Breast cancer is a malignancy that threatens women's health for a long time. Although there are many advanced therapeutic strategies till now, the clinical outcomes of BCa are still not ideal (18). Recent study showed that some molecules that involved in tumor progression could serve as biomarkers to improve the diagnosis and prognosis of patients with cancer, which had promoted the therapeutic strategies (19, 20). Among these functional molecules, lncRNAs and miRNAs are considered a group of important component, owing to their significant clinical significance and biological function (21, 22). For example, the increased expression of serum lncRNA UFC1 has been demonstrated to serve as a diagnostic and prognostic biomarker in patients with pancreatic cancer (23). Another study by Shi et al. provides evidence for the elevated serum miR-629 as a biomarker in the diagnosis and prognosis of pancreatic cancer (24). In BCa, Li et al. have found that the expression of lncRNA NEAT1 was upregulated, but the miR-211 expression was downregulated in BCa tissues and cell lines, which may serve as potential therapeutic targets by regulating BCa progression (25). These previous studies implied that the dysregulation non-coding RNAs, such as lncRNAs and miRNAs, in human malignancies have potencies to improve disease diagnosis, prognosis and treatment.
In the present study, we focused on the clinical and biological role of the lncRNA KCNQ1OT1/miR-935 axis in BCa progression. The expression and biological function of KCNQ1OT1 has been investigated in a study by Feng et al., which reported that KCNQ1OT1 expression was elevated in BCa tissues and cells, and the overexpression of KCNQ1OT1 could enhance BCa cell proliferation through the miR-145/CCNE2 pathway (11). In addition, the KCNQ1OT1 has been reported to facilitate the chemoresistance of colon cancer cells (26) and regulate tumor cell proliferation and apoptosis of tongue cancer cells (27). Similarly, our analysis results also detected the upregulated KCNQ1OT1 expression in BCa cells and serum samples, and found the promoting effect of KCNQ1OT1 on BCa cell proliferation, migration and invasion. Regarding the molecular mechanisms underlying the roles of lncRNAs in human cancers, numbers miRNAs have been found to be regulated by lncRNAs and thereby mediate the biological function of lncRNAs (28). By the prediction with bioinformatics analysis, a binding site of miR-935 was found at the sequences of KCNQ1OT1. miR-935 has been investigated in renal cell carcinoma (12), colorectal carcinoma (13) and non-small cell lung cancer (14), but little is known about its role in BCa.
According to the data of this study, the expression of miR-935 was decreased in BCa cell lines and serum samples, which was negatively correlated with KCNQ1OT1. The luciferase activity results provided evidence for the direct interaction between KCNQ1OT1 and miR-935. Furthermore, the overexpression of miR-935 in BCa cells led to decreased cell proliferation, migration and invasion, and the enhanced BCa cell biological processes induced by KCNQ1OT1 were reversed by the overexpression of miR-935, indicating that miR-935 might be a tumor suppressor and mediate the regulatory effect of KCNQ1OT1 on BCa cell proliferation, migration and invasion. A study Yu et al. has found that the elevated lncRNA CASC15 could accelerate BCa cell proliferation and invasion by sponging miR-153-3p (29). Another study by Lu et al. also reported the regulatory effect of lncRNA LINC00511 on BCa tumorigenesis through inhibiting miR-185-3p (30). The aforementioned studies indicate the important role and therapeutic potential of lncRNAs and miRNAs in the pathogenesis of BCa. Collectively, the KCNQ1OT1/miR-935 axis analyzed in this study provided a novel insight into the pathologic mechanisms of BCa, and the treatment of BCa might be improved by targeting this novel axis.
miRNAs have been widely investigated as a group of biomarkers in the diagnosis and prognosis in a variety of human cancers (31). The clinical significance of miR-935 has been reported in some malignancies. For instance, the aberrant expression of miR-935 in colorectal carcinoma tissues has been documented to serve a biomarker to predict the prognosis of cancer patients (13). Similarly, the decreased expression of miR-935 in non-small cell lung cancer also indicated a poor prognosis in cancer patients (14). In this study, the serum miR-935 was found to be downregulated in BCa patients. The further ROC analysis results showed that the serum miR-935 expression levels had relatively high diagnostic accuracy for the differentiation between BCa patients and healthy individuals. Additionally, a ROC curve based on serum KCNQ1OT1 also indicated that KCNQ1OT1 might also had diagnostic potency in BCa patients. Considering the direct interaction between KCNQ1OT1 and miR-935, the combined diagnostic accuracy of the two molecules was evaluated, which revealed that the synthetic use of KCNQ1OT1 and miR-935 had an improved diagnostic accuracy compared with any single indicator. Taken together, our data might provide novel diagnostic biomarkers for patients with BCa.
Although our study provided evidence for the biological function of the KCNQ1OT1/miR-935 axis in BCa progression, the downstream molecules or signaling that involving in the function remain unclear, which may be the limitation of this study. Wang et al. has demonstrated that miR-935 served as a tumor suppressive miRNA in non-small cell lung cancer by targeting E2F7 and through the AKT signaling pathway (14). In BCa progression, whether the previously reported target genes and signaling also involved in the mechanisms underlying the role of KCNQ1OT1/miR-935 axis warrant further investigations.
In conclusion, the findings in this study showed that miR-935, as a downstream target of KCNQ1OT1, is downregulated in BCa cell lines and serum samples. KCNQ1OT1 may accelerate BCa cell proliferation, migration and invasion by sponging miR-935, indicating the therapeutic potency of the KCNQ1OT1/miR-935 axis in BCa treatment. In addition, the serum reduced miR-935 and elevated KCNQ1OT1 levels may be candidate biomarker for BCa diagnosis. All the data of this study may provide novel insight into the pathogenesis of BCa and novel method to improve disease treatment.