MicroRNAs have been proved as hopeful biomarkers in the diagnosis and prognosis of BC [32]. Irregular expression of miRNAs impacts the processes involved in the development of BC such as invasion, metastasis, promoting tissue, stimulating antiapoptotic activity, drug resistance, and metabolism reprogramming [18, 33, 34]. These critical molecules have been found as key players in cancer metabolism by regulating genes related to metabolism pathways[35]. According to bioinformatics databases, miRNAs such as mir-513c and miR-3163 are involved in glutamine metabolism, which have been examined in the present work. Our outcomes demonstrate that mir-513c and mir-3163 have been downregulated considerably in BC tissues compared to margin tissues.
To the best of our knowledge, the downregulation and tumor suppressor role of miR-513c in multiple cancers has been proved. In R2N1d and MDA-MB-231 breast cancer cell lines treatment with HDACi , among the most considerably expressed miRNAs, mir-513c also emerged as the most regularly upregulated and act as a tumor suppressor, in induction cell death process [23]. Also, in hepatocellular carcinoma and glioblastoma (GBM), mir-513c is strictly downregulated and overexpression this miRNA prevented the proliferation of these cancer cells through targeting MET and Wnt/β-catenin signaling pathway, respectively [19] [21]. Additionally, in neuroblastoma, mir-513c is markedly downregulated. Moreover, mir-513c as a tumor suppressor plays an important role in regulating glutamine metabolism by targeting GLS [22].
Since the role of miR-513c-5p has not been fully understood, bioinformatics analysis was done to shed the light on molecular pathways and biological procedures that are potentially impacted by dysregulation of miR-513c-5p. In-silico studies proved that target genes of miR-513c are involved in pathways related to cancer progression. In the present study, miR-513c was relatively downregulated in BC tissues compared with margin tissues (p-value= 0.02062, Fold change= -2.3801)
. Based on our research, several studies have been carried out on mir-513c, but this is the first study that was done on clinical samples of BC. Therefore, it seems mir-513c may act as a tumor suppressor and offers as a considerable marker in diagnostic and prognostic aims of BC patients.
In several studies, the activity and expression of mir-3163 in multiple cancers such as NSCLC and Retinoblastoma (RB) have been evaluated. In NSCLC, mir-3163 as a moderator contributes to Meg3 to suppress and regulate the translation of skp2. However, mir-3163 expression does not differ in NSCLC compared with normal cells, which suppresses the skp2 translation and reduction of its level in corporation with Meg3 to decrease cell proliferation in NSCLC [26]. Also, in Retinoblastoma (RB), upregulation of mir-3163 via targeting ABCG2, reduced the multidrug resistance and promotion of apoptosis in RCSC [25].
Because the activity of miR-3163 has not been completely understood, bioinformatics analyses were performed to determine a significant relationship between cancer and miR-3163. This analysis provides an insight into molecular pathways and biological processes that are potentially regulated by target genes of miR-3163. Based on this analysis, among important biological processes, negative regulation of cellular macromolecule biosynthetic process (GO: 2000113) is associated to metabolism pathways[36]. Also, including significant cellular pathways enriched by miR-3163, which are related to cancer cells progression, such as MAPK signaling pathway, Hedgehog signaling pathway, and Wnt signaling pathway are the most important. MAPK and Hedgehog signaling pathways are critical key regulators in cellular functions such as cell differentiation, proliferation, differentiation, survival, and apoptosis. The higher activation of MAPK in subtypes of BC predicts invasive phenotypes and poor prognosis [37-39]. Furthermore, these signaling pathways involve in the regulation of glutamine metabolism pathway [40] [41, 42]. Also, Wnt signaling pathway as a master regulator, plays a significant role in the progression and development of BC by metabolism reprogramming [43] [44]. So, this information may provide a valuable clue about cancer metabolism and our preliminary theory.
In the present study, our data contrary to previous studies have proved that the expression of mi-3163 was relatively downregulated in BC tissues compared with margin tissues (p-value=0.02034, Fold change= -2.3792). Recent reports have shown that miR-3163 plays diverse roles in various cancers; nonetheless, further studies are needed to identify and validate the precise role of this microRNA. Based on our results and bioinformatics analyses, it seems that miR-3163 can play the master role in development of BC biology.
Overall, based on our analysis, no significant association was found between miR-513c and miR-3163 expression and variables such as age, cancer family history, and abortion.