Cancer metastasis is responsible for a significant portion of cancer deaths, and treatments are inadequate, and breast cancer (BC) is no exception (95). About 15% of patients with BC have distant metastases, usually to the brain, liver, lungs, and bones, and 90% of these people will die of metastasis (96, 97). Nevertheless, the processes behind metastatic dissemination remain unknown and represent a significant obstacle to the treatment of BC. In women, BC is the most common type of cancer worldwide (95). BC currently affects approximately 1.7 million individuals worldwide, significantly affecting public health (95). In BC, it was discovered that the expression of miRNAs was altered in different mechanisms of tumorigenesis by modulating different components in distinct signal transduction (98). Several miRNAs, including components of the miR-200 family, are associated with critical pathways of cancer development, including EMT and metastasis in BC (99). It has been found that miR-128-3p can reduce proliferation, differentiation, and motility in BC cells (58). Meanwhile, upregulation of miR-128-3p may affect cell cycle stages by suppressing the production of CDK2/Cyclin E1 and CDK4/6/Cyclin D1. Furthermore, it was found that miR-128-3p may suppress the LIM domain kinase 1 (LIMK1) signaling pathway in BC by targeting the LIM domain kinase 1 (LIMK1) gene (58). These findings point to a novel regulatory mechanism of miR-128-3p-LIMK1/CFL1 in BC, which may lead to new therapeutic approaches for BC.

Metastasis-related miRNAs acting as favorable or unfavorable regulators are known as “metastamirs” (100). Cao and colleagues showed that miR-128, a metastamir, significantly decreased expression levels in human BC samples, which was inversely related to tumor grade, with decreased expression levels higher in grade III (95). A significant correlation was reported in highly aggressive BC cell lines that showed relatively low expression levels of miR-128 (95). Wound healing assays, traditional or dynamic transwell invasion and migration assays, and other functional investigations revealed that aberrant expression of miR-128 in MDA-MB-231 cells [a triple-negative breast cancer (TNBC) cell line] significantly decreased cell migration and invasive potential (95). Moreover, Metadherin (MTDH), an oncogene that regulates bioactivities including apoptosis, longevity, cell metabolism, and revascularization, was discovered to be a specific target gene of miR-128 and is implicated in the miR-128-mediated reduction of initiation and progression in BC cells (95). These data show that miR-128 plays an essential part in BC metastasis and might be a prospective candidate for anti-metastasis treatment.

TNBC is a variant of BC responsible for about 15% of all cases of BC (101). Xiao and colleagues discovered that reduced expression of miR-128 was associated with a shorter lifespan and disease-free survival in TNBC patients but not with a significantly shorter lifespan (66). The finding that limited lifespan in TNBC is associated with reduced miR-128 expression suggests that the involvement of miR-128 in TNBC is consistent with a tumor suppressor, and miR-128 suppressor targets may be oncogenic (66). The involvement of miR-128 in TNBC cells decreased glucose metabolism and inhibited cell growth. It is important to note that glucose metabolism in tumor cells significantly affects cell proliferation. It is unclear whether the reported suppressed cell proliferation is caused by low glucose metabolism or a logical consequence of miR-128 upregulation. However, the finding that miR-128 inhibits the growth of TNBC cells is consistent with the decreased expression of miR-128 in TNBC tissues (66). According to the results of this research, miR-128 may be a suitable biomarker and treatment option in people with TNBC.

Wnt signaling pathways are related to stem cell growth, self-renewal, and migration. They are commonly considered a target for treating several tumor types (102). Activation of the Wnt signaling pathway may promote the cancer growth of BC cells (103). NIMA-related kinase 2 (NEK2) is a type of mitotic kinase involved in tumorigenesis and cancer progression (64). Overexpression of NEK2 in various types of cancer suggests that it could be a potential anticancer drug target (104). Furthermore, a previous study showed that BC’s NEK2 expression is often overexpressed (105). However, both miR-128-3p and NEK2 have been investigated in BC progression, and their exact function in this disease is currently unknown (106, 107). Consequently, Chen and colleagues studied the association between miR-128-3p and NEK2 and its contribution to BC progression in research (64). They discovered that by reducing NEK2 expression, miR-128-3 might reduce stem cell properties such as division, motility, invasion, and self-renewal in BC stem cells (BCSCs) ( Figure 2 ). Recent research showed that overexpression of miR-128-3p reduced BCSC development, motility, and invasion by downregulating the Wnt signaling pathway through downregulating NEK2 expression (64). This work established the promising clinical function of miR-128-3p and NEK2 in treating BC through modulating the Wnt signaling pathway. However, the research is still in its early stages, and more research on the molecular mechanism is needed. With increasing technology and a deeper understanding of cancer pathogenesis, more tumor-associated genes have been discovered, potentially providing new targets for therapeutic agents (108). These are hypermethylated in cancer 1 (HIC1), which encodes a transcriptional repressor with multiple partners and targets and is involved in various cancer functions, including cell longevity, proliferation, and migration (109, 110). HIC1 is consistently suppressed in human malignancies such as BC, PC, CC, lung, and liver cancer, thought to be due to promoter hypermethylation (110–113). In their investigation, Li and colleagues discovered that miR-128 was highly elevated in BC tissues (61). Their results suggest that miR-128 could function as an oncomiR in the etiology of BC. Mechanistic studies revealed that miR-128 might effectively bind the 3 untranslated regions (3’-UTR) of HIC1, downregulate its expression, enhance invasion and metastasis, and block apoptosis in BC cells (61). More importantly, restoring HIC1 expression with enhancer plasmids restored miR-128-induced cellular phenotypes, implying that HIC1 targeting is a major determinant through which miR-128 exerts its oncogenic effect. Furthermore, miR-128 control of HIC1 might elucidate, at least in some part, how miR-128 overexpression increases cell invasion and metastasis while inhibiting apoptosis in BC (61a). In conclusion, our findings point to a novel axis consisting of HIC1 and miR-128 that may lead to BC development and provide new possible directions for future BC therapy.

Lung cancer is a complex disease classified as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) based on pathophysiological features, and NSCLC accounts for 80-85% of all lung malignancies (67). As previously mentioned, dysregulation of miR-128 expression has been documented in various types of human cancers, suggesting that it plays an important role in carcinogenesis, and its role has been explored from tumor suppressor to tissue protumor. Accordingly, it has been found that mutant p53 induces miR-128-3p and its host gene ARPP-21, leading to p53 mutation-mediated chemoresistance in NSCLC and an oncogenic function for miR-128-3p shows in lung cancer (71). Donzelli and colleagues (71) observed that expression of miR-128-2 in lung cancer cells reduces cell apoptosis and induces tolerance to 5-fluorouracil, cisplatin, and doxorubicin treatments. miR-128-2 post-transcriptionally targets E2F5, leading to the loss of its inhibitory function on p21waf1 transcription (71). p21waf1 protein is found in the cytoplasm and has an anti-apoptotic effect by preventing the degradation of procaspase 3 (71). The above findings imply that miR-128-2 regulation promotes mutant p53His175 gain-of-function activities by increasing the multidrug resistance of lung cancer cells.

In a study, Frixa and colleagues showed that miR-128-3p has a direct and suppressive binding effect on Drosha and Dicer 3’-UTRs, leading to an overall downregulation of miRNA expression in NSCLC cells (72). The overexpression of miR-128-3p lowers the abundance of miRNAs targeting important EMT elements, which eventually enhances the aggressive capabilities of the cells transfected (72). In addition, reintroducing Drosha to such a cellular environment led to the restoration of migratory phenotypes, suggesting that Drosha plays an essential function in regulating lung cancer cell motility (72b). These results suggest that miR-128-3p-mediated deletion of Drosha and Dicer transcription may lead to the growth and metastasis of lung cancer cells by indirectly affecting the levels of several functional miRNAs.

Hu and colleagues discovered that miR-128 expression was highly diminished in tissues and cells of NSCLC and was strongly associated with NSCLC differentiating lymph node metastasis and cancer stage (25). The overexpression of miR-128 remarkably decreased in vitro growth, invasion, migration, and colony formation of NSCLC cells and triggered G1 arrest and death. Remarkably, miR-128 dysregulation dramatically inhibited the expression of vascular endothelial growth factor (VEGF)-C as well as reducing the activity of a luciferase reporter, including the untranslated domain of VEGF-C ( Figure 3 ) (25). Moreover, upregulation of miR-128 in NSCLC and human umbilical vein endothelial cells (HUVECs) resulted in decreased expression of VEGF-A, VEGF receptor (VEGFR)-2, and VEGFR-3, all of which are important factors in cancer lymphangiogenesis and tumorigenesis, as well as decreased phosphorylation of the phosphatidylinositol 3-kinase and extracellular signal-regulated kin (ERK) (25). Additionally, they discovered that restoring miR-128 in vivo significantly reduced the invasion and metastasis of A549 cells in nude mice and decreased both lymphangiogenesis and revascularization in tumor xenografts (25a). The above data support the hypothesis that miR-128 may have a function in NSCLC carcinogenesis, partly through the modulation of lymphangiogenesis and angiogenesis by targeting VEGF-C and concurrently blocking ERK, protein kinase B (PKB), also known as Akt, and p38 signal transduction pathways. Targeted therapies to reestablish miR-128 in NSCLC may be effective in inhibiting tumor development.

Notably, miR-128-3p antagonism profoundly affects metastasis and chemoresistance in aggressive phenotype NSCLC cells, which can be entirely reversed by restoring Wnt/β-catenin and TGFβ-activities, revealing that miR-128-3p might be a candidate for both tumor growth and chemoresistance in NSCLC (69b). In the current work, Cai et al. induced a model of NSCLC xenografts (chemoresistance-associated cancer progression). They showed that in several NSCLC cell lines, cancer stem cell (CSC) programming and EMT are driven by miR-128, which indicates tumorigenesis, chemoresistance, and disease progression through simultaneous activation of β-catenin and TGF-β signaling (69b). Remarkably, they discovered that reactivation of TGF-β and Wnt/β-catenin signaling pathways restored the antagonistic action of miR-128-3p on chemoresistance and proliferation in highly aggressive NSCLC cells (69b). As a result of these discoveries, it is possible to block both pathways simultaneously by targeting a single molecule to improve chemoresistance and metastasis in NSCLC.

According to the literature, miR-128-3p expression is decreased in lung cancer tissue compared to normal tissue (114). Nevertheless, the therapeutic significance of this miRNA in the early detection of lung cancer is unknown. Pan and colleagues discovered that the expression levels of miR-33a-5p and miR-128-3p were decreased in lung cancer cell lines and tissues (115). They identified that the expression levels of miR-33a-5p and miR-128-3p in lung cancer tissues were substantially linked with the tumor, node, and metastasis (TNM) grades. Significantly, the levels of miR-128-3p and miR-33a-5p in the blood of patients with lung cancer or initial lung cancer subjects (TNM grade I-II) were lower than in normal participants (115). Receiver operating characteristic curve (ROC) analysis revealed that miR-33a-5p and miR-128-3p, alone or in combination, had higher AUC scores and enhanced sensitivity/specificity than conventional biomarkers in their study (115). Remarkably, although under severe conditions, miR-128-3p and miR-33a-5p were very stable in blood. These findings suggest that miR-33a-5p/miR-128-3p in the blood may be used as new markers for lung cancer diagnosis. Mitomycin C (MMC), a potent DNA cross-linker, acts against NSCLC, a process that requires interstrand DNA cross-linking to inhibit the replication and proliferation of malignant cells (116). Although II Sp is involved in the repair of DNA interstrand cross-links (DNA ICLs) as a structural protein, the interaction between miRNAs and SPTAN1 in DNA repair and the potential role of MMC in suppressing tumor cells are unknown. Zhang et al. revealed a unique function for miR-128-3p in MMC-exposed lung cancer cells, where chromosomal viability and cell cycle progression are regulated through SPTAN1 (116).

In summary, these findings add to our understanding of the dynamics of miR-128-3p in lung cancer sensitivity to chemotherapy. The miR-128-3p-SPTAN1 axis opens up a new window into the chemosensitivity process, and miR-128-3p may be a possible molecular candidate to improve the lung chemotherapy process. Finally, while these studies have shown that miRNA deregulation is responsible for chemoresistance, the function of miRNAs in controlling CSC chemoresistance is unclear. In this regard, Jiang et al. discovered that in lung cancer cells, the expression of miR-128 is reduced, which is associated with gefitinib tolerance in these cells (68). Increased expression of miR-128 was later reported to increase PC9-CSC sensitivity to gefitinib, thus limiting the efficacy of gefitinib in enhancing the CSCs population in vitro and in vivo (68). Furthermore, they discovered that gefitinib did not inhibit the Phosphoinositide 3-kinase (PI3K)/AKT pathway in PC9-CSCs.These results suggest that the miR-128/c-met axis improves gefitinib susceptibility in lung cancer stem cells by inhibiting the PI3K/AKT axis.

Thyroid cancer is a frequent endocrine cancer that has been rising globally over the last several decades (117). Follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC) (well-differentiated), and also anaplastic thyroid carcinoma and imperfectly differentiated, are the histotypes of thyroid cancer (118, 119). Despite substantial research on the role of genetic defects and environmental variables in thyroid tumorigenesis, the specific molecular pathways behind the development of thyroid malignancy remain unclear. Cao and colleagues discovered that miR-128 expression was significantly decreased in tissue and several human PTC and FTC cell lines (86). Restoration of miR-128 activity in PTC and FTC cells significantly reduced cell survival, motility, and invasion. In addition, upregulation of miR-128 induced cell cycle arrest in G0/G1 phase and apoptosis. Sphingosine kinase 1 (SPHK1) was also a primary target of miR-128 (86). SPHK1 regulates cellular activities and tumorigenesis, including reproduction, apoptosis, and proliferation (120). Cao et al. found an inverse correlation between SPHK1 and miR-128 expression in FTC and PTC samples, and luciferase reporter assays and RT-qPCR analyzes showed that miR-128 downregulates SPHK1 expression by targeting its 3’UTR (86). In addition, they discovered that up-regulated miR-128 suppressed cancer growth in vivo and was found to be a tumor suppressor in thyroid cancer. Also, recent research shows that 5-aza-20-deoxycytidine significantly increases the expression of miR-128 in thyroid cancer cell lines, suggesting that miR-128 plays a vital role in regulating thyroid cancer proliferation (86).

Furthermore, the researchers discovered that upregulation of miR-128 significantly increased apoptosis in thyroid cancer cell lines, primarily through overexpression of caspase-3 and polyadenosine diphosphate-ribose polymerase (PARP) was confirmed. Upregulation of SPHK1 inhibits miR-128-induced apoptosis, suggesting that SPHK1 may contribute to miR-128-regulated apoptosis (86). These findings showed that in PTC and FTC tissue or cells, the expression of miR-128 was decreased, and SPHK1 was increased. Based on functional experiments, apoptosis and cell cycle arrest in G0/G1 phase were observed after restoring miR-128 expression, which inhibited thyroid cancer progression and also reduced invasion and metastasis. SPHK1 has been discovered to be a primary target of miR-128. According to the findings, miR-128 might be a promising treatment target for thyroid prevention and therapy by decreasing SPHK1.

Anaplastic thyroid carcinoma (ATC) is an uncommon thyroid cancer characterized by rapid growth, extrathyroidal infiltration, and lymph node metastasis to the brain, lungs, and bones (121, 122). ATC has a significant mortality rate, with a median survival time of 5 months and 20% overall survival at one year (123). Human leukocyte antigen (HLA) complex P5 (HCP5) has recently been shown to be a tumor suppressor in the formation of PTC, which accounts for 80–85% of thyroid malignancies (124). On the other hand, the function of HCP5 in ATC is unclear. Chen et al. studied the expression of HCP5 in ATC and determined if HCP5 modulated miR-128-3p in ATC to control ATC cell survival and apoptosis. They found that the expression of miR-128-3p was decreased in the ATC cell line and tissue, and miR-128-3p was the substrate of HCP5 in ATC cells in further experiments (87). Chen and colleagues also found that HCP5 regulates miR-128-3p expression (87). Taken together, the HCP5/miR-128-3p axis plays a critical function in controlling the survival and death of ATC cells, suggesting that HCP5 can be used as a therapeutic approach for ATC operation.

Head and neck cancer (HNC) has become one of the malignancies whose prevalence has increased over the past decade, although survival rates have not increased significantly (125, 126). Squamous cell carcinoma (HNSCC) occurs in the epithelial lining of the nasopharynx, pharynx, larynx, and oral cavity, accounting for more than 90% of HNC (127, 128). Research demonstrates that miR-128 regulates E2 promoter-binding factor a (E2Fa), Bmi-1, and other regulatory regions, including transcriptional WEE1-A (a tyrosine kinase) that phosphorylates CDK1 to promote tumorigenesis (129). Overexpression of miR-128 suppresses HNSCC development by directly modulating its targets, Paip-interacting protein 2 (Paip2), BAG Cochaperone 2 (BAG-2), H3F3B, Bmi-1, and Bcl-2-associated X protein in proliferative and apoptotic processes, indicating that miR-128 acts as a tumor suppressor, in vitro and in vivo. Hauser et al. examined the function of miR-128 in the control of HNSCC development as well as its potential targets (91). They showed that almost all target mRNAs contain a complementary 3’UTR sequence that may pair with miR-128 to inhibit target mRNA translation and lead to decreased protein levels. Paip2, Bmi-1, and H3F3B proteins are involved in tumor growth, and downregulation of Bmi-1 and H3F3B expression reduces cancer growth and xenograft development in JHU-22 miR-128 cells (91). In addition, Hauser and colleagues discovered that JHU-13 miR-128 inhibited cell growth and confirmed the binding of miR-128 to the 3’UTR of BMI-1 mRNA (91). They also found that the expression levels of cell proliferation regulators were altered with lower protein levels of cyclin D1 and PCNA in JHU-22 miR-128 cells. Current findings suggest that miR-128 is involved in several signaling pathways related to the development and growth of HNSCC. Further research is needed to confirm the expression and activity of miR-128 in HNSCC as well as other pathogenic forms of human cancer. Bmi-1 has been found to contribute to laryngeal squamous cell carcinoma (LSCC) progression and maintain tumorigenic laryngeal growth, suggesting that miR-128 plays a tumor suppressor role in laryngeal cancer (130, 131). In addition, the involvement of miR-128 in this cancer should be confirmed. Wan and colleagues first reported that miR-128a expression is decreased in primary laryngeal cancer and that upregulation of endogenous miR-128a reduces cell growth and increases apoptosis in research (90). In conclusion, according to the latest research, miR-128a is significantly downregulated in LSCC. In addition, they discovered that the upregulation of miR-128a decreased the growth of laryngeal Hep2 cells and accelerated apoptosis (90). Moreover, miR-128a overexpression inhibited cancer progression in vivo. As a result, targeting miR-128a might be a unique strategy for treating LSCC.

Osteosarcoma (OS) is the most common type of bone cancer, accounting for 20% of primary bone tumors and the second leading cause of tumor-related deaths among young adults (132, 133). Survival rates remain low, with 80% of surgically treated patients experiencing recurrence or dissemination (134, 135). Consequently, it is important to investigate the molecular processes behind the overall development of survival and develop promising drug options for the treatment of survival rates. Zhang and colleagues investigated the physiological role of its long non-coding RNA (lncRNA) myocardial infarction-associated transcript (MIAT) in survival through miR-128-3p/VEGFC axis control in OS tissues and cell lines (88). It is generally understood that lncRNAs act as ceRNAs and regulate functional gene expression by sponge miRNAs (136). To confirm these findings, Zhang and colleagues used bioinformatics methods to predict MIAT-miRNA and dual luciferase reporter analysis to test the effect of target binding, and they discovered that MIAT is the primary target of miR-128-3p (88). Their findings showed that miR-128-3p transcription was significantly decreased in cell lines and tissues and inversely correlated with MIAT expression in survival rate. The above results suggest that miR-128-3p acts as an inhibitor of survival rate. They used DIANA and TargetScan v 7.2 techniques to predict the target genes of miR-128-3p and discovered that VEGFC is a possible predisposing factor of miR-128-3p.

In addition, recent research has shown that VEGF is a major downstream substrate of miR-128-3p and affects the growth of lymphatic endothelial cells (137). Zhang and colleagues showed that VEGFC expression was found to be negatively related to miR-128-3p expression in survival rate and validated that VEGFC was a primary target of miR-128-3p in MG63 cells, implying that there was a ceRNA circuit in OS between VEGFC, MIAT, and miR-128-3p (88). They showed that suppressing miR-128-3p diminished the effect of MIAT knockdown on VEGFC protein levels and the growth, apoptosis, and metastasis in MG63 cells. According to the findings of this research, the MIAT/miR-128-3p/VEGFC axis may be a unique prospective treatment method to improve the survival rate in OS.

About 20,000 new cases of glioma are diagnosed in the United States each year, and even with aggressive surgery, chemotherapy, and radiation therapy, the median survival for the most malignant type (glioblastoma) is approximately 14 months (74, 138). miRNA analysis has revealed different expression profiles in glioblastoma and other human malignancies (139). Several miRNAs have recently been discovered to have a significant function in glioblastoma. miR-7 expression was found to be decreased in glioblastoma, inhibiting the invasion and metastasis of primary glioblastoma lines, whereas miR-26 enhances glioblastoma cancer development in vitro and in vivo by attempting to target numerous tumor suppressor genes, including RB Transcriptional Co-repressor 1 (RB1) and Phosphatase and tensin homolog (PTEN) (140, 141). The majority of miR-128 research on tumorigenesis has focused on glioblastoma. For example, miR-128 is downregulated in glioblastoma (74, 139). Upregulation of miR-128 reduces cell proliferation by targeting the transcription factor E2F 3a (E2F3a) and Bmi-1 while blocking the Reel and Doublecortin (DCX) promoters reduce neuroblastoma cell migration and metastatic spread (24, 74, 139).

Shi et al. discovered that the miR-128 expression is reduced in glioblastoma and acts as a tumor suppressor by specifically targeting p70S6K1 (75). They determined that miR-128-induced transcription downregulated the expression of VEGF, p70S6K1, and Hypoxia-Inducible-Factor 1α (HIF-1α). Transformation of p70S6K1 restored miR-128-inhibited expression of HIF-1a and VEGF, indicating that p70S6K1 is a target of miR-128 (75). Furthermore, in their research, upregulation of miR-128 inhibited cell proliferation, tumor development, and revascularization in vivo. These findings add to our knowledge of the importance and process of miR-128 in glioblastoma pathogenesis and suggest a promising therapeutic approach for the treatment of glioblastoma.

According to a study carried out by Godlewski et al., miR-128 expression is downregulated in glioblastoma, and Bmi-1 is the primary target of miR-128 (74). Upregulation of Bmi-1 was observed in various types of cancer and is a potent stimulator of stem cell regeneration. Also, research on transgenic mice showed that Bmi-1 plays an essential role in the formation of glioblastoma (142–144). These findings show that the effect of miR-128 on glioblastoma cells is consistent with the reduction of Bmi-1 expression, including one with a reduction in self-renewal of glioblastoma stem cells, suggesting that miR-128 may have the potential for clinical translation of glioblastoma stem cells. Shang et al. observed that miR-128 expression was lower in glioblastoma specimens compared to the control group (78). Increased miR-128 expression suppressed U251 cell growth by targeting the RhoE gene at the translational level. The increase in RhoE expression restored the progressive effects of pre-miR-128 on growth and apoptosis in U251 cells (78).

In conclusion, abnormally produced miR-128 modulates apoptosis and reproduction in U251 cells, partially via inhibiting RhoE. These data imply that aberrant miR-128 expression is critical for glioblastoma cell death and growth. Additional studies in this area may help to develop new anti-glioma treatment techniques. Ye and colleagues indicated that the miR-128 expression in glioblastoma tissues was much less than in healthy brain tissues (76). miR-128 expression was associated with tumor volume and aggressiveness of glioblastoma in their study but not with the gender or age of glioblastoma patients. However, miR-128 upregulation induced apoptosis in U87 cells and high protein content of degraded Caspase-3, Bcl-2, and Bax (76). The researchers showed that miR-128 was clearly associated with NEK2 using a dual luciferase reporter gene assay, and additional investigations showed that upregulation of NEK2 partially restored the effect of miR-128 on glioblastoma cell death. These findings suggest that upregulated miR-128 prevents apoptosis in glioblastoma cells by targeting NEK2 and contributes to the occurrence and development of glioblastoma.

Qu and colleagues investigated whether and how abnormal expression of miR-128 might alter the metabolic activity of glioblastoma (145). They found that miR-128-3p inhibited lactate synthesis, elevated ROS, and impaired mitochondrial activity in glioblastoma cells by targeting Pyruvate Dehydrogenase Kinase 1 (PDK1). PDK1 is a critical enzyme in converting glycolysis into the tricarboxylic acid cycle by suppressing Pyruvate dehydrogenase and transforming oxidative phosphorylation to the Warburg process, which increases lactate production (145). Suppression of PDK1 expression decreased lactate and ATP levels, increased reactive oxygen species (ROS) formation, mitochondrial dysfunction, decreased cell proliferation, and increased cell death. Their findings indicated that the miR-128-3p/PDK1 axis is important in the metabolism and development of tumor cells (145). These data suggest that pharmacological efforts to control the Warburg effect, including inhibition of PDK1, might be a potential therapy for treating glioblastoma.

Glioblastoma is the most severe type of glioma and the most common invasive and lethal brain tumor in children and adults with a catastrophic prognosis (82, 146). The expression of Runt-related transcription factor 1 (RUNX1) is significantly higher in the mesenchymal subtype of glioblastoma and is strongly linked to the mesenchymal subtype initiated through miRNA-mediated pathways (147). Previous researchers reported that RUNX1 is involved in the aggressive nature of glioblastoma (148). A new study showed that the upregulation of RUNX1 can significantly enhance glioma growth and metastasis (149). It has also been observed that the downregulation of RUNX1 improves temozolomide sensitivity and suppresses glioblastoma growth (150). However, the regulation of RUNX1 expression in glioblastoma remains unknown. A growing body of data indicates that multidrug resistance protein 1 (MRP1), which is upregulated in cancers, modulates cellular chemoresistance, and temozolomide has been identified as a target of MRP1 (151, 152). In conclusion, Zhou and colleagues investigated the underlying mechanisms of temozolomide tolerance and discovered the miR-128-3p/RUNX1 pathway as a novel target for temozolomide tolerance in glioblastoma (82). They confirmed the oncogenic involvement of RUNX1 in glioblastoma cells and discovered miR-128-3p as a potent inhibitor of RUNX1. The researchers also discovered that RUNX1 upregulated MRP1 to induce temozolomide tolerance (82). These findings suggest that miR-128-3p/RUNX1/MRP1 axis modulates temozolomide resistance in glioblastoma cells, and these molecules may be used to regulate temozolomide responsiveness in glioblastoma.

ALL and AML are genetically distinct and arise from myeloid blood cells, lymphoid progenitors, or primary stem cells with multilineage potential (153, 154). Because the treatment and prognosis of ALL and AML are significantly different, ALL must be differentiated from AML in the evaluation (155, 156). While ALL and AML may be differentiated using appropriate morphologic, immunohistochemical, and immunological methods, the traditional clinical practice requires competent staff, and currently, no single test is sufficient to diagnose a patient (157). Mi and colleagues performed a genome-wide miRNA expression assessment in a breakthrough study to discover biomarkers for the diagnosis and treatment of ALL and AML and to provide insight into the unique pathways of leukemogenesis between ALL and AML (50). miR-223, miR-128b, miR-128a, and let-7b were the most significant and differentially expressed among the 27 miRNAs expressed between ALL and AML. miR-128a and -128b were significantly more abundant in ALL, while miR-223 and let-7b were significantly more abundant in AML. May and colleagues showed that overexpression of miR-128 in ALL was not associated with duplication of genomic loci compared to AML and normal control samples (50). However, researchers demonstrated that the methylation of CpG islands in the miR-128b promoter was much lower in ALL samples than in AML samples and that there was an inverse correlation between miRNA expression and CpG island methylation.

In conclusion, overexpression of miR-128 in ALLs versus AMLs was related to epigenetic changes, i.e., hypomethylation of CpG islands in the promoter region. Remarkably, Although miR-128 was expressed in almost every AML as well as normal control samples at a significantly reduced level compared to ALL samples, the degrees of miR-128 promoter methylation were almost identical in control subjects and subgroups of AML samples. This suggests that another process influencing expression may warrant further investigation (50). Overall, their work suggests that the expression characteristics of miRNAs such as miR-128 may reliably distinguish ALL from AML and that epigenetic regulation may significantly govern miRNA expression in acute leukemias.

MLL-AF4 ALL, caused by a symmetric translocation between MLL and AF4, accounts for approximately 50% of ALL cases in infants, 2% in children, and 5% to 6% in adults (158). Kotani and colleagues showed that reexpression of miR-128b rendered two MLL-AF4 ALL cell cultures susceptible to death with high and low doses of glucocorticoid and etoposide and serum deprivation (19). They discovered that several miRNAs, such as miR-128b and miR-221, are decreased in MLL-rearranged ALL primary cell samples in comparison to other types of ALL (19). Given their fundamental involvement in virtually all ALL therapies, the mechanism by which glucocorticoids act on their target cells and the molecular pathways that confer glucocorticoid resistance remain largely unknown. In conclusion, miR-128b and miR-221, which restore steroid sensitivity, may provide a clear picture of the process of glucocorticoid activity. Administration of miR-128b and miR-221 to MLL-AF4 ALL leukemia cells via a carrier, including a suitable liposome, could complement conventional chemotherapy. Most importantly, these two miRNAs work together to induce chemoresistance. Two chimeric mRNAs, AF4-MLL and MLL-AF4, caused by the disease-causing t(4;11) chromosomal translocation, are two key targets of miR-128b (158). Their findings suggest that miR-128b and miR-221, especially miR-128b, play important roles in lymphoid biosciences. Most importantly, the effects of miR-128b and miR-221 on drug resistance are additive, suggesting that the binding of these miRNAs is a suitable target for treating diseases.

Multiple myeloma is a frequent hematologic malignancy with a significantly higher incidence and mortality rate than non-Hodgkin’s lymphoma (89). Despite recent advances in traditional chemotherapy and stem cell transplantation, the five-year survival rate for people with multiple myeloma remains poor. Consequently, a thorough knowledge of the putative mechanistic interactions involved in multiple myeloma at the genomic/transcriptional levels is essential.