Glioblastoma (GBM) is an aggressive brain tumor (WHO Grade IV astrocytoma) associated with a poor survival rate ^[1][18].

Polypyrimidine tract-binding protein (PTBP) 1 is an oncoprotein that supports the growth of tumor cells and maintains the metastatic potential of cancer. PTBP1 amplification was found in GBM due to the loss of brain-enriched miR-124 ^[2][19]. miR-124 was significantly reduced in GBM and exogenous transfection of miR-124 into GBM cells induced a G₀/G₁ cell cycle phase arrest and reduced the expression of cyclin-dependent kinase (CDK)6 and phosphorylated retinoblastoma (pRb) proteins ^[3][20]. miR-124 targets many proteins like SCP1, Rho-associated protein kinase 1 (ROCK1), STAT3, matrix metallopeptidase 9 (MMP9), and inhibits tumor cell proliferation in GBM [4]. miR-124 targets cyclin-dependent kinase-4 (CDK4) and sensitizes cells to radiotherapy. Exogenous delivery of miR-124 enhances temozolomide sensitivity in GBM cells, such as U87MG. In addition, it reduces the migration of tumors by targeting CDK6 ^[5][21] GBM cells like U87MG and T98G, which have a high expression of the clock circadian regulator (CLOCK) gene; this plays a vital role in maintaining tumorigenesis. miR-124 can effectively silence the CLOCK gene directly, by inhibiting the activation of NF-kB. Overexpression of miR-124 decreases SOX9 protein, reduces tumorigenicity, and enhances radiosensitivity of GBM cells ^[6][22]. miR-124 has been found to be a potent anti-glioma molecule against glioma stem cells (GSC) ^[7][23]. Exosome delivery (exo) with miR-124a (exo-miR-124a) revealed a significant decrease in the viability and clonogenicity in the intracranial GSC xenograft model compared to a control. miR-124a targets and downregulates Forkhead box A2 (FOX A2), an oncogenic transcription factor, and intermediary of lipid metabolism in GSCs. In vivo studies revealed that exo-miR-124 was found in around 50% of animals living long term when compared to a control, suggesting that exo-miR-124 is an effective anti-glioma agent ^[8][24]. miR-124 targets aurora kinase A (AURKA), inhibits growth of LN229 GBM cells, and potentiates chemosensitivity against temozolomide ^[9][25]. miR-124 targets NRAS, PIM3, and inhibits GSC proliferation and growth ^[10][26]. Neuropilin-1 (NRP-1) receptors are expressed in various cancers including glioma cells. miR-124 particularly targets NRP-1, as well as PI3K/Akt/NFkB signaling pathway, which inhibits tumor progression ^[11][27]. Upregulation of p62 oncogene is targeted and inhibited by miR-124-3p and serves as a novel therapeutic molecule to control glioma cell progression ^[12][28]. miR-124 directly interacts and inhibits the signal transducer and activator of transcription 3 (STAT3) signaling pathway and acts as an immuno-therapeutic molecule in the GSC tumor microenvironment. Upregulation of miR-124 acts as a potent anti-tumor agent and inhibits GBM cell invasion ^[13][29]. Syndecan binding protein (SDCBP) was widely distributed in intracellular proteins containing physiological and pathological role in cancers. miR-124-3p upregulation depletes the SDCBP expression and inhibits the proliferation, migration, and invasion of GBM ^[13][29].

Pilocytic astrocytoma, a common pediatric cancer type, is associated with a high mortality rate and poor prognosis. Irregular expression of miR-124 was identified in pilocytic astrocytoma tissues compared to healthy brain tissues. There is a proven correlation between miR-124 downregulation and pilocytic astrocytoma ^[14][30]. miR-124-3p has emerged as a potential biomarker and an effective therapeutic molecule for the treatment of ependymomas by targeting tumor protein p53 nuclear protein 1 (TP53INP1) ^[15][31]. In medulloblastoma, miR-124 was expressed 6.5-fold lower than in normal cerebellum [4]. miR-124 acts as a tumor suppressor gene in medulloblastoma pathogenesis by inhibiting cell cycle progression in the G₀/G₁ phase without affecting apoptosis, slows down tumor growth by targeting CDK6 proto-oncogene, and inhibits cell proliferation in DAOY and D283 cells and solute carrier family 16 (SLC16A1) ^[16][32]. Several transcriptional factors such as SOX9, Forkhead box protein G1 (FOXG1), and MEIS1 are regulated by miR-124 in medulloblastoma ^[17][33]. The nuclear receptor Nur77 is upregulated in medulloblastoma, thus acting as an oncogene promoter by inducing cell proliferation and tumor spheroid size. Modulating miR-124 to physiological levels suppressed the Nur77 and prevented cancer progression ^[18][34]. miR-124 thereby is considered a promising therapeutic miR in medulloblastoma patients with elevated Nur77 protein.

miR-124 is highly enriched in primary CNS lymphoma ^[19][35]. miR-124 was aberrantly expressed in the pituitary adenoma ^[20][36]. miR-124 suppressed the migration and invasion of pituitary adenoma cells by targeting FSCN1, pituitary tumor-transforming gene 1 protein-interacting protein (PTTG1IP), and Ezrin (EZR) ^[21][37]. Targeting miR-124 could potentially play a key role in various neurological cancers including GBM.

Breast Cancer (BC) is a very prevalent in women and is associated with high morbidity and mortality rates. BC has a high metastatic potential affecting physical and psychological health. The expression of miR-124 has been found to be low in BC tissues, thereby promoting invasion and metastatic potential ^[22][38]. Transfection of miR-124 into MDA-MB-231 cells suppressed tumor cell progression and increased the sensitivity to chemotherapy ^[23][39]. The restoration of miR-124 to physiological levels improved survival outcomes in breast invasive carcinoma as compared with miR-124 low mammary carcinoma ^[24][40]. miR-124 suppressed the BC cells induced by bone metastasis via downregulating IL-11 ^[23][39]. CD151 is a tetraspanin family member that regulates cell development, growth, and motility. CD151 is over expressed in the BC cell lines MCF-7 and MDA-MB-231. miR-124 targets CD151 and inhibits rapid proliferation, suggesting that CD151 is a potential mediator for miR-124 mediated targeting of BC ^[25][41].

Studies revealed that CDK4 was a target for miR-124 in the MCF-7 cell line ^[26][42]. Restoration of miR-124 levels were found to lower cell proliferation, viability, and growth of BC ^[26][42]. Cell cycle was arrested in the G₁/S phase by miR-124 via EGFR signaling that further impedes cell proliferation in BC ^[27][43]. AKT2 is a potential biomarker and is targeted by miR-124 in ERα-positive BC cells ^[25][41]. Ets-1 is an oncoprotein that regulates tumor progression and survival in BC. ETS-1 is a potential target for miR-124 and controls the growth of BC cells ^[28][44]. Flotillin-1 (FLOT1) is a novel target for miR-124. miR-124 is considered to be a tumor suppressor protein via regulation of FLOT1 protein. FLOT1 is overexpressed in BC and is inhibited by miR-124 and control cell proliferation and migration ^[23][39]. Doxorubicin resistance was reversed by miR-124 via the STAT3/HIF-1 signaling pathway ^[23][39]. miR-124 level was downregulated in BT474, SKBR3, and MCF7 via monocarboxylate transporter 1 (MCT1) (SLC16A1)-mediated glucose metabolism in BC cell lines. Transfection of miR-124 into these cells depletes Taxol-resistance and aids the killing of cancer cells ^[29][45]. These studies demonstrate the potential role of miR-124 to target breast cancer.

Hepatocellular carcinoma (HCC) is a liver tumor which accounts for over 90% of primary liver tumors. Hepatocellular carcinoma occurs in approximately 85% of patients diagnosed with cirrhosis ^[30][46]. Hepatocellular cancer (HCC) is another prevalent cancer with a high mortality rate. HCC is now the fifth most widespread form of cancer worldwide. Additionally, among men, it is the second leading cause of cancer-related deaths, behind lung cancer ^[31][47]. Previous studies have demonstrated that expression of miR-124-3p is lower in hepatocellular carcinoma (HCC) as compared to that of healthy hepatocytes ^[32][48].

Sorafenib is a multi-kinase inhibitor frequently used to treat patients with advanced hepatocellular carcinoma (HCC). Resistance to sorafenib is a significant hindrance to the treatment’s efficacy. miRNA-124-3p.1 has been found to sensitize HCC cells to sorafenib-induced apoptosis through the regulation of FOXO3a phosphorylation as well as deacetylation by targeting AKT2 and SIRT1 ^[33][49]. Aquaporin 3 (AQP3) is a type of aquaporin located in the plasma membrane of cells. In HCC, AQP3 is often overexpressed, leading to the promotion of stem cell-like properties in hepatoma cells by regulating CD133. Additionally, AQP3 is a direct target of miR-124 and its expression can be suppressed through enrichment of miR-124 ^[34][50].

Sp1 protein and integrin αV were directly targeted by miR-124, which plays a role in cell migration and invasion; this is demonstrated in SMMC-7721 and BEL-7404 cells ^[35][51]. HepG2 cell proliferation was inhibited via miR-124 transfection by targeting STAT3 protein. Overexpression of miR-124 initiated HCC apoptosis ^[36][52]. miR-124 restoration in HCC leads to cell cycle arrest in G₁ phase, affects cell proliferation, and reduces tumorigenesis ^[36][52]. In HCC cells, miR-124 reduces the activity of cancer susceptibility candidate 3 (CASC3) and deactivates key molecules involved in cell proliferation, such as extracellular signal-regulated kinase (ERK), MAPK, p38, phosphoinositide 3-kinase catalytic subunit alpha (PIK3CA), and CD151. miR-124-3p expression is associated with changes tumor size and its potential as a biomarker has been demonstrated in ^[37][53]. Studies have indicated that patients with CD133+ HCC are resistant to chemotherapy. By restoring miR-124, CD133+ HCC were responsive to cisplatin therapy, leading to apoptosis through the targeting of the SIRT1/ROS/JNK pathway ^[38][54]. miR-124 inhibited tumorigenesis and progression in HCC by targeting Kuppel-like factor 4 (KLF4) ^[39][55].

More than 85% of lung cancers (LC) have been identified as non-small-cell lung cancer (NSCLC). In NSCLC, miR-124-3p significantly suppressed metastasis through extracellular exosome transport and intracellular PI3K/AKT signaling ^[40][56]. miR-124 targets disintegrin and a metalloproteinase 15 (ADAM 15), which are related to several cellular regulations, including metastatic progression. miR-124 inhibits ADAM15 and prevents NSCLC invasion. NSCLC cell invasion and migration are actively inhibited by miR-124 via repressing zinc finger E-box binding homeobox 1 (ZEB1) ^[41][57]. Overexpression of miR-124 inhibits SOX9 and controls cell proliferation and migration in lung adenocarcinoma ^[42][58]. miR-124 acts as a tumor suppressor and inhibits cancer cell proliferation by targeting oncogenic CD164 and Cadherin-2 (CDH2) signaling pathways in NSCLC ^[43][59]. Gefitinib resistance is a threat for NSCLC patients and low expression of miR-124 has been linked to gefitinib resistance in NSCLC patients. Upregulation of miR-124 in NSCLC inhibits SNAI2 and STAT3 and reverses gefitinib resistance in NSCLC, thus acting as a prognostic factor ^[44][60]. miR-124 controls the cellular glycolysis and metabolism processes via targeting AKT1/2–glucose transporter 1/hexokinase II in NSCLC ^[45][61]. Rab27A gets targeted by miR-124a and inhibits lung cancer cell lines like PC9 and H1299 ^[46][62]. HOXA11-AS expression was upregulated in A549 lung cancer cells and contributes to tumor size enlargement and lymph node metastasis. miR-124 reverses the HOXA11-AS expression in the lung cancer cell and halts tumor progression ^[47][63].

miR-124 disturbs autophagy and reduces cell survival by depleting p62, which is an autophagy regulator of the transcription factor NF-kB in the KRAS mutant NSCLC patients ^[48][64]. miR-124 represses autophagy by targeting sirtuins 1 (SIRT1) and improves the cisplatin sensitivity against NSCLC ^[49][65]. LIM-homeobox domain 2 (LHX2) plays an essential role in cell proliferation and differentiation. The aberrant nature of LHX2 has been associated with cancer and promotes irregular cell proliferation. In NSCLC, LHX2 is upregulated which in turn promotes cell growth in A549 and H1299 lung cancer cells. miR-124 represses the LHX2 expression and inhibits migration, invasion, and arrests the cell cycle at the G1 phase in NSCLC ^[50][66]. MYO10 expression is inhibited by miR-124 by regulating NF-kB and depletes cell migration in NSCLC ^[51][67]. miR-124 is a tumor suppressor in lung adenocarcinoma associated with epithelial-to-mesenchymal (EMT) phenotypes and targets the enhancer of zeste homolog 2 (EZH2) to suppress lung cancer cells like A549, H1299, SPC-A1, and H1975 ^[52][68].

Cervical cancer (CC) is associated with high morbidity and mortality in women. miR-124 is downregulated in CC cell lines HeLa and SiHa ^[53][69]. Astrocyte-elevated gene-1 (AEG-1), an oncogene, is involved in tumor progression and chemotherapy resistance. Studies found that AEG-1 has been upregulated in CC patients. miR-124 targets AEG-1 and inhibits cell proliferation and migration, in addition to invasion ^[54][70]. Restoration of miR-124 suppresses the inhibitor of apoptosis-stimulating protein of p53 (iASPP) and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) expression and attenuates the CC cells’ growth and invasions ^[55][71].

In colorectal cancer (CRC), miR-124-3p.1 inhibits the CRC cells like HCT116, and suppresses cell proliferation and migration along with invasion via downregulation of AKT3 ^[56][72]. miR-124 inhibits CRC cell growth via targeting DNA methyltransferase 3B (DNMT3B) and DNMT1. miR-124 modulation increases radiosensitivity, targets paired related homeobox 1 (PRRX1), and inhibits the growth of CRC cell lines SW480 and SW620 ^[57][73]. miR-124 targets STAT3 and represses CRC cell proliferation and growth ^[58][74].

Pancreatic ductal adenocarcinoma (PDAC) progression can be halted by miR-124 modulation that targets monocarboxylate transporter-1 (MCT-1), integrin α3 (ITGA3), and integrin β1 (ITGB1). miR-124 presents as a therapeutic biological strategy to treat PDAC ^[59][75]. Expression of miR-124 was lower in various PDAC cells like AsPC-1, PANC1, and SW1990. Exogenous transfection of miR-124 into these cells suppressed the metastatic potential and induced apoptosis ^[60][9]. miR-124 can act as a diagnostic tool in PDAC patients ^[61][12]. miR-124 targets Ras-related C3 botulinum toxin substrate 1 (Rac1) and inactivates the MKK4-JNK-c-Jun pathway. This inhibits the proliferation and invasion of pancreatic cancer cells (PCC). miR-124 inhibits MCT1 leading to cell acidification, which represses PCC [4].

Gastric cancer is the fourth highest cause of cancer-related deaths globally. Unfortunately, patient outcomes are often unfavorable due to the recurrence of tumors and metastasis. Previous studies have shown that a rise in HRCT1 expression is a clear indication of poor prognosis among individuals diagnosed with gastric cancer. HRCT1 actively promotes tumor growth by activating the ERBB2-MAPK pathway. Furthermore, it has been found that HRCT1 is negatively regulated by miR-124-3p ^[62][76].