppress ATG16L1 expression [ 74 ] while miR-567 and miR-638 could negatively regulate ATG5 expression [ 78 , 79 ]. Overexpression of miR-101 was linked to ATG4 downregulation [ 80 ] whereas upregulation of miR-1275 was related to ATG7 suppression [ 69 ], and both ATG4 and ATG7 are important in the LC3-II production [ 16 ].…”

“…A number of miRNAs have been reported to target various ATGs (Fig. 3 ) and these include miR-20a (ATG16L1) [ 74 ], miR-567 and miR-638 (ATG5) [ 78 , 79 ], miR-101 (ATG4) [ 80 ] and miR-1275 (ATG7) [ 69 ]. ATG16L1 has been proven to be able to bind to WIPI2 protein directly and this helps recruiting the ATG12/ATG15/ATG16L1 protein complex to the pre-autophagosome (PAS) [ 46 ].…”