In different cancers, miR-1908 has different regulatory effects on cell proliferation. miR-1908 promotes cell proliferation in glioma, hMADS cells, breast cancer, and human SSCs while inhibiting cell proliferation in NSCLC and chordoma. In addition, there are still inconsistent results regarding the effect of miR-1908 on cell proliferation in osteosarcoma.

miR-1908 can promote cell proliferation by targeting 11 genes, including PTEN, SPRY4, ID4, LTBP4, GPM6B, RGMA, EFCAB1, ALX1, OSR1, PPAPA, and KLF2. As shown in Figure 2 , miR-1908-5p can target the tumor suppressor gene PTEN, activate the PI3K/AKT signaling pathway, and then promote the proliferation and angiogenesis of 12 types of glioma cells including A127 (8). At the same time, it can also target SPRY4, promote the expression of the proto-oncogene RAF1, and further promote the development of glioma (13). In hMADS cells, miR-1908-5p can induce cells in the G1 phase to enter the S phase, thereby promoting the proliferation and growth of hMADS cells (33). miR-1908-3p promotes the proliferation of breast cancer MCF-7 cells by inhibiting the expression levels of 8 target genes such as ID4 (37). miR-1908-3p promotes the long-term non-tumorigenic proliferation of human SSCs by targeting KLF2, reflecting that miR-1908-3p is a regulatory factor that maintains the stemness of human SSCs (30).

miR-1908 can inhibit cell proliferation by targeting genes such as AKT1S1, PP5, TGF-β1, and JunD. In most cancers, high expression of miR-1908-5p usually promotes cancer cell proliferation. However, the expression level of miR-1908-5p is decreased in non-small cell lung cancer (NSCLC). In a mildly hypoxic environment, miR-1908-5p targets AKT1S1 to up-regulate the expression of marker genes in the RP/p53/p21 signaling axis and inhibit the proliferation of NSCLC cells (including SK-MES-1, A549, and NCI-H460) (22). Experimental results in athymic mice and SPC-A1 cell lines show that miR-1908-5p targets PP5 and inhibits the proliferation of NSCLC cells (23). In addition, as shown in Figure 2 , in chordoma, miR-1908-5p can target TGF-β1 and JunD, inhibit the MAPK signaling pathway, and thereby hinder the proliferation of cancer cells (6).

In osteosarcoma, the effect of miR-1908 on cancer cell proliferation still has inconsistent results. miR-1908-5p can activate the PI3K/AKT signaling pathway by inhibiting PTEN, thereby promoting the proliferation of osteosarcoma cells (143B, MG63, SAOS2, and U2OS) (9). But on the contrary, another study found that miR-1908-5p can target ROCK1, thereby inhibiting the proliferation of osteosarcoma cells (HOS, MG293, G63, SAOS2, and U2OS) (38). In the future, more rigorous research is needed to clarify the reasons for the inconsistent results of miR-1908 in osteosarcoma.

Cell differentiation can produce cells with different structures and different functions (41). miR-1908-5p can target and inhibit the expression of EXO1, PLIN4, and STAT3, and indirectly hinder the transcription of PPARγ and C/EBPα genes, thereby promoting the differentiation of bone marrow mesenchymal stem cells, adipocytes, CD4⁺ T cells, and hMADS cells. In patients with type 2 diabetes (T2DM), miR-1908-5p can target EXO1, thereby inhibiting the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells, thereby increasing the risk of fractures (20). Lipid droplets (LD) are an important subcellular organelle, which has the function of storing neutral lipids and replenishing energy by releasing fatty acids. During the formation of LD, miR-1908-5p targets PLIN4, which is involved in adipocyte differentiation (31). In RA, miR-1908-5p is down-regulated by competitive inhibition of lncRNA HOTTIP. Overexpression of miR-1908-5p can target STAT3 and inhibit Th17 cell differentiation, leading to a decrease in the proportion of Th17 cells and an increase in the proportion of Treg cells in the CD4⁺ T cell population, and then reduce inflammation (19). In another study, miR-1908-5p can promote the growth of hMADS cells, and inhibit the differentiation of adipocytes by blocking the transcription of adipogenesis-determining genes PPARγ and C/EBPa (33).

Apoptosis is a programmed death triggered by multiple biological factors and mediated by multiple signaling pathways (42). Phagocytosis and clearance of apoptotic cells by macrophages are killed by caspase family proteins, avoiding the release of intracellular components and inflammatory factors (43). Apoptosis defect is closely related to the occurrence and development of cancer and the resistance of cancer cells to chemotherapeutic drugs (44, 45). Apoptosis plays a very important role in a variety of tumors (45).

miR-1908-5p can simultaneously target the anti-apoptotic protein PP5, and inhibit the pro-apoptotic protein Bax, thereby playing a dual role in regulating apoptosis. In EOC, miR-1908-5p can significantly increase the apoptosis of two cell lines A2780 and SK-OV-3 (28). The anti-apoptotic protein Bcl-2 strictly controls the entry of cytochrome c from the mitochondrial intermembrane space into the cytoplasm by regulating the expression level of the effector protein Bax (46). Cytochrome c released into the cytoplasm can promote the generation and activation of apoptotic bodies, and further facilitate the maturation of caspase family proteins, and promotes apoptosis (47). In glioma, miR-1908-5p can promote the expression of anti-apoptotic protein Bcl-2 and down-regulate the expression of pro-apoptotic protein Bax, thereby inhibiting the activation of apoptotic body pathway and the level of caspase family proteins, enhancing the anti-apoptotic capacity of U251 cells (13). In NSCLC, miR-1908-5p promotes SPC-A1 cell apoptosis by targeting the anti-apoptotic protein PP5 (23).

Tumor metastasis is an invasion-metastasis cascade process. Its main steps are divided into the local invasion and breakthrough of the basement membrane by cancer cells, intravasation and invasion of blood vessels and lymphatic vessels, and then the process of proliferation, proliferation, and colonization, and finally the formation of secondary tumors (48, 49). Tumor metastasis is an important reason for the high recurrence and mortality of cancer (50). miR-1908 regulates the invasion and metastasis of various cancer cells by regulating the expression of target genes.

Among the target genes of miR-1908-5p, PTEN, DNAJA4, ApoE, and HDAC10 were associated with cancer cell invasion and metastasis. In glioma and osteosarcoma, miR-1908-5p activates the PI3K/AKT signaling pathway by targeting the tumor suppressor gene PTEN and promotes cancer cell proliferation, invasion, spheroid formation, and angiogenesis (8, 9). In glioma, activation of AKT/FOXO3a and AKT/mTOR signaling pathways mediates the promotion of miR-1908-5p on the malignant phenotype of glioma cells U87. As shown in Figure 3 , in melanoma, miR-1908-5p can target DNAJA4 and ApoE to promote the invasion and metastasis of MeWo-LM2 cells. Among them, DNAJA4 can positively regulate ApoE, and extracellular ApoE can target the LRP1 receptor of melanoma cells and the LRP8 receptor of endothelial cells, thereby inhibiting cancer cell invasion, metastasis, colonization, and endothelial recruitment (35). In cervical cancer, miR-1908-5p promotes metastasis and colony formation of Ca-Ski, SiHa, and C-4I cancer cells by targeting HDAC10 (26). In breast cancer, miR-1908-3p promotes the invasion and metastasis of breast cancer MCF-7 cells by targeting eight genes including ID4, thereby promoting the progression of breast cancer (37).

Extracellular vesicles (EV) are micro-membrane vesicles actively released by cells, and they are an important carrier for cell-to-cell communication. miR-1908 can regulate cell secretion of EV. In prostate cancer (PCa) tissues, the expression level of spermidine synthase (SRM) is elevated. SRM can promote EV secretion in 22Rv1 cells, thereby regulating the cancer microenvironment and promoting cancer progression. miR-1908-5p can target SRM to regulate EV secretion and inhibit the pathogenesis of PCa (29). Exosomes are a type of EV, a new type of mediator for tumorigenesis and immune escape. In nasopharyngeal carcinoma (NPC), miR-1908-5p is overexpressed in TW03 (EBV-) cell exosomes, which can down-regulate the MARK1 signaling pathway, thereby promoting the proliferation and differentiation of NPC cells (21).

MiR-1908 plays a role in many aspects of cancer biology, including proliferation, apoptosis, invasion and metastasis, and angiogenesis, and plays an important role in the occurrence and development of cancer. Abnormally high expression of miR-1908 can promote the development of glioma, cervical cancer, PCa, chordoma, melanoma, and breast cancer, but it inhibits the risk of NSCLC. In addition, the role of miR-1908 is inconsistent in osteosarcoma. The relationship between miR-1908 and cancer susceptibility is race-specific (53).

MiR-1908-5p promotes the proliferation, differentiation, invasion, and metastasis of glioma cancer cells by targeting PTEN, and SPRY4, and inhibits the apoptosis of glioma cancer cells (8, 13). miR-1908-5p targets HDAC10 to promote the growth, invasion, and metastasis of cervical cancer cells (Ca-Ski, SiHa, and C-4I) (26). miR-1908-5p can target SRM to regulate extracellular vesicle (EV) secretion (29), thereby promoting PCa cancer progression (54). miR-1908-5p targets TGF-β1 and JunD in the MAPK pathway to promote the proliferation of chordoma tissue (6). miR-1908-5p targets APOE and DNAJA4 and promotes the invasion and metastasis of melanoma cells (MeWo-LM2) (35). miR-1908-3p targets 8 genes including ID4 and promotes the proliferation, invasion, and metastasis of breast cancer cells (MCF-7) (37).

In contrast to the above, miR-1908-5p targets AKT1S1 and PP5 in NSCLC, inhibits cancer cell proliferation and promotes cancer cell apoptosis (22, 23). In addition, miR-1908-5p may have two-way functions in osteosarcoma. On the one hand, miR-1908-5p targets PTEN to promote the proliferation, invasion, and metastasis of osteosarcoma cells such as 143B, U2OS, MG63, and SAOS2 (9); on the other hand, miR-1908-5p can also target ROCK1 and inhibit the proliferation of osteosarcoma cells such as HOS, MG63, G293, SAOS2, and U2OS (38). It is worth noting that the mode of action of miR-1908 in osteosarcoma is still not fully understood. miR-1908 can not only inhibit the development of osteosarcoma by targeting ROCK1, but also activate the PI3K/AKT signaling pathway to promote the development of osteosarcoma.

The role of miR-1908 in different cancers may be due to the differential expression of miR-1908-related genes in different tissues. In different cancers, the upstream factors of miR-1908 are differentially expressed, resulting in differences in the downstream regulation patterns of miR-1908. In the future, more in-depth studies are still needed to understand the molecular mechanism by which miR-1908 plays a role in cancer, to provide a theoretical basis for miR-1908-targeted therapy.

Fibrosis is a pathological process that occurs in organ tissues with excessive accumulation of extracellular matrix, and the gradual decrease of substantive functional cells, which eventually leads to organ dysfunction (7). As shown in Figure 5 , in the myocardial border zone and renal interstitial tissue of patients with renal fibrosis after myocardial infarction, miR-1908-5p can inhibit the TGF-β1-smad2/3 signaling pathway by targeting TGF-β1 to reduce the key phosphorylation of intracellular signaling protein smad2/3, thereby alleviating organ fibrosis and improving organ function (1). At the same time, in renal interstitial cells overexpressing miR-1908-5p, the expression level of the important extracellular matrix hydrolase MMP-2 and the cell proliferation rate were significantly diminished (7). After skin burns, the expression of miR-1908-5p is increased in wound tissues, and by targeting to inhibit Ski, it promotes the formation of scars (32).

Alzheimer’s disease (AD) is a common disease that affects memory and thinking skills (55). Aβ gradually precipitates and accumulates in cells, causing neurotoxicity, which in turn leads to a series of AD symptoms such as memory loss and progressive neurologic deterioration (56). In AD, miR-1908-5p can target ApoE, thereby inhibiting ApoE-mediated β-amyloid (Aβ) clearance (15).

High expression levels of miR-1908-5p are closely related to low levels of low-density lipoprotein (LDL), total cholesterol, fasting glucose, and glycosylated hemoglobin (51). The high expression of miR-1908-5p is significantly related to the decrease of LDL-C levels in the population. As shown in Figure 5 , miR-1908-5p does not affect the expression of low-density lipoprotein receptor (LDLR) but can reduce the expression of bone morphogenetic protein 1 (BMP1) by targeting TGF-β1. Down-regulation of BMP1 expression can increase the stability of LDLR, which in turn promotes the absorption of LDL-C by liver cells, thereby reducing circulating low-density lipoprotein-cholesterol (LDL-C) levels (11), and ultimately reducing the risk of cardiovascular disease (57).

In the initial stage of obesity, fat is mainly deposited under the skin, and then gradually transferred to the internal organs (58). The correlation between visceral adipose tissue (VAT) and cardiovascular disease is stronger than that of subcutaneous adipose tissue (SAT) (59). As shown in Figure 6 , the different miR-1908-5p expression patterns between VAT and SAT may facilitate this process. In the serum of most IS patients, the expression level of miR-1908-5p is down-regulated (18). This may be due to the overload of cholesterol in liver cells inhibiting the expression of miR-1908-5p. The low expression level of miR-1908-5p further inhibits the recovery of LDL-C from the blood by hepatocytes and promotes the occurrence of atherosclerosis (11).

The mitogen-activated protein kinase (MAPK) signaling pathway regulates cell growth, proliferation, and apoptosis through Jun N-terminal kinase (JNK) and p38 (60–62). In chordoma, miR-1908-5p targets TGF-β and JunD, thereby inhibiting the JNK and p38 MAPK signaling. Downregulation of miR-1908-5p can lead to aberrant activation of the MAPK signaling pathway, thereby promoting the occurrence of cancer (6).

The transforming growth factor β (TGF-β) signaling pathway can regulate cell proliferation, differentiation, migration, apoptosis, and EMT (63, 64). SMAD proteins play a role in signal transduction and transcriptional regulation in the TGF-β signaling pathway (65). Smad2/3 proteins are phosphorylated upon TGF-β signaling, bind to Smad4, and enter the nucleus as transcription factors to induce cell proliferation, migration, and EMT (65, 66). Studies have shown that the targeted inhibition of TGF-β by miR-1908-5p can reduce the phosphorylation level of downstream smad2/3 proteins, thereby inhibiting the process of cardiac/kidney fibrosis (1, 7), or reducing the level of BMP1 and promoting blood LDL-C levels, which are then taken up by hepatocytes (11).

The TGF-β signaling pathway plays a bidirectional role in cancer. TGF-β can not only inhibit tumor progression by promoting apoptosis, but also promote cancer cells to initiate immune evasion, invasion, and metastasis (67). The inhibitory effect of miR-1908 on the TGF-β signaling pathway may also play a role in cancer.

The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway is primarily responsible for cellular responses to changes in the extracellular environment and plays a regulatory role in proliferation, differentiation, apoptosis, and metabolic activities (68). The tumor suppressor gene PTEN is a specific phosphatase of PIP3, which can dephosphorylate PIP3 to generate 4,5-bisphosphate (PIP2), resulting in the inability of Akt to be recruited and activated on the plasma membrane, thereby inhibiting the PI3K/Akt signaling pathway (69). In glioma and osteosarcoma, miR-1908-5p can target and inhibit the expression level of PTEN and promote the activation of the PI3K/Akt signaling pathway, thereby promoting cancer cell proliferation and angiogenesis (8, 9).

AMP-activated protein kinase (AMPK) is a kinase related to cellular metabolism. Activation of the AMPK signaling pathway can promote catabolism and inhibit anabolism, reducing the intracellular AMP/ATP ratio (70). Dysregulation of energy metabolism is an important reason for inducing cancer, and abnormal activation of the AMPK signaling pathway is considered to be closely related to the occurrence and development of cancer (71). LKB1 is an important upstream kinase of the AMPK signaling pathway that controls cell metabolism and growth in tumor suppression (72). In liver cancer cell HuH-7, miR-1908-5p could downregulate the expression of LKB1 and further inhibit the activity of AMPK (10). This may be related to the occurrence of obesity, but the mechanism of miR-1908-5p in the process of hepatocarcinogenesis is still not fully understood.

In HCC, obesity, and BD, miR-1908 can respectively inhibit the activity of cancer cells, promote fat conversion, and cause emotional excitement. As shown in Figure 7 , a variety of drugs have affected the expression level of miR-1908 in these diseases.

OSW-1 is an anticancer drug of cholestane saponins. A study found that after OSW-1 treatment of liver cancer Hep3B cells, the expression of miR-1908-5p increased by 5 times, thereby inhibiting the proliferation, invasion, and metastasis of cancer cells, thereby exerting anti-cancer effects (77). miR-1908-5p plays an important role in obesity-related complications. In human adipocytes, growth hormone (GH) can significantly inhibit the expression of miR-1908-5p in a short time and then promote lipolysis (34). In BD patients, the expression level of miR-1908-5p is low. Sodium valproate is a commonly used drug for the treatment of BD. Treatment with sodium valproate can significantly increase the expression of miR-1908-5p, thereby reducing the symptoms of BD (39). At the same time, in the plasma of OC patients, the high expression of miR-1908-5p is significantly associated with platinum resistance (78).

The abnormal expression of miR-1908 is also closely related to the patient’s pathological conditions. As shown in Table 4 , miR-1908-5p can be used as a biomarker for the diagnosis and prognosis of various diseases.

In cervical cancer, HGSOC, osteosarcoma, and breast cancer, patients, high expression of miR-1908-5p is significantly associated with lower overall survival (OS) (9, 26, 28, 37). In HGSOC patients, high serum miR-1908-5p expression is significantly associated with poor progression-free survival (PFS) (28). In patients with osteosarcoma, high expression of miR-1908-5p points to poor disease-free survival (DFS). In addition, the high expression of miR-1908-5p is also significantly associated with poor chemotherapy efficacy and a higher recurrence rate in patients with osteosarcoma (12).

In contrast to the above, in NSCLC, patients with low miR-1908-5p expression have a lower five-year survival rate (23). In PCa patients, higher miR-1908-5p expression may indicate a better prognosis for patients (29). In OC, patients with low miR-1908-5p expression have lower OS and DFS (79).

In addition, there are inconsistencies in the correlation between the expression level of miR-1908-5p and the prognosis of brain tumors. Among the 47 patients with glioblastoma, patients with high miR-1908-5p expression had shorter DFS (8). Among 206 patients with TCGA glioma, patients with high expression of miR-1908-5p had shorter OS and DFS (13). In contrast, among 24 patients with grade III glioma and 50 patients with grade IV glioma from the GEO database (GSE4412), patients with low expression of miR-1908-5p had a shorter OS (14).

MiR-1908 has different prognostic roles in various cancers. More experimental evidence is needed in the future to further demonstrate the role of miR-1908 in cancer therapy, diagnosis, and prognosis.