Lung cancer includes small cell carcinoma and NSCLC, with NSCLC being the predominant form, constituting 80-85% of cases and associated with 2-year relative survival rate of ~42% (35). NSCLC cells do not express endogenous miRNA-122. miRNA-122 inhibits the PI3K/AKT signaling pathway through suppression of its target gene insulin-like growth factor 1 receptor (IGF1R). This suppression blocks PI3K and AKT phosphorylation, enhances E-cadherin expression and decreases N-cadherin and vimentin expression. This disruption impedes epithelial-mesenchymal transition (EMT), thereby inhibiting migration and invasion of NSCLC cells (17).

Long-term exposure of NSCLC cells to gefitinib leads to emergence of gefitinib-resistant A549/GR cells. As a target of miRNA-122, peroxiredoxin II (Prx II) inhibition suppresses the self-renewal and EMT of A549/GR stem cells, which is characterized by an increase in E-cadherin and decrease in vimentin expression following miRNA-122 knockout. This process involves inhibition of Hedgehog, Notch and Wnt/β-catenin signaling pathways following Prx II targeting by miRNA-122. Knockout of miRNA-122 reverses these effects (Fig. 1) (18).

NPC arises from the nasopharyngeal crypt, originating from mucosal epithelium of the nasopharynx, and is characterized by high malignancy (36). NPC cells exhibit significantly decreased expression of miRNA-122. miRNA-122 suppresses PI3K and AKT phosphorylation, inhibits the PI3K/AKT signaling pathway and decreases the expression of E-cadherin, metastasis-associated gene 1, MMP2 and tissue inhibitor of metalloproteinase 2 by targeting tripartite motif-containing protein 29. This inhibition suppresses the proliferation, migration and invasion capabilities of NPC cells (20). Moreover, the long non-coding RNA (lncRNA) DRAIC (downregulated RNA in cancer) upregulates special AT-rich binding protein 1 (SATB1) expression by binding to miRNA-122, thereby alters the configuration of the miRNA-122 binding site on SATB1 and suppressing miRNA-122 expression. This promotes the proliferation, migration and invasion of NPC cells; these effects are reversed by miRNA-122 overexpression (Fig. 2) (21).

Prostate cancer is a prevalent malignancy in male patients, accounting for ~26% of newly diagnosed cancer cases (35). Tumor cells obtain their energy supply through relatively low-yield glycolysis, which does not involve oxygen or mitochondria (37). Pyruvate kinase M2 (PKM2) serves as a key rate-limiting enzyme in glycolysis, driving tumor cell proliferation (38). In docetaxel-resistant prostate cancer cells, miRNA-122 expression is notably decreased. This leads to increased PKM2 expression, enhancing glycolysis, promoting proliferation and reducing apoptosis in these resistant cells. The mechanism involves miRNA-122 targeting and inhibiting PKM2 to suppress prostate cancer progression (39).

miRNA-122 inhibits the proliferation of prostate cancer cells by downregulating Rho-associated protein kinase 2 (ROCK2) expression (22). ROCK2, a member of the Rho family, promotes invasion and metastasis in prostate cancer (40). Additionally, silencing ROCK2 expression counteracts enzalutamide resistance in enzalutamide-resistant prostate cancer cells, leading to inhibition of cancer cell proliferation (Fig. 3) (41).

BDC is a malignant tumor of the epithelial cells of the bile ducts; it is insidious and the 5-year survival rate drops to 2% if distant metastasis occurs (42). Expression of miRNA-122 is notably decreased in BDC compared with normal bile duct tissue. Overexpressed miRNA-122 in BDC cells significantly inhibits tumor cell proliferation and invasion while promoting apoptosis. However, the specific mechanism by which miRNA-122 inhibits BDC progression has not been fully elucidated (43). Wu et al (44) demonstrated that overexpression of miRNA-122 in BDC cells upregulates P53 expression, thereby suppressing tumor cell proliferation and invasion while promoting apoptosis. Additionally, miRNA-122 also inhibits BDC cell migration and invasion by targeting the downstream target gene chloride intracellular channel 1 (CLIC1). lncRNA urothelial cancer associated 1 (UCA1) regulates CLIC1 expression through sponging miRNA-122 to promote BDC metastasis (Fig. 4) (19).

In 2018, 549,393 patients were diagnosed with bladder cancer worldwide and 199,922 died from the disease (1). Angiogenesis is key for tumor development, making its inhibition a potential treatment strategy. Vascular endothelial growth factor (VEGF) is associated with tumor progression (45). miRNA-122 expression is downregulated in human bladder cancer tissue. By binding to the 3'-UTR of VEGFC, miRNA-122 significantly decreases VEGFC expression, inhibiting AKT and mTOR phosphorylation. This inhibition ultimately suppresses angiogenesis, invasion, migration and proliferation of bladder cancer cells (8). Furthermore, miRNA-122 overexpression enhances sensitivity of bladder cancer cells to cisplatin and promotes cancer cell apoptosis (8).

Prior research (16) has established that the cAMP-response element-binding protein (CREB) 1 serves as a downstream target of miRNA-122. miRNA-122 directly inhibits CREB1 to suppress proliferation and invasion in bladder cancer cells (Fig. 5) (16).

Breast cancer is the most common cancer in female patients and the leading cause of cancer mortality in female patients worldwide (46). lncRNA ribonuclease P RNA component H1 (RPPH1) is highly expressed in breast cancer tissue. lncRNA RPPH1 promotes the expression of downstream genes, such as PKM2 and IGF1R, by sponging miRNA-122, which further promotes proliferation of breast cancer cells; by contrast, miRNA-122 overexpression reverses this process (24). miRNA-122 overexpression enhances sensitivity of breast cancer cells to radiotherapy, thereby inhibiting tumor cell survival (23). Radioresistant breast cancer cells show significantly increased miRNA-122 expression, whereas miRNA-122 knockout decreases the survival of these cells. This mechanism may involve miRNA-122 oncogenic potential through targeting zinc finger proteins 611 (ZNF611) in radioresistant breast cancer cells (23). Therefore, in primary breast cancer cells (before radiation therapy and without radioresistance), elevated miRNA-122 expression inhibits cancer progression and serves as a tumor suppressor. Conversely, in radiotherapy-resistant breast cancer cells, elevated miRNA-122 expression can promote radiotherapy resistance, demonstrating its dual role as both a tumor suppressor and oncogene depending on the cellular context (Fig. 6).

Hepatocellular carcinoma (HCC), the predominant form of liver cancer, is the fifth most common cause of cancer deaths In the United States (47). miRNA-122 disrupts mesenchymal cytoskeleton, upregulates E-cadherin and α-catenin expression and downregulates vimentin and fibronectin expression by binding to the 3'-UTR of Ras homologous gene family member A (RhoA); this triggers mesenchymal-epithelial transition, reverses EMT and thus inhibits the invasion and migration of HCC cells (48).

In a study on adriamycin resistance in HCC (49), overexpression of miRNA-122 suppressed expression of ATP-binding cassette superfamily member 2 and multidrug resistance-associated protein 1. This overexpression enhances sensitivity of HCC cells to chemotherapeutic drugs and inhibits proliferation.

Polyploidy is a balanced amplification of the genome and is common in the liver. Hepatocytes become polyploid mostly due to failure of cytoplasmic division. Approximately 30% of hepatocytes in the human liver are polyploid. Liver polyploidy prevents gene mutations in hepatocytes and decreases the formation of liver tumors (50). miRNA-122 directly targets cytoplasmic cleavage genes cut-like homeobox protein-1, RhoA, microtubule-associated protein RP/EB family member 1, IQ-containing GTPase-activating protein 1, neural precursor cell-expressed developmentally down-regulated protein 4-like and solute carrier family 25 member 34, thereby resulting in cytoplasmic cleavage failure to increase hepatic polyploidization, thus suppressing liver tumorigenesis (51). Other studies have shown that frequent ploidy reduction in polyploid hepatocytes results in predisposition to liver tumor formation, which may imply that notable reduction in hepatic polyploidy contributes to cancer development, as this leads to genetic mutations (Fig. 7) (52,53).

CRC accounted for 9.4% of all new cases of cancer in 2020 (54). The liver is the most important target organ for hematogenous metastasis of CRC. Liver metastasis is the main cause of death due to CRC (54). Studies have found elevated miRNA-122 expression in liver cells of metastatic CRC, contrasting high expression was not detected in CRC cells. miRNA-122 correlates negatively with cationic amino acid transporter protein 1 (CAT1) expression and can enhance liver migration by targeting CAT1 (26). In oxaliplatin-resistant CRC cell lines, miRNA-122 expression is reduced while X-linked inhibitor of apoptosis protein (XIAP) expression is increased. miRNA-122 downregulates XIAP to restore oxaliplatin sensitivity in resistant cells, thereby suppressing CRC progression (27). Thus, elevated miRNA-122 levels in untreated CRC cells may indicate potential liver metastasis, suggesting an oncogenic role. Conversely, decreased miRNA-122 expression in oxaliplatin-treated CRC cells may indicate drug resistance, highlighting its role as a tumor suppressor. In summary, miRNA-122 exhibits dual roles as both a tumor suppressor and an oncogene in CRC (Fig. 8).

Due to changes in dietary habits and genetic factors, esophageal cancer is a significant health challenge worldwide, with overall 5-year survival rate of ~10% and a propensity for early metastasis (55). KIF22, a kinesin-like DNA-binding protein, can promote cancer progression. Kinesin superfamily protein 22 (KIF22) is prominently expressed in esophageal squamous carcinoma tissue and cells, correlating significantly with poor prognosis (28); miRNA-122 negatively regulates KIF22, downregulates the expression of cyclin G1 (CCNG1), Cyclin dependent kinase 2, N-cadherin and vimentin and upregulates p21, p27 and E-cadherin expression; this induces S phase arrest and apoptosis of esophageal squamous carcinoma cells and inhibits EMT (28) (Fig. 8). Additionally, the response elements of miRNA-122 and miRNA-143 mediated by adenoviral vectors cause tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL) to be highly expressed in esophageal cancer, but not in normal cells; this selectively induces apoptosis in esophageal cancer cells and protects against the toxicity of TRAIL to the liver (56). This may be an effective approach to treat esophageal cancer and prevent liver toxicity.

Glioma is the most common primary malignant tumors of the brain. Glioma grows invasively and often involve surrounding normal brain tissue. RUNX2, part of the RUNX transcription factor family, regulates gene expression and enhances tumor cell proliferation by binding to specific DNA sequences (57). Additionally, miRNA-122 is downregulated in glioma compared with normal tissues (29). By targeting RUNX2, miRNA-122 inhibits proliferation and migration of glioma cells (29). Moreover, miRNA-122 induces cell cycle arrest, promotes apoptosis, and decreases proliferation in transglioma cells by targeting SOX6. However, this inhibitory effect on glioma cells can be reversed by circular RNA pleiotrophin, which serves as a miRNA-122 sponge (Fig. 8) (30).

RCC, is a prevalent form of kidney cancer, constituting for 2 to 3% of all adult malignancies, with 1.8% mortality rate (1). Fan et al (31) observed elevated miRNA-122 expression in RCC cells, correlating with poor prognosis. miRNA-122 induces EMT by suppressing Dicer, a downstream target gene, thereby enhancing migration and invasion of RCC cells (31). Similarly, Nie et al (32) found increased miRNA-122 expression in RCC cells, which promotes cell proliferation, migration and invasion by targeting FOXO3. Thus, miRNA-122 plays an oncogene role in RCC (Fig. 8).

Acute myeloid leukemia (AML) is a blood cancer characterized by abnormal cell proportions due to impaired differentiation of hematopoietic stem cells (58). Zhang et al (59) reported that patients with AML with low miRNA-122 levels in their bone marrow have poorer overall survival and lower rates of complete remission compared with those with high miRNA-122 expression (59). Yang et al (60) found that miRNA-122 expression is significantly reduced in AML bone marrow compared with non-malignant tissue and high miRNA-122 levels inhibit AML cell proliferation by affecting cell cycle pathways (60). However, further research is needed to understand how miRNA-122 suppresses AML progression.

Osteosarcoma, a common bone malignancy in children and adolescents, is associated with high mortality rates (61). miRNA-122 suppresses proliferation, migration, and invasion of osteosarcoma cells by decreasing the expression of CCNG1, Bcl-w and a disintegrin and matrix metalloproteinase-10 (33). However, this inhibitory effect is reversed by miRNA-122 sponging (33). Additionally, Liu et al (62) noted varied miRNA-122 expression between different osteosarcoma cell lines; while miRNA-122 is upregulated in HOS, Saos-2 and U2OS cell lines, it is downregulated in MG-63 cells. High miRNA-122 levels inhibit the proliferation, invasion and migration of Saos-2 osteosarcoma cells, indicating its role as a tumor suppressor despite being highly expressed in this cell line (62).

Cervical cancer is a common malignant tumor affecting female patients accounting for about 3.2% of all cancers (1). According to Yang et al (34), miRNA-122 targets RAD21, a component of the cohesin complex, thereby inhibiting the PI3K/AKT signaling pathway in cervical cancer cells. This inhibition suppresses cervical cancer cell proliferation and promotes apoptosis. Elevated levels of miRNA-122 are associated with improved prognosis in patients with cervical cancer (34).

The expression levels of miRNA-122 in the urine of patients with clear cell renal cell carcinoma (ccRCC) show a significant 13.9-fold elevation; alongside miRNA-1271 and miRNA-15b, this may be useful in diagnosing ccRCC (66). In prostate cancer, both tissue and serum levels of miRNA-122 are notably decreased and serum miRNA-122 levels effectively distinguish patients with prostate cancer from healthy individuals (22). Additionally, a model combining six miRNAs, including miRNA-122, has superior accuracy in differentiating patients with oral squamous cell carcinoma from healthy controls compared with serum squamous cell carcinoma antigen (68). The aforementioned studies suggest that miRNA-122 has potential to be used as an additional diagnostic marker for certain types of cancer.

In CRC, miRNA-122 is associated with increased risk of tumor metastasis (69). Conversely, miRNA-122 expression is associated with improved prognosis in HCC (70), AML (59) and bile duct cancer (43). Low miRNA-122 expression also correlates with poor outcomes following radical resection in liver cancer (71). Yang et al (20) found that decreased miRNA-122 expression significantly correlates with advanced tumor node metastasis stage and distant metastasis in NPC. Therefore, miRNA-122 shows promise as a useful tool for predicting cancer prognosis.

miRNA-122 expression is indicative of treatment response and aids in tailoring effective treatment plans. Elevated miRNA-122 levels predict early resistance to transcatheter arterial chemoembolization in patients with HCC (72). Additionally, patients with HCC who are responsive to sorafenib exhibit higher miRNA-122 expression post-chemotherapy compared with non-responsive patients, underscoring its potential to predict sorafenib efficacy (65).

Exosomes are active vesicles secreted by cells to facilitate intercellular substance exchange and information transfer. They are commonly utilized as carriers for delivering miRNA (81). A recent study demonstrated that exosomes derived from adipose-derived mesenchymal stem cells effectively deliver miRNA-122 into HCC cells (82). This results in significant downregulation of CCNG1, disintegrin, MMP10 and IGF1R expression, enhancing the sensitivity of HCC cells to 5-FU and sorafenib (82).

Viral vectors widely used include lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses (AAVs) (83,84). In an in vivo mouse xenograft model, tumor growth of human HCC is notably suppressed by AAV3 along with miRNA-122 and miRNA-26a lentiviral delivery systems (85). Additionally, tumor necrosis factor-associated apoptosis-inducing ligands selectively expressed in osteosarcoma cells through adenoviral vectors of miRNA-122 and miRNA-34 promote apoptosis and inhibit cell proliferation (86). Notably, linking and cloning miRNA-21 and pre-miRNA-122 sequences into viral-like particle expression vectors and delivering them into HCC cells inhibits proliferation, migration and invasion of HCC cells and promotes apoptosis (87). While advantages such as easy cell access and high expression of introduced genes are offered by viral vectors, concerns about immunogenicity and potential promotion of gene mutagenesis have prompted a search for alternatives (88).

Nanocarriers offer advantages such as low toxicity, minimal immunogenicity, high permeability and non-integration of genes into the host cell genome, making them essential alternatives to viral vectors (89). Sendi et al (90) developed a galactose-targeted lipid calcium phosphate nanoformulation noted for its stability and efficient delivery of miRNA-122 to CRC liver metastatic hepatocytes. This formulation effectively prevents liver metastasis and prolongs survival in CRC mouse models without significant toxicity (90). Additionally, an ultrasound-triggered, phase-transitioning cationic nanodroplet delivers miRNA-122 to HCC cells, resulting in a significant increase in miRNA-122 expression and substantial inhibition of HCC cell proliferation, migration, and invasion (91). Zeng et al (92) created graphene-P-gluoprotein loaded with miR-122-InP@ZnS quantum dot nanocomposites, demonstrating effective delivery of miRNA-122 to multidrug-resistant HCC cells and induction of apoptosis (92). Furthermore, Zhang et al (93) utilized amphiphilic gemcitabine-oleic acid prodrug nanoparticles for encapsulating miRNA-122, effectively targeting HCC cells and significantly inhibiting proliferation in xenograft nude mice (93).