Worldwide, BC is the most prevalent malignant illness and the main cause of cancer-related mortality among women. It affects ~12% of women worldwide, including 25% (1.7 million) of patients newly diagnosed with cancer and is responsible for 15% (>0.5 million) of all cancer-related deaths (53,54). Accumulating evidence has suggested that the etiology of BC is predominantly hormonal, with an increased lifetime exposure to endogenous and exogenous hormones related to the development of the disease (55,56). The most severe form of BC occurs when the tumor spreads from the breast tissue to other parts of the body (metastasis), which markedly increases the tumor burden and often leads to a terminal diagnosis (57,58). Recently, early diagnosis and novel treatments for BC have achieved notable advancements, and the OS of patients has also improved. However, tumor recurrence and metastasis remain the main cause of mortality for a large number of patients with BC, and represent the main obstacles for the reduction of the mortality rates of patients with terminal BC (59,60). In order to increase the OS and disease-free survival (DFS) rates of patients with BC, it may be useful to investigate the biomarkers of BC cell metastasis.

Feng et al (61) and Yang et al (62) explored the expression of miR-124 in 40 pairs of BC and neighboring non-tumor tissues using reverse transcription-quantitative PCR (RT-qPCR). Compared to the neighboring normal tissues, miR-124 expression in BC tissues was markedly reduced. Furthermore, the expression of miR-124 in the BC cell lines, MCF-7 and MDA-MB-231, was likewise markedly reduced. In addition to resulting in mortality, miR-124 suppression notably decreased BC cell proliferation, migration and invasion in vivo and in vitro (26). Moreover, miR-124 overexpression has been shown to contribute to an increase in the number of cells present in G₀/G₁ phase from 34.8 to 41.2% (26,62). Of note, Ji et al (63) revealed that transfection with miR-124 mimics significantly increased the expression of the epithelial marker, E-cadherin, in MDA-MB-231 and BT549 cells. However, the expression of the mesenchymal markers, N-cadherin and vimentin, was reduced as a consequence of miR-124 overexpression in MDA-MB-231 and BT549 cells as compared to the control group (63). Simultaneously, the cell shape changed from a fusiform mesenchymal to a polygonal epithelial one when miR-124 was overexpressed in MDA-MB-231 and BT549 cells, demonstrating that the epithelial cell polarity of MDA-MB-231 and BT549 cells was partly regained following transfection with miR-124 mimics (63). It was hypothesized that the anti-metastatic effect of miR-124 was associated with the control of EMT. TargetScan analysis and dual-luciferase reporter assays revealed that a miR-124 binding site was present in the zinc finger E-box binding homeobox 2 (ZEB2) 3'-UTR region, which was later verified to be significantly elevated in BC tissues. Additionally, it was shown that ZEB2 expression in BC tissues was adversely linked with miR-124 expression. miR-124 could suppress EMT via ZEB2, thus further suppressing the metastasis and invasion of BC cells (63). According to the study by Shi et al (64), miR-124 may inhibit STAT3 production by interacting with the protein's 3'UTR and controlling the malignant behavior of BC cells. miR-124 is a key modulator of cholinergic anti-inflammatory effects, and it can inhibit the expression of STAT3 and TNF-α converting enzyme (65). Therefore, miR-124 can achieve its antitumor effect by inhibiting these two inflammatory factors. STAT3 is a gene that has been extensively studied in a variety of cancer types. The close interaction between miR-124 and SATA3 makes miR-124 position in anticancer treatment even more critical. STAT3 is closely associated with the proliferation, invasion and natural killer cell tolerance of tumor cells. By suppressing the expression of miR-124, Zhang et al (66) reported that LINC00240 caused a number of tumor-promoting behaviors by overexpressing STAT3. Additionally, in another study, rescue experiments revealed that the overexpression of miR-124 had negative effects on cell survival and invasion; however, these effects were substantially reversed by the high expression of STAT3 (64). It has also been found that miR-124 inhibited STAT3 to render BC stem cells less resistant to the therapeutic agent, doxorubicin (DOX), indicating that miR-124 restoration and STAT3 suppression may be an effective combination for combating drug resistance (67). The formation of numerous cancer types has been connected to the nuclear enriched abundant transcript 1 (NEAT1), a new long non-coding RNA (lncRNA) found in nuclear paraspeckles that is essential for sustaining paraspeckles (68). According to the study by Jiang et al (69), NEAT1 may target the miR-448/ZEB1 axis to promote the progression of BC. Of note, Pang et al (70) demonstrated that NEAT1 functioned as a competitive endogenous RNA (ceRNA) that increased STAT3 expression by sponging miR-124 in BC, and the overexpression of miR-124 attenuated the effects of NEAT1 on the growth of BC cells. Furthermore, the high expression of miR-124 reduced BC cell growth by concentrating on STAT3. In BC tissues, miR-124 levels were inversely linked with NEAT1 and STAT3 expression levels (70). In summary, the aforementioned studies indicate that NEAT1 and STAT3 are connected by a positive feedback loop, which contributes to the proliferation of BC cells. miR-124 is considered to be a key target in the treatment of BC. Shi et al (71) indicated that circular RNA HIPK3 (circHIPK3) contained in BC cell-derived exosomes increased metadherin expression in endothelial cells by sponging miR-124-3p, thus promoting tube formation in human endothelial cells and potentially serving as a therapeutic target for anti-angiogenesis treatment in BC. The effects of anticancer medications on tumor-associated macrophages (TAMs) may affect their therapeutic efficacy, and the combined use of anticancer drugs with TAM modifiers may be necessary to achieve significant clinical success, according to Wang et al (72), who hypothesized that miR-124 could downregulate enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and thereby promote chemokine ligand 2 expression, thus affecting TAM polarization and infiltration. Guo et al (73) identified that an alternatively spliced p62 isoform provided resistance to treatment in BC. These findings increase the current understanding of the molecular processes underlying BC development, and raise the possibility of using miR-124 as a therapeutic target for BC.

Bladder cancer is considered one of the most common malignant urinary system cancer types. Bladder cancer is listed as the second highest cause of cancer-related mortality among all genitourinary tumors (74). It is estimated that there are currently 765,950 patients in the USA with bladder cancer (75). Urothelial carcinomas comprise ≤90% of all bladder cancer cases, including invasive and non-invasive bladder cancer. Approximately 15% of urothelial bladder cancer cases may worsen to muscle-invasive cancer (76). Surgery, often an en bloc resection, followed by adjuvant intravenous chemotherapy is the conventional course of treatment for non-muscle invasive bladder cancer (77). The 5-year survival rate for individuals with muscle-invasive cancer is 70%, and the 10-year survival rate is significantly lower (78,79). The highly metastatic nature of bladder cancer is the main reason for its high recurrence and mortality rates. In order to improve the clinical treatment efficiency and patient survival, it is essential to identify effective therapeutic targets and to develop efficient treatment techniques.

miR-124 has been shown to be a crucial regulator of bladder cancer. Previous studies by Zhou et al (37) and Zo and Long (38) on miR-124 expression in bladder cancer tissues found that its expression was significantly lower than that in adjacent noncancerous tissues. HT-1376, T24 and 5637 bladder cancer cell lines had considerably lower levels of miR-124 than did SV-HUC-1 normal human bladder epithelial cells. Furthermore, miR-124 overexpression could effectively suppress bladder cancer cell proliferation, while miR-124 downregulation markedly improved the proliferative ability of bladder cancer cells. Compared with the control cells, silencing of miR-124 promoted the invasive and migratory abilities of bladder cancer cells, while these migratory and invasive capacities were impeded by the high expression of miR-124, suggesting that bladder cancer growth and invasion may be inhibited by miR-124. In addition, miR-124 was confirmed to be associated with angiogenesis (80). Vasculogenic mimicry (VM), MMP-2, VEGF and MMP-9 are valid indications of angiogenesis that have been described in previous research (81,82). Wang et al (83) observed that miR-124 overexpression notably inhibited the tubular channels formed, and considerably decreased VEGF, MMP-9 and MMP-2 expression levels, thus highlighting the suppressive effects of miR-124 overexpression on bladder cancer angiogenesis. Moreover, the knockdown of miR-124 exerted opposite effects on VM, as well as on the protein level of VEGF, MMP-2 and MMP-9, thus indicating that the ectopic expression if miR-124 can inhibit the angiogenesis of bladder cancer cells (83). Mechanistic analyses demonstrated that miR-124 could interact with ubiquitin-like with PHD and RING finger domain 1 (UHRF1), acting as an important modulator of epigenetic modifications, and significantly decreasing UHRF1 expression in bladder cancer cells. In contrast to UHRF1 overexpression, the aforementioned results demonstrated that miR-124 reduces bladder cancer development, migration, invasion and angiogenesis (83). In several cancer types, lncRNA X-inactive specific transcript (XIST) is associated with cancer progression (84). By controlling the expression of AR, Xiong et al (85) demonstrated that the bladder cancer cell proliferation and migration may be affected by XIST; AR is a ligand-dependent transcription factor that regulates biological functions (86). To inhibit the formation of miR-124, XIST can function as a ceRNA. miR-124 may also bind to the protein's 3'-UTR in order to regulate the production of AR (85). miR-124 suppression cab partially override the impact of XIST downregulation on the expression level of AR, c-Myc, p27, MMP-13 and MMP-9 (85), indicating that the newly identified XIST/miR-124/AR axis may regulate bladder cancer cell proliferation, invasion, and migration and may act as a marker and target for bladder cancer patients. The pattern of miR-124 expression in bladder cancer remains unclear, and further studies are required to determine the predictive value of miR-124 and the association between its expression and clinical indicators.

CRC, which affects >1.2 million individuals per year and is the third highest cause of cancer-related mortality globally, has a 5-year survival rate of 63.5% (87). In 2020, the number of confirmed cases of CRC reached 147,950, and there were 53,200 related deaths. Among patients <50 years of age, 17,930 patients were diagnosed with CRC, and 3,640 patients succumbed to the disease (88). Despite the existence of screening and prevention strategies, due to the frequent occurrence of CRC, it has long been a severe global wellness issue. Despite recent advancements in surgical techniques and comprehensive therapy, CRC is still associated with a poor prognosis, particularly the low long-term survival rate of patients with advanced-stage CRC (89,90). Thus, precise prognosis estimation is essential for physicians, in order to improve and individualize therapeutic strategies. Any novel prognostic signal needs to be verified due to the poor prognosis of patients with CRC.

Zhou et al (39) and Taniguchi et al (40) investigated the expression profile of miR-124 in CRC tissues and cell lines, and observed that miR-124 expression was markedly decreased in CRC tissues and cell lines. Functional assays further revealed the inhibitory role of miR-124 in regulating the cell viability and proliferative ability of CRC. EdU assay revealed that, in the negative control (NC) small interfering RNA (siRNA) group, the average proportion of new cells incorporating EdU was 27.1%, which increased to 39.8% in miR-124 inhibitor-transfected cells. Furthermore, the proliferative capacity of SW620 cells transfected with miR-124 inhibitor declined with increasing miR-124 inhibitor concentrations (from 80 to 120 nmol/µl) and transfection times (from 24 to 48 h), which demonstrated that it suppressed the proliferation of miR-124-induced cells. High levels of miR-124 expression, on the other hand, prevented cell survival and proliferation. Similar to this, a colony-forming assay revealed that CRC cells transfected with miR-124 inhibitor had improved transformation ability compared to cells treated with negative control siRNA, whereas CRC cells overexpressing miR-124 had significantly decreased transformation ability, showing that miR-124 could prevent the invasion and migration of CRC cells (39). Taniguchi et al (40) found that the ectopic expression levels of miR-124 induced the apoptosis and/or the autophagy of CRC cell lines. Mechanistically, prokaryotic and eukaryotic genomes undergo DNA methylation, a post-replication alteration that plays crucial biological roles, such as controlling gene expression, deactivating the X chromosome and maintaining chromosomal integrity (91-94). miR-124 is silenced in CRC via promoter methylation, among other mechanisms that contribute to its downregulation, which was first reported by Lujambio et al (95), who found that CpG island hypermethylation caused miR-124 transcriptional inactivation in human malignancies. The activation of cyclin D kinase 6, a known oncogenic factor, and the phosphorylation of the tumor suppressor gene, retinoblastoma, were both shown to be causally related to the epigenetic loss of miRNA-124a (95). A previous study examined how miR-124 effectively controlled DNA hypomethylation by targeting DNA-methyltransferase (DNMT)3B and DNMT1. As a consequence of the elevated expression of miR-124, the hypermethylated and suppressed E-cadherin, methylguanine methyltransferase, and P16 genes in CRC were also re-expressed (96). The expression of polypyrimidine tract-binding protein 1 (PTBP1) may be regulated by miR-124. PTBP1 is able to alternatively splice pyruvate kinase muscle isoform 1 (PKM1) to create pyruvate kinase muscle isoform 2 (PKM2). This causes the PKM2/PKM1 ratio to increase, which prevents tumor cells from performing aerobic respiration even when oxygen levels are adequate. The proliferation of neoplastic cells may be affected by improper metabolism. Through a PTBP1/PKM1/PKM2 feedback loop, miR-124 was shown to reduce the development of CRC cells (40). Bioinformatics analysis and dual luciferase assays conducted by Zhu et al (97) revealed that XIST served as a ceRNA to modulate miR-124 activity and inhibit the transcriptional degradation of miR-124 targets, such as serum/glucocorticoid regulated kinase 1 (SGK1). By serving as a miR-124 sponge and therefore reducing SGK1 protein expression in DOX-resistant CRC cells, XIST knockdown reduced the ability of these cells to withstand DOX. Consequently, miR-124 may be a promising therapeutic target for enhancing the efficacy of DOX-based chemotherapy in patients with CRC (97). In terms of the impact of miR-124 on radiotherapy and drug resistance, miR-124 overexpression has been shown by Zhang et al (98) to increase the sensitivity of CRC cells to radiation, while knockdown of miR-124 induces cell resistance to irradiation by targeting paired related homeobox 1. The study by Xie et al (99) demonstrated that miR-124 directly targeted calpain 2 to enhance oxaliplatin-based chemotherapy. The clinical importance of C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C chemokine receptor type 7 (CXCR7) aberrant signaling in driving EMT and invasion during CRC development was identified by Si et al (100). These results indicate the possibility of inhibiting CXCL12/CXCR7 aberrant signaling-induced metastasis of CRC by targeting yes-associated protein 1 nuclear translocation. In summary, these results indicate a major anticancer role of miR-124, which may serve as a fresh point of focus for the diagnosis and treatment of CRC.

Liver cancer is the sixth most prevalent solid cancer worldwide, particularly in China. There are ~841,000 new cases and 782,000 deaths associated with this disease worldwide, rendering it a serious health concern (4). HCC is the most common type of liver cancer and comprises >90% of all instances of primary liver cancer. Patients typically succumb to intrahepatic or extrahepatic metastasis in the absence of suitable therapy. Metastasis is often coupled with the development of new tumors (101,102). Consequently, further research on the metastatic mechanisms of HCC may help to elucidate HCC metastasis factors and to identify novel therapeutic targets.

RT-qPCR and immunohistochemical analysis conducted by Wang et al (103) revealed that miR-124 was notably downregulated in a cohort of 60 pairs of HCC tissues and Hca-F cells in contrast to nearby normal tissues and the normal hepatic cell line, NCTC1469, suggesting that miR-124 may play a critical role in regulating HCC tumorigenesis. Moreover, biological function assay demonstrated that miR-124 overexpression markedly suppressed the viability and proliferation of HepG2 cells. The results of wound healing assay indicated that the overexpression of miR-124 in HepG2 cells attenuated the wound healing process compared with the control cells. Importantly, the results of Transwell assay without Matrigel coating demonstrated that HepG2 cells expressing miR-124 migrated to the lower chamber to a lesser extent, in comparison to the control cells. Likewise, cell invasion was also observably inhibited by transfection with miR-124, as confirmed in the Transwell assay with Matrigel (104). All the aforementioned findings indicate that miR-124 functions as a tumor inhibitor in HCC. Furthermore, in HCC cell lines, miR-124 overexpression was shown to decrease the expression levels of three mesenchymal markers (fibronectin, vimentin, and N-cadherin), whereas it increased the expression levels of three epithelial indicators (E-cadherin, α-catenin and β-catenin). Additionally, immunofluorescence labeling revealed that in HCC cell lines, the expression of those three epithelial markers increased whereas the expression of the aforementioned three mesenchymal markers decreased (105). Adrenoceptor β2 and E-cadherin are directly suppressed by EZH2, which contributes to the activation of EMT (106,107). The association between EMT and the invasion and metastasis of cancer cells is widely recognized (108). Notably, miR-124 specifically targets the 3'-UTR of EZH2 to alter the synthesis of E-cadherin, according to Zheng et al (105), suggesting that miR-124 can control the progression of EMT. A previous study demonstrated that circHIPK3 served as a miR-124 sponge and significantly inhibited the expression level of miR-124 in HCC cells. These findings suggested that circHIPK3 may promote HCC cell proliferation and migration, whereas opposite effects were observed upon the overexpression of miR-145, which indicated that miR-124 inhibition rescued the decrease in the proliferation and migration of HCC cell lines caused by circHIPK3 knockdown (109).

A family of transmembrane channels termed aquaporins (AQPs) transport solutes, such as glycerol and water (110,111). Previous studies have reported a critical role for AQPs in tumorigenesis and cancer progression (112,113). AQP3 has been shown to be overexpressed in HCC, and patients with elevated levels of AQP3 have a negative prognosis (114). Moreover, Chen et al (109) confirmed that AQP3 was a target of miR-124 and inhibited the expression of AQP3. The knockdown of circHIPK3 reduced the proliferation and migration abilities of HCC cells, which could be rescued by a miR-124 inhibitor. Furthermore, the circHIPK3-induced suppression of AQP3 expression may be reversed by miR-124 inhibition. These results demonstrated that circHIPK3 controlled the migration and proliferation of HCC cells by sponging miR-124, which in turn controlled the expression of AQP3 (109). Further research on the circHIPK3-miR-124-AQP3 axis may provide new perspectives for the future therapy of HCC. Yu et al (115) suggested that circHIPK3 accelerated cell proliferation and invasion by sponging miR-124. MALAT1, a lncRNA linked with lung adenocarcinoma, may promote the growth of HBx-induced malignancy (116). The 3'-UTR of miR-124 in cancer stem cells (CSCs) can specifically bind caveolin-1 (CAV1), which indicates that miR-124 can be overexpressed by targeting CAV1. Therefore, the high expression of CAV1 can inhibit the self-renewal and tumorigenesis of liver CSCs. When miR-124 is absent, this effect disappears. Other lncRNAs, such as DS cell adhesion molecule-antisense RNA 1 and miR-124 have also been found to interact in HCC (117). Taken together, these findings may provide new perspectives on the pathogenesis of HCC and may provide underlying strategies for miRNA-directed therapy. However, future studies are required to determine and elucidate the in vivo implications and other potential mechanisms of miR-124.

Lung cancer is the leading cause of cancer-associated mortality worldwide, accounting for ~1.4 million deaths each year (118). The two main types of lung cancer are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) (119). NSCLC is diagnosed in ~85% of patients, while the remaining ~15% of patients are diagnosed with SCLC (120). Despite the therapeutic progress that has recently been made, the 5-year OS rates of patients with NSCLC remain low (121). Increasing evidence has indicated that cancer metastasis or recurrence is frequent in NSCLC therapy, and is mainly responsible for the low 5-year survival rate (122,123). Thus, understanding the mechanisms of NSCLC progression is critical.

miR-124 has been found to function as a regulator in lung cancer. Yang et al (124) demonstrated that miR-124 expression was significantly lower in 40 NSCLC tissues compared with paired non-cancerous lung tissues. Furthermore, the miR-124 expression level was strongly decreased in several NSCLC cell lines (LTEP-a-2, H226, A549, H460, 95C, 95D and H1299) compared with HBE cells. Transwell assays revealed that the A549 and H1299 cells with an elevated expression of miR-124 exhibited reduced migratory and invasive abilities. Furthermore, the A549 and H1299 cells with a downregulated expression miR-124 exhibited increased migratory and invasive abilities (124). According to a previous study, TGF-stimulation can cause A549 cells to initiate EMT, which is followed by a loss of cell-to-cell adhesion and an increase in cell mobility (125). Zu et al (126) demonstrated that miR-124 expression could partially induce EMT by suppressing the expression of N-cadherin and vimentin, whether it was transfected before or after TGF induction. A549 cell EMT morphology was also observed when miR-124 was transfected, and the authors of that study noted that miR-124 expression in A549 cells lowered N-cadherin and vimentin expression, but had no effect on E-cadherin expression, particularly in the absence of TGF stimulation. These data revealed that expression of miR-124 had the ability to partly reverse the EMT process (126). Previous studies have suggested that the methylation of the miR-124 promoter may reduce the production of the gene in human tumors (127,128). Moreover, Zu et al (126) discovered that the miR-124 promoter was hypermethylated in NSCLC cells. Additionally, 5-azacytidine therapy significantly increased the expression of miR-124 in these cells. The authors found that TGF-stimulated miR-124-1/2 promoter hypermethylation could be significantly reduced, but miR-124-3 promoter hypermethylation showed no effect. Further analysis using bisulfate sequencing and PCR revealed that TGF-β induction hypermethylated the miR-124-2 promoter but had no effect on the miR-124-3 or miR-124-1 promoter methylation (126). Moreover, A549/DDP cells have been shown to be more sensitive to cisplatin as a result of miR-124 overexpression; their apoptotic rate has been shown to increase, and their invasive and metastatic capacities have been found to be inhibited by miR-124 mimics (129). Another study revealed that miR-124 may interact with circHIPK3 to regulate the expression of miR-124 targets in lung cancer cells, including as STAT3, sphingosine kinase 1 (SphK1) and cyclin-dependent kinase 4 (CDK4). CircHIPK3 siRNA increased miR-124 expression, whereas circHIPK3 hyperexpression by LV-circHIPK3 decreased it (130). Notably, a miR-124 inhibitor significantly decreased lung cancer cell death and proliferation, as well as the downregulation of miR-124 targets caused by circHIPK3 siRNA (130). Wu et al (131) demonstrated that lncRNA MALAT1 could competitively regulate miR-124 after reacting with argonaute 2 to form a complex. lncRNA MALAT-1 could sponge miR-124 to regulate EMT. A decrease in the expression of miR-124 could significantly reverse the inhibition of cell proliferation, variability, invasion and migration, and EMT mediated by lncRNA MALAT1 knockdown. Li et al (132) found that lncRNA 1308 contributed to the sponging of miR-124, which resulted in the overexpression of a disintegrin and metalloproteinase 15 (ADAM15). The reduced expression of miR-124 and the enhanced expression of ADAM15 may clearly counteract the inhibitory effects of lncRNA 1308 knockdown on cell invasion, proliferation and migration. It was identified that the lncRNA 1308/miR-124/ADAM15 regulatory network was associated with NSCLC cell invasion and proliferation, and may promote carcinogenesis in NSCLCs; thus, it could be used to develop novel diagnostic and treatment methods for NSCLC (132). Similarly, Liu et al (133) reported that exosomal circRNA plasmacytoma variant translocation 1 (PVT1) derived from lung cancer mediated macrophage polarization via the miR-124-3p/EZH2 axis to potentiate lung cancer cell proliferation, invasion and migration. These findings demonstrated that miR-124 may inhibit the ability of NSCLC cells to become malignant via an mRNA-guided mechanism. However, further research is warranted to elucidate the alternative regulatory mechanisms, as well as the therapeutic utility of miR-124 in lung cancer.

With a high mortality rate observed over the past few decades, ovarian cancer continues to be one of the major causes of mortality among women worldwide (134-136). The primary factor behind this high mortality rate is the fact that >70% of patients are diagnosed at an advanced stage of the disease and have already developed distant tumors (137,138). According to previous studies, complex changes in the genome, particularly in the expression and function of several miRNAs, are linked to ovarian cancer (137,139). The exact mechanisms through which miRNAs are associated with the invasion and migration of ovarian cancer cells remain unclear, despite the fact that multiple studies have suggested the potential utility of miRNAs in ovarian cancer diagnosis, prognosis and therapy (140,141). Therefore, it would be crucial for clinical practice to identify effective biomarkers for ovarian cancer diagnosis and therapy.

Yuan et al (41) evaluated the expression of miR-124 in 30 clinical tumor samples of tissue and 30 non-neoplastic ovarian tissue, and demonstrated that compared to non-neoplastic reference tissues, the majority of ovarian cancer tissues exhibited considerably reduced expression levels of miR-124. In the study by Zhang et al (142), miR-124 expression was also found to be reduced in ovarian cancer cell lines. The biological effects of miR-124 on the proliferation and invasion of ovarian cancer cells were then demonstrated by various functional assays. A wound healing assay revealed that the overexpression of miR-124 mimics markedly decreased the migration of the ovarian cancer cell lines, SKOV3 and OCVAR,3 as compared to the scramble control or NC at 24 and 48 h. Furthermore, the ectopic synthesis of miR-124 considerably decreased the invasion of these cell lines in comparison to the scramble control or NC groups. miR-124 overexpression reduced the proportion of cells in the S phase, and significantly increased cell apoptosis and the proportion of OVCAR3 and SKOV3 cells in the G0/G1 phase (142). In terms of the mechanisms, Yuan et al (140) found that miR-124 directly suppressed the expression of PDCD6 in ovarian cancer. Notably, the expression of PDCD6 reversed the inhibition of cell migration and invasion caused by miR-124, as well as the activation of cell death (141). In the study by Zhang et al (142), SphK1 was shown to be a predicted target of miR-124, and miR-124 functioned as an inhibitor by directly binding to the anticipated binding location of the 3'-UTR of SphK1. SphK1 overexpression prevented cells from miR-124 from inhibiting cell migration and invasion (142). Additionally, Deng et al (143) demonstrated that the overexpression of miR-124-3p.1 reduced the apoptotic cell death induced by carboplatin in ovarian cancer cell lines. They established miR-124-3p.1-targeted CAV1 in ovarian cancer as the mechanism behind this effect. The overexpression of miR-124-3p.1 prevented CAV1 from being expressed, which reduced AKT activation and Bad phosphorylation. As a result, Bcl-xL function was downregulated, and carboplatin enhanced the induction of mitochondrial death (143). It has been shown that the miR-124-3p/jagged canonical Notch ligand 1 (JAG1) pathway promotes the apoptosis and inhibits the proliferation of ovarian granulosa cells (144). In conclusion, these results highlight the tumor suppressive function of miR-124, and highlight its potential as a prognostic indicator for patients. Further mechanistic studies including larger tumor samples are, however, urgently required.

The most frequent disease among males and the subsequent largest reason for cancer-related mortality is prostate cancer, with >29,000 males succumbing to prostate cancer in the USA in 2020 (145). Despite the fact that prostate cancer may be treated with cutting-edge techniques, such as androgen deprivation therapy and docetaxel chemotherapy (146,147), the survival rate of patients with prostate cancer remains low, and the 5-year survival rate is only 29% (74,148). In addition, 30% of patients relapse after receiving first treatment (149). Thus, identifying novel diagnostic biomarkers and therapeutic targets for enhancing the survival rate of patients with prostate cancer is of utmost importance.

Zhang et al (150) investigated miR-124 expression in 37 pairs of surgical specimens from patients with prostate cancer using RT-qPCR, and found that miR-124 expression was reduced at varying degrees in cancerous tissues. Shi et al (42) examined the level of miR-124 expression in prostate cancer cell lines, and found that the expression of miR-124 was lower in malignant cell lines compared with benign cell lines, Northern blot analysis was performed on these cell lines and similar results were obtained. Functionally, Transwell and cell attachment assays demonstrated that upregulation of miR-124 led to a marked reduction in the attachment to fibronectin, a vital component of the extracellular matrix, and impaired the abilities of cell migration and invasion (42). Another study suggested that upregulation of miR-124 may prevent prostate cancer cells from proliferating, indicating that miR-124 functions as a tumor inhibitor (151). It was demonstrated that the tumor inhibitor miR-124 was a critical regulator of an oncopathway in prostate cancer, modulating the expression of EZH2, Src and AR variants that contribute to the pathogenesis of the disease and resistance to treatment, and that miR-124 recovery decreased the proliferation of enzalutamide-resistant prostate cancer cells, rendering them more responsive to the drug (151). Importantly, it was found that synthetic miR-124 delivered systemically via polyethylenimine (PEI) reduced the growth of both androgen-dependent and androgen-independent prostate cancer cells as well as that of cells resistant to enzalutamide (151). Another study observed that lncRNA opioid growth factor receptor pseudogene 1 (OGFRP1) induced cell proliferation and inhibited cell apoptosis by modulating miR-124, which was expected to interact with lncRNA OGFRP1 (152). Additional analyses confirmed that miR-124 and lncRNA OGFRP1 may interact, and that miR-124 downregulation partially counteracted the stimulation of proliferation and the suppression of apoptosis caused by lncRNA OGFRP1 overexpression in prostate cancer cells (152). Taken together, these findings provide a preclinical justification for monitoring miR-124 levels in cancer treatment. However, further research is necessary to validate the probable mechanisms and clinical significance of miR-124 in prostate cancer.

With ~600,000 new cases and a mortality rate of 223,000-300,000 fatalities per year, head and neck cancer is the sixth most common type of cancer worldwide (153,154). Squamous cell carcinomas, which develop in the squamous epithelial cells of the nasal cavity, paranasal sinuses, oral cavity, oropharynx, larynx and hypopharynx, account for the majority of instances of head and neck cancer (153). Currently, alcohol misuse, long-term cigarette use and human papillomavirus infection are the primary risk factors for HNSCC and are connected to age, sex and ethnicity (155). The relative frequency of these risk factors causes a variance in the distribution of HNSCC internationally. The most hazardous characteristic of HNSCC is that cancer is commonly identified at late stages (T3 or T4), when the survival rate is decreased to 20%, resulting in high mortality and morbidity rates (156,157). By contrast, the 5-year survival rate of patients is 80% if HCSCC is identified at an early stage (T1 or T2) (158,159). Therefore, including biomarkers unique to various ethnic groups holds promise for screening, early identification and tracking therapy response in HNSCC, rendering it an indispensable aspect of modern clinical practice.

Zhao et al (160) and Yang et al (161) measured the expression level of miR-124 in HNSCC tissue samples and cells. Their findings demonstrated that miR-124 expression in HNSCC tumors was markedly reduced as compared to that in surrounding healthy tissues. The expression of miR-124 in HNSCC cell lines was also significantly lower than that the in non-cancerous oral keratinocyte cell line. The downregulation of miR-124 has been implicated in tumor-promoting activities, whereas its upregulation is associated with tumor-suppressing functions in HNSCC (160,161). Zhao et al (160) demonstrated that the upregulation of miR-124 caused the substantial suppression of cellular proliferation in vitro, as well as a reduction in tumor xenograft growth in animal models. Moreover, the upregulation of miR-124 led to G1 phase cell cycle arrest, and promoted the creation of fewer and smaller colonies, thereby substantiating its role as a suppressor of tumors in HNSCC. Additionally, Zhao et al (160) demonstrated that miR-124 specifically bound to the complementary 3'-UTR sequence motif of SphK1 in HNSCC, inhibiting SphK1 production. Instead of using vector-transfected JHU-22 cells and tumor xenografts, miR-124 mimics were used to transfect JHU-22 cells; the results demonstrated a buildup of ceramide, higher levels of the pro-apoptotic proteins, Bax, PARP and Bad, the reduced expression of the anti-apoptotic proteins, Bcl-xL and Bcl-2, as well as the increased production of caspase proteins and cytochrome c (160). Yang et al (161) investigated the biological consequences of miR-124 in cetuximab-treated HNSCC cells. In comparison to cetuximab treatment, their study found that miR-124 overexpression dramatically decreased the viability of cells. In comparison to cetuximab therapy, the overexpression of miR-124-3p increased the apoptosis of CAL27 and SCC-9 cells by 11.23 and 9.76%, and the number of TUNEL-positive cells by 7.87 and 8.15%, respectively (161). miR-124-3p overexpression consistently enhanced the inhibitory effects of cetuximab on Bcl-2 expression and the activation of broken caspase 3 and Bax, indicating that it may improve the sensitivity of HNSCC cells to cetuximab (161). It was also revealed that lncRNA PVT1 downregulation resulted in the decreased methylation of the miR-124-3p promoter, which led to the increased expression of miR-124-3p. Functional rescue experiments revealed that the overexpression of miR-124 markedly suppressed the effects of PVT1 overexpression on apoptosis and cell proliferation. This demonstrated the functional role of miR-124-3p as a target in the control process of PVT1-mediated cetuximab chemosensitivity (161). In conclusion, these findings provide insight into the ability of miR-124 to inhibit the malignant characteristics of HNSCC cells through the modulation of mRNA and lncRNA interactions. It thus would be prudent to determine whether miR-124 expression changes according to the stage of HNSCC.

It was discovered that the Wnt/β-catenin signaling pathway controls the proliferation, invasion and metastasis of CRC cells (182,183). miR-124 regulates Wnt4, a component of the Wnt/β-catenin signaling system, decreasing CRC cell proliferation in vitro and inhibiting tumor development in vivo (182). A recent study indicated that miR-124 suppresses CRC proliferation, migration and invasion by downregulating the DNMT3B and DNMT1 level (184). The inhibition of DNMT1 and DNMT3b activity has been demonstrated to regulate the expression of genes involved in the Wnt/β-catenin pathway (185). Thus, miR-124 may be involved in the Wnt/β-catenin pathway by regulating DNMT3B and DNMT1, leading to the inhibition of CRC development.

It is widely recognized that the Axin family, which includes Axin1 and Axin2, regulates the amount of Wnt/β-catenin to negatively modify the Wnt/β-catenin signaling pathway, and is crucial for the development and pathophysiology of a number of human illnesses, including cancer (165,186,187). The study by Yang et al (62) revealed that miR-124-3p.1 targeted the 3′-UTR of Axin1 mRNA in BC cells. miR-124-3p.1 overexpression promoted cell proliferation, which was suppressed by the overexpression of Axin1 in BC cells. Therefore, utilizing miR-124-3p.1 mimics to target Wnt/β-catenin signaling pathway genes, including cyclin D1 and c-Myc prevented Axin1 from being overexpressed (62). They also found that miR-124-3p.1 mimic therapy mimicked the effects of Axin1 knockdown by upregulating β-catenin and Bcl-2, while downregulating β-catenin phosphorylation and the levels of the apoptosis-related protein, Bax. Taken together, these findings demonstrated that miR-124 regulated growth of BC by regulating Wnt/β-catenin signaling (62).

Lang and Ling (188) identified that PIK3CA played a direct role in targeting miR-124 in HCC cells, and thus contributed to marked decrease in PIK3CA at the mRNA and protein level. Notably, the overexpression of miR-124 suppressed Akt and mTOR mRNA, as well as their total and phosphorylated protein levels, suggesting that miR-124 may be a crucial modifier of the PI3K/Akt signaling pathway, thereby resulting in the suppression of proliferation and tumorgenicity of HCC cells (188). According to Cao et al (36), miR-124 controls the NF-κB signaling pathway, which prevents HCC from proliferating and migrating. The researchers discovered that the overexpression of miR-124 in HCC was linked to a significant decrease in the protein level of p-p65, p-nuclear factor of light polypeptide gene enhancer in B-cells inhibitor and c-Myc. By contrast, the downregulation of miR-124 suppressed the expression level of p-p65, c-Myc and p-IκBα in HCC (36). TNF receptor associated factor (TRAF6) is a critical player in the NF-κB signaling pathway, in addition to being triggered by various stimuli, such as DNA damage. The expression and activity of TRAF6 are closely controlled (189,190). A dual-luciferase reporter assay conducted by Xie et al (191) revealed that the upregulated expression of miR-124 markedly suppressed the activity of Firefly luciferase with the TRAF6-3'-UTR, thus inhibiting the expression of TRAF6, resulting in the inhibition of the DNA damage-activated NF-κB signaling pathway and in the enhancement of tumor chemosensitivity in HCC. The aforementioned studies on the miR-124/TRAF6/NF-κB axis illustrate that the combined targeting of the NF-κB signaling pathway may provide a possible approach for HCC therapy.

Lv et al (192) revealed that the overexpression of miR-124 markedly downregulated the protein levels of p-PI3K and p-AKT in endometrial cancer cells. Further evidence that the intergenic non-protein encoding RNA, regulator of reprogramming, was responsible for the activation of the PI3K/Akt signaling pathway in carcinoma of the endometrium was provided by the considerable increase in the expression levels of these proteins when miR-124 was inhibited. Previous research has demonstrated that miR-124 controls the development of various targets in endometrial cancer. Li et al demonstrated that miR-124 directly targeted STAT3 or indirectly inhibited the phosphorylation of STAT6 by targeting IL-3R, thereby inhibiting the proliferation migration and invasion of EC cells (193). A recent study suggested that miR-124-3p is a downstream molecule of NEAT1 and is negatively regulated by it; thus, the silencing of NEAT1 may inhibit EC endometrial stromal cell proliferation, migration and invasion and promote apoptosis by targeting miR-124-3p (194).

It has been reported that JAG1 and COL4A1 are direct targets of miR-124 in GC (195). Furthermore, the expression of JAG1 and the Notch signaling pathway have been found to be inhibited. By contrast, the suppression of miR-124 has been shown to lead to an increased JAG1 expression and improve Notch signaling pathway. Importantly, blocking Notch signaling results in the amplification of miR-124 expression (196). By contrast, epidermal ectopic activation of Notch signaling could repress miR-124 expression (196). Xiao et al (197) discovered that miR-124 suppressed the function of the Notch signaling pathway in order to target the JAG1 gene, thus suppressing the invasion, migration and proliferation of GC cells. These findings demonstrated that the miR-124/Notch axis that may have therapeutic potential in GC by functioning as a tumor inhibitor throughout the development of GC and by interacting with the Notch signaling pathway. Furthermore, Zheng et al (198) revealed that miR-124 overexpression suppressed the expression of p-PI3K and p-AKT in GC cells, resulting in the repression of cell proliferation and the promotion of cell apoptosis in GC.

Wu et al (199) demonstrated that the decreased expression of miR-124 reduced the G₀/G₁ phase ratio, inhibited cell apoptosis, and promoted the expression of STAT3, p-STAT3, cyclin D1 and Bcl-2, as well as the ratio of the S and G₂/M phases in prostate cancer. The overexpression of miR-124 attenuated clonal formation, cell invasion, the ratio of S and G₂/M phase and cell apoptosis, and also enhance the G₀/G₁ phase ratio in prostate cancer. This finding suggested that miR-124 downregulation induced the upregulation of STAT3 expression and facilitated prostate cancer initiation, while miR-124 overexpression decreased prostate cancer proliferation, invasion and resistance to apoptosis via the JAK-STAT3 signaling pathway (199). Taken together, these data suggest that miR-124 may become a novel therapeutic target and biomarker for prostate cancer in the future.

Patients with bladder cancer are divided into two distinct categories: One with high levels of expression and one with low levels of expression based on the average level of miR-124 expression. It has been shown that bladder cancers with lymph node metastasis (LNM) and advanced-stage cancers clinically have a lower expression of miR-124 (202). In addition, patients with bladder cancer with a low expression of miR-124 exhibit a shorter OS time than those with miR-124 overexpression (37). As shown by Xie et al (99), the OS has been shown to be worse in patients with a low miR-124 expression than in those with a high miR-124 expression.

Previous studies have shown that miR-124 expression is significantly downregulated in CRC compared to normal mucosa and that the downregulated expression of miR-124 is significantly associated with a poorer prognosis (98). Chen et al (96) suggested that miR-124 may be a valuable marker for CRC prognosis. According to Gao et al (203), the pri-miR-124 rs531564 polymorphism was significantly linked to a lower incidence of CRC. They demonstrated a strong correlation between differentiation status and LNM in patients with CRC and the pri-miR-124 rs531564 polymorphism.

Long et al (204) evaluated the level of miR-124 expression in HCC samples and cell lines. Their results revealed that HCC samples and cell lines had a downregulated expression of miR-124. The number of foci and tumor width were higher in individuals with a lower expression of miR-124, according to the authors' investigation into the association between the expression of miR-124 and the clinicopathological characteristics of patients with HCC. Furthermore, Kaplan-Meier survival analysis observed that decreased miR-124 expression was notably associated with shorter a DFS and OS. Cox regression analysis demonstrated that a downregulated expression of miR-124 was associated with a poor prognosis (204). The results of a Cox regression model employing multivariate analysis revealed that the findings for the prognosis of reduced expression, clinicopathological features (tumor length 5 centimeters), or amount of lesions (plural) were worse than those from univariate analysis (204). A low miR-124 expression and a high tumor size (5 cm) have also been linked to a reduction in OS and DFS (204). This proved that a key therapeutic approach for the care of patients with late-stage HCC may include producing larger amounts of miR-124 in cells. Another potential new and significant tumor marker is miR-124.

Cong et al (205) detected the expression of blood miR-124 in 114 individuals suffering from osteosarcoma, 40 individuals with periostitis and 50 normal controls; they found that patients with the tumor had substantially lower levels of miR-124 expression than patients with periostitis and normal controls. Furthermore, a receiver operating characteristic curve analysis with an area under the curve of 0.846 suggested that blood miR-124 levels may serve as an underlying biomarker for separating patients with osteosarcoma from healthy controls. In addition, the specificity and sensitivity were 86.0 and 79.8%, respectively. The expression level of serum miR-124 was highly associated with clinical stage and distant metastasis, whereas it was not associated with age, sex, tumor site, tumor diameter or tumor grade (205). Patients with stage III disease had considerably lower serum levels of miR-124 than those with stage II disease. Similar to this, blood miR-124 levels were noticeably lower in patients with positive distant metastasis than they were in individuals without metastasis. According to the results of Kaplan-Meier analysis and the log-rank test, individuals with osteosarcoma who had a high serum expression of miR-124 had substantially longer survival times than those who had a low miR-124 expression. Individuals with osteosarcoma in the low blood miR-124 expression group had a poorer DFS compared to those in the high serum miR-124 expression group. Multivariate Cox proportional hazards model analysis identified that clinical stage, distant metastasis and expression of serum miR-124 were independent prognostic factors for OS and DFS (205). In summary, the aforementioned data demonstrated that miR-124 may be utilized as a diagnostic and prognostic biomarker for osteosarcoma.

The majority of human malignant central nervous system tumors are gliomas (3). Almost 20,000 new glioma cases are diagnosed in the USA each year (206). Chen et al (207) revealed that the miR-124 expression level was considerably reduced in glioma tissues. Moreover, the miR-124 expression level in glioma tissues from high-grade tumors (grade III and IV) was much lower than that of glioma tissues from low-grade tumors (grade I and II). In addition, the miR-124 expression level exhibited a positive correlation with the Karnofsky performance scale scores of glioma tissues. Kaplan-Meier analysis and the log-rank test demonstrated that the OS and progression-free survival of patients with glioma with a low expression of miR-124 was markedly shorter than those of patients with miR-124 overexpression. The results of univariate and multivariate analyses revealed that the downregulated expression of miR-124 and an advanced histological grade were independent prognostic parameters that indicated a worse prognosis for patients with glioma (207). Thus, these findings indicated that miR-124 expression played a critical role in the progression of tumors; thus, it may be applied as a novel potential biomarker for evaluating clinical prognosis. At present, the greatest obstacles to cancer treatment are a delay in diagnosis, recurrence and metastasis.

Thus, finding ideal cancer biomarkers is crucial to improving the early diagnosis rate. The aforementioned findings indicate that miR-124 may be used as a potential marker for the diagnosis of multiple cancer types. However, the precise molecular mechanisms by which miR-124 functions in several types of cancer remain unclear. Therefore, the function of miR-124 in cancer needs to be further investigated and confirmed, particularly in clinical applications.

Since miRNAs can inhibit tumor development through a variety of mechanisms, the notion of treating tumors through miRNAs was born (164,208-212). In addition to its role in diagnosis and prognosis as a potential marker for cancer, miR-124 can make tumors more sensitive to treatment through different targets, thereby improving patient survival. For example, miR-124 can reverse radioresistance in esophageal cancer radiotherapy by targeting CDK4 to increase cancer cell sensitivity to radiation, and also plays a role in immunotherapy (213,214). It has been demonstrated that miR-124 not only reverses the resistance of BC stem cells to DOX by targeting STAT3 to control the hypoxia-inducible factor-1 signaling pathway (67), but also increases the sensitivity of BC cells to adriamycin by reducing DNA strand-break repair (215). A previous study inferred that miR-124 inhibited the expression of EphA2, which was beneficial for attenuating K-RAS mutation-mediated resistance to erlotinib in pancreatic cancer (216). In retinoblastoma, the miR-124/c-Myc axis exerts an oncogenic effect on disease progression, suggesting that miR-124 may be a promising therapeutic target (217). A previous study demonstrated that bio-carrier neural stem cell-derived exosomes (NSC-EXOs) loaded with miR-124-3p suppressed glioma growth via the EXO-miR-124-3p/FLOT2/AKT1 pathway, thus providing a possible measure for glioma treatment (218). miR-124 should be explored for the reversal of drug resistance in tumor treatments in the future.