MiRNAs are a kind of endogenous non-coding single-stranded small RNAs that are key regulators of gene expression and are involved in almost all tumor-related processes (9, 18). Because the miRNAs effect the post transcriptional expression of different genes, they are currently the focus of cancer studies (19). By different upregulation or downregulation and affecting the expression of genes involved in cancer cell signaling, miRNAs regulate cancer cells proliferation, invasion and apoptosis (20). Therefore, miRNAs are divided into two kinds: oncogenic miRNAs and suppressive miRNAs (20). For example, Cai et al. (21) found that miR-519a is a suppressive miRNA in gastric cancer and the downregulation of miR-519a predicts poor prognosis. While the study of Jian et al. (22) indicated that miR-193-3p functions as an oncogenic miRNA in gastric cancer progression. All these studies showed that the functional miRNAs could be used as novel therapeutic targets for cancer targeted therapy.
Increasing evidence have documented that miRNAs play vital roles in NSCLC progression by regulating NSCLC cell biological function. For example, overexpression of miR-24 could significantly enhanced NSCLC cell migration and invasion by inhibiting ZNF367 (23). MiR-451a inhibits the migration and invasion of NSCLC cells by accelerating AFT2 (5). MiR-135a inhibited proliferation, migration and invasion in NSCLC cells through targeting IGF-1 gene (24). And miR-185 inhibited the proliferation, migration and invasion of NSCLC cells by targeting KLF7 (25). Our study found that the expression level of miR-1231 was downregulated in NSCLC tissues and cell lines, which led us to further explore the relationship between miR-1231 and NSCLC.
In this study, we found that the expression level of miR-1231 was significantly lower in NSCLC controls compared with normal tissues. Similarly, the miR-1231 expression in NSCLC cell lines was significantly lower than those normal cells. It also indicated that the expression level of miR-1231 in NSCLC was downregulated. Additionally, most of the patients with low miR-1231 expression showed lymph node metastasis and presented with an advanced TNM stage. Thus, it is assumed that miR-1231 may be associated with the development of NSCLC. Moreover, the miR-1231 expression was also altered in other types of human cancers. MiR-1231 plays a tumor-suppressive role through regulating the EGFR/PI3K/AKT AXIS in glioma and was an independent prognosis factor for glioma (26, 27). MiR-1231 expression was downregulated in prostate cancer and may suppress prostate cancer cell proliferation, migration and invasion by targeting EGFR (28). Exosomal miR-1231 inhibit the expression of pancreatic cancer (29, 30). The upregulated miR-1231 was found in colorectal cancer, which may be related to the onset of colorectal cancer (31). Therefore, we predicts that miR-1231 may act as a suppressive miRNA in NSCLC.
By analyzing the 5-year survival information, we also explored the prognosis value of miR-1231 in NSCLC patients. The relationship of miR-1231 with survival outcomes has been analyzed in some cancers, such as pancreatic cancer, glioma and prostate cancer (26–29). However, as far as we know, the clinical significance of miR-1231 in NSCLC has rarely been reported. In our study, we plotted the Kaplan-Meier survival curves of NSCLC patients based on the recorded 5-year survival information. The curves showed that patients with low miR-1231 expression had shorter survival time than those patients with high miR-1231 expression. Additionally, the Cox regression data indicated that the expression of miR-1231 was an independent prognosis factor. Overall, the decreased miR-1231 may predict the poor prognosis of NSCLC.
To further explore the biological function of miR-1231 in NSCLC progression, we used the miR-1231 mimic and miR-1231 inhibitor to perform cell experiments. After cell transfection, the miR-1231 expression was promoted by the miR-1231 mimic and was reduced by the miR-1231 inhibitor. The upregulation of miR-1231 could inhibit, whereas the downregulation of miR-1231 could enhance the NSCLC proliferation, migration and invasion, indicating that miR-1231 acted as a tumor suppressor in NSCLC. Previous studies have reported that miR-1231 plays a tumor-suppressive role through regulating the EGFR/PI3K/AKT signaling in glioma (26, 27).However ,whether this signaling pathway also mediated the regulatory effect of miR-1231 on NSCLC progression remains unclear, and further investigations are needed to further uncover the molecular mechanisms underlying the role of miR-1231 in NSCLC.