A huge effort has gone into finding acceptable miRNAs and it has been indicated that miRNAs are promising biomarkers for the diagnosis and monitoring of several malignancies. Circulating miR-409-3p was found to be dysregulated in various types of cancers (Table II). Zhou et al (13) examined six miRNAs, including miR-409-3p, in the plasma, which may contribute to the detection of LUAD to a certain extent. Similarly, Wang et al (18) revealed that miR-409-3p had high sensitivity and specificity in differentiating lung adenocarcinomas (LUADs) from healthy individuals and was able to detect early-stage LUAD in patients. In addition, it was able to diagnose stage I or II BC when compared to healthy controls (22). In patients with BC, miR-409-3p was shown to have the highest sensitivity and specificity for distinguishing patients with BC from healthy subjects (23,25). Besides, when combined with miR-32-5p, the sensitivity and specificity of the detection of CC in tissue and serum samples were the highest (31). The combined panel of ratios of five miRNAs possessed a diagnostic capability to make a distinction between CRC and colorectal adenoma (52). Furthermore, Wang et al (47) used a panel of miR-409-3p, miR-7 and miR-93, which had great diagnostic accuracy in distinguishing CRC from a healthy group. In PC and BTC, Kim et al (63) demonstrated that miR-409-3p was also downregulated by sequencing serum miRNAs. In AML, Li et al (65) discovered that miR-409-3p had the best diagnostic value, with a sensitivity of 93.3% and a specificity of 87.9%. In addition, miR-409-3p could be combined with other miRNAs to create a signature model for the diagnosis of NPC (69). Most strikingly, when comparing the serum concentrations of eight preoperative and postoperative patients with carbon ion radiotherapy (CIRT)-localized PCa, Yu et al (74) found that the expression level of miR-409-3p was higher than that of patients with CIRT following the surgical removal of primary tumors, and the patients with higher preoperative miR-409-3p levels had a better response to CIRT. The same result was found in the prediction of meningioma (68).

In general, the aforementioned results proved that miR-409-3p may serve as a promising biomarker for the diagnosis and therapeutic monitoring of cancers.

MiR-409-3p has been discovered to be a prognostic marker in a variety of malignancies. The varied expression of miR-409-3p in various neoplasms may indicate that miR-409-3p expression and survival have different relationships.

In NSCLC, miR-409-3p expression was an independent prognostic marker. In general, patients with low miR-409-3p expression exhibit poor prognosis. Patients with LUAD with low miR-409-3p expression display a lower overall survival (12,14,16,20), recurrence-free survival (12) and disease-free survival (14,20) than patients with high miR-409-3p expression. Furthermore, a low median survival time was associated with pTNM (III+IV) and lymph node metastasis. Clinically, reduced miR-409-3p expression was found to be substantially associated with poor tumor differentiation, tumor size, advanced pTNM stage, lymph node metastasis, pleural invasion and smoking (12,14,20). In BC, the level of tissue miR-409-3p was negatively associated with TNM stage, lymph node metastasis, pathological differentiation, tumor size and Ki-67 status (27). In osteosarcoma, miR-409-3p expression was associated with advanced clinical stage and distant metastasis (38). In addition, miR-409-3p was usually decreased in GC. Among patients with GC, changes in miR-409-3p expression were associated with local invasion, TNM stage and tumor size (40-42). Studies investigating miRNA profiles in CRC showed that downregulation of miR-409-3p was associated with tumor size, local invasion and metastasis (45,46). In addition, in OC, lower miR-409-3p levels were closely associated with the International Federation of Gynecology and Obstetrics stage (55). Furthermore, miR-409-3p, when combined with other miRNAs, was negatively associated with age and the age at which non-muscle-invasive BCa develops (61). In patients with AML, a low level of miR-409-3p was associated with poorer event-free survival and white blood cell count (65). Another study assessing oligodendrogliomas confirmed that miR-409-3p was inversely associated with progression-free survival (67). With regard to TSCC, downregulation of miR-409-3p was associated with TNM stage and lymph node metastasis (70). On the contrary, a previous study has shown that in other neoplasms, including PCa, patients with high miR-409-3p expression had a poorer prognosis than those with low miR-409-3p expression. More importantly, a higher Gleason score was positively associated with the expression of miR-409-3p (71). In addition, the high recurrence rate of meningioma was substantially connected with miR-409-3p expression, indicating that miR-409-3p may have predictive utility for patients with meningioma following tumor removal (77).

In summary, these findings suggested that miR-409-3p was significantly linked to the survival of cancer patients. Therefore, miR-409-3p may function as an independent prognostic molecular biomarker in malignancies.

Several diseases, particularly cancer, are caused by a disruption in the balance between cell growth and death. Targeted genes of miR-409-3p are closely associated with the development and apoptotic processes of tumor cells. In most cases, miR-409-3p acts as a tumor suppressor. A tyrosine kinase receptor called MET proto-oncogene, receptor tyrosine kinase (MET) triggers the mitogenic signaling pathway, which leads to the development of tumors and malignant transformation (93,94).

In LUAD, miR-409-3p suppressed the proliferation of A549 and SPC-1 NSCLC cells and promoted caspase-3-dependent apoptosis by directly targeting MET (12). Subsequently, Song et al (14) reported that miR-409 upregulation clearly inhibited proliferation by inhibiting spindlin 1 (SPIN1), a component of the SPIN/SSTY gene family. A study by Qu et al (15) unveiled that lncRNA zinc finger E-box binding homeobox 1 antisense 1 (ZEB1-AS1) functioned as a competing endogenous RNA (ceRNA) to facilitate NSCLC tumorigenesis by regulating the ZEB1-AS1/miR-409-3p/ZEB1 signaling pathway. Mounting evidence suggests that the ZEB1-AS1 signaling pathway may aggravate NSCLC cell proliferation and reduce apoptosis (15). Furthermore, Yin et al (16) revealed that by regulating the miR-409-3p/hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA) axis, double homeobox A pseudogene 8 (DUXAP8) promoted the viability of A549 and H1299 NSCLC cells. Liu et al (17) also demonstrated that loss of miR-409-3p inhibited the expression of superoxide dismutase 1 (SOD1) and its oncogenic activity. Recently, a publication described carbonyl reductase 3 (CBR3)-AS1 as a ceRNA interacting with miR-409-3p in NSCLC. Furthermore, NSCLC development and miR-409-3p suppression were facilitated by the overexpression of CBR3-AS1. In addition, the CBR3-AS1/miR-409-3p/SOD1 axis could promote the proliferation of H1650 NSCLC cells (20). In addition to CBR3-AS1, circ_0079530 also had an oncogenic role in NSCLC through the inhibition of miR-409-3p. Yang et al (21) revealed that the circ_0079530/miR-409-3p/aquaporin 4 (AQP4) axis promoted the proliferation and invasion of H1270 and A549 NSCLC cells.

According to Zhang et al (26), overexpression of miR-409-3p, which has a crucial role in cell development, significantly hampered the proliferation and colony formation of MDA-MB-231 and MDA-MB-468 BC cells and accelerated apoptosis by targeting AKT serine/threonine kinase 1 (AKT1), which was essential for cell growth (95). By contrast, anti-miR-409-3p led to the inhibition of the proliferation of T47D BC cells. In addition, despite the fact that upregulation of miR-409-3p did not affect AKT1 mRNA, the protein level decreased, indicating that the regulation of AKT1 by miR-409-3p was post-transcriptional. Ma et al (27) also concluded that increased miR-409-3p expression impeded cell proliferation and regulated the process of BC by targeting the important nuclear transcription factor ZEB1. Furthermore, miR-409-3p was predicted to mainly target caspases, BCL2 and cell cycle cyclins involved in anti-tumor drug-induced apoptosis (27). However, the finding was not demonstrated by a corresponding functional analysis in animals. Recently, by targeting miR-409-3p, circRNA tripartite motif-containing 28 (circTRIM28) was reported to upregulate oncogenic high mobility group AT-hook 2 (HMGA2) in BC. Regulation of the miR-409-3p/HMGA2 axis also accounted for the influence of circTRIM28 on cell proliferation and apoptosis (30).

The direct binding between miR-409-3p and HPV16/18 E6 mRNA was identified in cervical dysplasia tissues. Despite the regulation of miR-409-3p levels having no effect on colony development, miR-409-3p overexpression also attenuated the proliferation of CaSki, C-4I and Hela cells. Vice versa, miR-409-3p knockdown promoted the proliferation of CaSki and C-4I CC cells, but there was no change in HeLa CC cells (32). Cui et al (33) revealed that miR-409-3p was involved in CC progression through the ceRNA mechanism. On the one hand, circ0000745 regulated activating transcription factor 1 (ATF1) expression to regulate CC progression by sponging miR-409-3p. Of note, the proliferation of cells was negatively related to the expression level of miR-409-3p. Co-transfection of miR-409-3p with circ0000745 alleviated the promoting effects of overexpression of circ0000745 on CC cell proliferation (33). On the other hand, circRNA FAT atypical cadherin 1 (circFAT1) also had a crucial role in CC by acting as a sponge for miR-409-3p. Increased circFAT1 promoted CC progression, including enhancing proliferation and repressing apoptosis via the miR-409-3p/cyclin-dependent kinase 8 (CDK8) axis (34). In addition, Wu et al (35) reported that miR-409-3p, targeted by circEPSTI1, regulated the expression of solute carrier family 7 membrane 11 (SLC7A11) expression. The proliferation of Hela and CaSki cells in CC was influenced by the circEPSTI1-miR-409-3p-SLC7A11 axis.

With regards to osteosarcoma, Zhang et al (37) revealed that E74-like factor 2 (ELF2), an ETS family transcription factor, served as an oncogene and played prominent roles in cell proliferation, differentiation and apoptosis. Therefore, the ectopic expression of miR-409-3p clearly hampered cell proliferation, induced G0/G1 arrest and promoted apoptosis in osteosarcoma cells. Shortly after, Wu et al (38) found that ZEB1 was also regulated by miR-409-3p in HOS and MG63 osteosarcoma cells, thus inhibiting cell proliferation. Furthermore, Long et al (39) discovered that circ0000285, which is increased in osteosarcoma, acted as a ceRNA of miR-409-3p to promote insulin-like growth factor binding protein 3 (IGFBP3). More importantly, miR-409-3p overexpression clearly reduced cell viability and colony numbers of osteosarcoma cells, and enhanced cell apoptosis, which was reversed by IGFBP3. In conclusion, circ0000285 could promote the proliferation and suppress the apoptosis of osteosarcoma via the miR-409-3p/IGFBP3 axis. It was also the first ceRNA mechanism to be explored in osteosarcoma.

MiR-409-3p was also mentioned in connection with the cellular biological processes in GC. The 2020 study by Wang et al (44) demonstrated that, compared with adjacent tissue, circ0001023 expression was conspicuously upregulated. Mechanistically, miR-409-3p was positively correlated with PHD finger protein 10 (PHF10), which was identified as a direct target of circ0001023 and negatively modulated by circ0001023 via the ceRNA network. Circ0001023 silencing could inhibit the proliferation and trigger the apoptosis of GC cells, while miR-409-3p inhibitors could partially inhibit apoptosis and promote the proliferation of GC cells. Similarly, Li et al (40) also found that miR-409-3p overexpression reduced the level of PHF10, thus markedly limiting the proliferation and colony numbers of tumor cells and slowing the transition from the G1 to the S phase of the cell cycle. CircRNA NIMA-related kinase 9, which is enhanced in GC cells, could promote the proliferation of GC cells by targeting the miR-409-3p/microtubule associated protein 7 (MAP7) axis. MiR-409-3p has been shown to bind to MAP7 mRNA directly, causing cell cycle arrest in the G0/G1 phase and limiting GC cell growth and colony formation (42). Furthermore, consistent with previous findings, the expression of miR-409-3p had been confirmed to decrease, and high levels of miR-409-3p were found to be able to inhibit proliferation and trigger apoptosis. Surprisingly, when GC cells were treated with precision hyperthermia, miR-409-3p could positively regulate the targeting gene Kruppel-like factor 17 (KLF17) and induce GC cell apoptosis (43).

Liu et al (45) showed that miR-409-3p overexpression in CRC targeted nemo-like kinase (NLK), which is implicated in the formation, progression and signaling pathways of cancer. In addition, in cells resistant to oxaliplatin, a platinum-based chemotherapeutic drug, such as oxaliplatin-resistant LoVo (Oxa-R) and HCT-116/L-OHP cells, miR-409-3p was found to regulate cell proliferation, the cell cycle and apoptosis by targeting beclin-1 and ERCC excision repair 1 (ERCC1), respectively (48,50). This phenomenon was also observed in drug-resistant OV-1063 cells by inhibiting FIP200 (54). In CRC, LINC00630 functioned as an endogenous sponge for miR-409-3p and relieved the inhibition of miR-409-3p on HK2. By repressing miR-409-3p, LINC00630 upregulated HK2 and promoted cell proliferation, and inhibited apoptosis in the CRC cell lines SW480 and HCT116 (51).

In addition, another group provided evidence that miR-409-3p had effects on OC cells, including proliferation, colony formation and apoptosis, by targeting RAB10, member RAS oncogene family (RAB10), whereas its downregulation inhibited the apoptosis and promoted the proliferation as well as colony formation (56).

In BCa, Xu et al (60) also observed that MET could regulate 14q32.2 miRNA clusters, including miR-409-3p, and miR-409-3p could directly target MET. In addition, miR-409-3p participated in the miR-433-mediated inhibition of cell motility.

Of note, Zhao et al (62) reported that miR-409-3p upregulation in PTC weakened PTC cell proliferation and induced cell cycle arrest in G0/G1 phase by modulating cyclin D2. In DLBCL, miR-409-3p overexpression significantly inhibited the proliferation of SU-DHL-4 compared with SV_Co10 (64). In AML, Xie et al (66) revealed that miR-409-3p negatively regulated the expression of RAB10, sequentially inhibiting proliferation and promoting apoptosis. In TSCC, Chen and Dai (70) concluded that miR-409-3p negatively regulated the expression of radixin (RDX), sequentially inhibiting proliferation in vitro. Furthermore, miR-409-3p could act as an oncogene. In PCa, Josson et al (71,73) noted that through the negative regulation of Ras suppressor protein 1, miR-409-3p enhanced cell proliferation and inhibited cell apoptosis. Simultaneously, circular dedicator of cytokinesis 1, which promoted proliferation and inhibited apoptosis in human brain vascular smooth muscle cells through the miR-409-3p/myeloid cell leukemia sequence 1 (MCL1) axis, sponged miR-409-3p to boost MCL1 expression, which helped inhibit certain targets in the treatment of intracranial artery tumors (78). Of note, a study by Cao et al (79) found that high mobility group nucleosome binding domain 5 (HMGN5) acted as an oncogene in glioma. By suppressing HMGN5, miR-409-3p suppressed glioma cell proliferation and colony formation and blocked glioma cells in the G0/G1 phase. Angiogenin (ANG), a gene involved in cell proliferation, has also been studied in the context of fibrosarcoma. HT1080 cell transfection with a miR-409-3p mimic could suppress cell proliferation by targeting ANG (81). In general, miR-409-3p has been strongly connected with cell growth and apoptosis in various cancers. In HCC, Li et al (84) found that silencing LINC00886 upregulated the expression of miR-409-3p, weakened the proliferation of HCC cells (Hep3B, Huh7) and promoted apoptosis. Conversely, it promoted the proliferation of Hep3B as well as Huh7 proliferation and inhibited apoptosis.

The process through which independent cells travel from the main tumor to distal organs through blood arteries or lymphatic vessels is referred to as metastasis and invasiveness of malignant tumors (96). Metastasis, the most prominent feature of malignant tumors, is responsible for the majority of cancer-related fatalities and has become a major impediment to cancer treatment. MiR-409-3p influences tumor migration and invasion by altering target genes to further regulate the progression of cancer (Fig. 3).

A consensus has been reached that epithelial-mesenchymal transition (EMT) plays a significant role in cancer metastasis (97), which is characterized by decreased E-cadherin expression and increased N-cadherin/vimentin expression (98,99) and allows the cells to acquire the properties of migration and invasion. Twist family bHLH transcription factor 1 could induce EMT and participate in cancer metastasis (100). A Transwell assay performed by Su et al (29) found that miR-409-3p overexpression could limit the EMT in MCF7 BC cells. KLF17 is a member of a conserved family of transcription factors that regulates cell migration and invasion. A certain range of heat treatments accelerated the expression of miR-409-3p in SGC-7901 and BGC-823 GC cells and indirectly upregulated KLF17, further inhibiting the migration, invasion and the EMT pathway (43). In addition, Josson et al (71,73) found an elevated level of miR-409-3p/5p in PCa, suggesting that it may promote tumorigenesis, EMT and bone metastasis of PCa. In addition, increased miR-409-3p has also been observed in PCa cells and tissues in bone metastasis.

Matrix metalloproteinases (MMPs), a type of proteolytic enzyme that break down the structural components of extracellular matrix and contributes to the loss of intercellular connection, promote cell migration and invasion, in addition to the EMT process.

In NSCLC, miR-409-3p mimics were able to suppress the protein levels of phosphorylated AKT (p-AKT), ultimately resulting in the decrease of the expression of MMP2 and MMP9, which in turn reduced the migration and invasion of A549 and SPC-1 NSCLC cells (12). In addition, a study by Song et al (14) found that SPIN1 is associated with cancer metastasis, as a direct miR-409-3p target in A549 NSCLC cells. In line with this, miR-409-3p overexpression evidently inhibited A549 NSCLC cell invasion and migration, but this inhibition could be reversed by anti-miR-409-3p. In addition, Yin et al (16) reported that the inhibition of miR-409-3p in NSCLC rescued the number of migrated H1299 and A549 NSCLC cells transfected with small interfering RNAs targeting DUXAP8. Wang et al (19) verified the above mechanism in another NSCLC cell line, H1299. They used miR-409-3p inhibitor and negative control, leading to the weakening of the inhibitory effect on SPIN1, which then promoted H1299 NSCLC cell metastasis and invasion. Liu et al (20) showed that miR-409-3p mimics also mitigated the effects of CBR3-AS1 on NSCLC cell invasion and migration. A ceRNA named circ_0079530 was overexpressed in NSCLC cells and sequestered miR-409-3p. Increased rates of cell migration and invasion are carried on by low levels of the miRNA, on the contrary, the increase of migration and invasion rate (21).

By targeting AKT1, Zhang et al (26) found that miR-409-3p overexpression also hindered BC cell motility and invasion. Ma et al (27) also found that a low abundance of miR-409-3p and high expression of ZEB1 in BC may be responsible for the high metastasis rate of BC. Yang et al (30) reported that circRNA tripartite motif-containing 28 (circTRIM28) contributed to the migration and invasion of BC cells by downregulating miR-409-3p.

An array of studies observed that when using particular inhibitors and mimics of miR-409-3p in SiHa CC cell lines, miR-409-3p displayed a pattern of overexpressed and downregulated HPV16/18 E6, boosting or inhibiting migration, respectively (32). Despite the inhibition of miR-409-3p on cell migration and invasion reported by Cui et al (33), miR-409-3p may suppress ATF1 expression, and thus negatively regulate the migration and invasion of CaSki and Siha CC cells. The tumor suppressor role of miR-409-3p lies at least in part in the negative regulation of CDK8. miR-409-3p/CDK8 modulated CaSki and C-33A CC cell invasion and migration behaviors (34).

In osteosarcoma, Wu et al (36) found that functionally decreased miR-409-3p markedly increased the migration and invasion of osteosarcoma cell lines (U2OS and SAOS-2) by directly targeting catenin-δ1, further promoting the metastasis of osteosarcoma. In a different study, the miR-409-3p-mediated inhibition of the invasion of another two osteosarcoma cell lines (MG63 and HOS) was examined and ZEB1 was identified as a new target gene (38). Another publication reported that overexpression of miR-409-3p clearly reduced SJSA1 as well as U2OS cell invasion and migration in osteosarcoma, whereas its downregulation increased migration and invasion rates (39).

In GC, one group indicated that miR-409-3p functioned as a tumor suppressor by validating its targeting of PHF10, inhibiting AGS GC cell invasion and migration, and stimulating invasion and migration of MKN-28 and SGC-7901 GC cells (44). In addition, the constitutive expression of miR-409-3p in three GC cell lines, including SGC-7901, HGC-27 and MKN45, reduced their migration and invasion rates (41). Furthermore, Yu et al (42) also found that this miRNA could downregulate MMP2 and MMP9, while MAP7 was another gene tightly associated with EMT and could partly rescue its expression, thereby boosting the invasion and migration of XGC-1 and MKN45 cells in GC. In addition, a similar regulation mechanism pattern was also observed by Xu et al (59) in T24 and 5637 BCa cells in that miR-409-3p may regulate cell migration and invasion in part by indirectly controlling MMP2 and MMP9.

In CRC, Liu et al (45) showed that high expression of miR-409-3p induced SW480 and SW1116 CRC cell migration and invasion by repressing the expression of NLK. Furthermore, Bai et al (46) detected that miR-409-3p was a metastasis-specific miRNA in CRC. MiR-409-3p directly linked to cell invasion and migration in CRC through targeting GRB2-associated binding protein 1 (46). Another study found that miR-409-3p has an inhibitory role in CRC, where it noticeably reduced HCT-116 and HCT-116/L-OHP migration and invasion, which occurred by suppressing ERCC1 under certain experimental conditions (50).

Simultaneously, Chen and Dai (70) also reported that miR-409-3p strongly modulated the development of TSCC by targeting RDX, thus inhibiting or stimulating the migration and invasion of Tca8113 TSCC cells.

In OC, miR-409-3p reversely regulated fatty acid binding protein 4 (FABP4) in OC cell lines (HeyA8 MDR and Ovcar5). In addition, hypoxia and hypoxia-inducible factor-1α (HIF-1α) could reduce miR-409-3p, which may eliminate its inhibitory effect on FABP4, leading to increased FABP4 levels to further promote the metastasis of OC cells (53). MiR-409-3p suppressed cell migration of SKOV3 OV cells (56), whose mediated target RAB10, a type of small GTPases belonging to the Ras protein family (101). The MET oncogene is a tyrosine kinase with a well-defined receptor, which is generally upregulated in various cancers. Tumor invasion and metastasis are aided by MET activation caused by aberrant paracrine stimulation of hepatocyte growth factor (102). In NSCLC, miR-409-3p inhibited the invasion and migration of A549 and SPC-1 NSCLC cells by negatively regulating MET, thereby exerting a tumor-suppressive effect (12). Similarly, following the transfection of miR-409-3p into T24 and 5637 BCa cell lines, the expression of MET, which could induce migration and invasion, was directly reduced (59). In addition, the downregulation of HMGN5 also accounted for the anti- and pro-metastatic action of miR-409-3p in U251 and U87 glioma cells, respectively. In addition, the downregulation of HMGN5 also accounted for the anti-metastatic action of miR-409-3p in glioblastoma (79). In HCC, Chang et al (83) observed that the relative migration and invasion rate of Huh-7 cells treated with miR-409-3p mimics was significantly decreased by regulating BRF2 RNA polymerase III transcription initiation factor subunit (BRF2). After silencing LINC00886, the expression level of miR-409-3p was upregulated, which weakened the invasion and migration of HCC cells (Hep3B, Huh7). Conversely, overexpression of LINC00886 has the opposite effect (84).

MiR-409-3p regulates numerous genes involved in autophagy, chemoresistance and radioresistance (Fig. 4).

Generally speaking, autophagy is a normal physiological process within cells, which involves loading damaged proteins and organelles from the cytoplasm into autophagosomes, and then fusing with lysosomes for degradation and reuse (103). Phosphatidylinositol 3-kinase class III and beclin-1 are involved in autophagosome formation (104). In a previous study, when the ratio of light chain (LC)3I and LC3II decreased, it was used as one of the criteria for autophagy. Autophagy is thought to be a primary mechanism of cancer cell chemoresistance (105,106). Recent studies have discovered that abnormal miRNA expression has a role in the molecular mechanisms of chemoresistance. The regulatory function of miR-409-3p on cancer cells' chemoresistance has been discussed in previous studies. In BC, circTRIM28 knockdown improved tamoxifen sensitivity through the miR-409-3p/HMGA2 axis (30). Furthermore, miR-409-3p, as a promising therapeutic target in CRC, has been shown to improve CRC cell susceptibility to chemotherapeutic drugs such as oxaliplatin (48,50). Of note, Tan et al (48) found that miR-409-3p expression was clearly upregulated in CRC cells with sensitivity to oxaliplatin, and promoted the chemosensitivity of LoVo Oxa-R CRC cells by inhibiting beclin-1-mediated autophagy. Most importantly, the autophagy-related protein LCII was higher and lower expressed in LoVo Oxa-R and LoVo CRC cells, respectively. Furthermore, Han et al (50) discovered that curcumin treatment increased the expression of miR-409-3p in HCT-116/L-OHP CRC cells in a concentration-dependent manner, increasing the sensitivity of CRC cells to chemotherapeutic drugs through the partial inhibition of survivin, P-glycoprotein and multidrug resistance-related protein. Of note, Cheng et al (54) found that miR-409-3p acting as an anti-cancer factor enhanced the sensitivity of OC cells to cisplatin treatment by inhibiting FIP200-mediated autophagy. Furthermore, in contrast to OC cells responsive to cisplatin treatment, cells resistant to cisplatin treatment had a lower miR-409-3p expression and significantly higher autophagic activity. It was indicated that miR-409-3p could also be a therapeutic target in OC resistance. In addition, DLBCL is a heterogeneous disease and the most common lymphoid malignancy. Using lentiviral vectors, Leivonen et al (64) found that the functional overexpression of miR-409-3p improved the sensitivity of DLBCL cells to chemotherapeutic agents such as rituximab and doxorubicin. These findings suggested that miR-409-3p can enhance the effects of chemotherapeutic agents in several types of cancers and act as a chemosensitizer. Of note, despite abundant evidence pinpointing that chemoresistance is caused by autophagy, two research teams found the opposite results: The first was that L-6-hydroxymethyl-c hiro-inositol 2[R]-2-O-methyl-3-O-octadecyl carbonate, an AKT inhibitor, could accelerate radiosensitivity by guiding autophagy (107), and the other was that rapamycin, an inhibitor of mTOR, radiosensitized HCC827 NSCLC cells by inhibiting the action of phosphatase and tensin homolog (108), a tumor suppressor, to positively regulate autophagy (109). Hence, based on the relationships between autophagy and treatment resistance, whether these contrasting findings reflect the differences between different treatment regimens such as chemotherapy or radiotherapy and different types of cancer is worthy of further exploration.

Another popular cancer treatment is radiotherapy. In NSCLC, Liu et al (20) found that CBR3-AS1/miR-409-3p/SOD1 signaling reduced reactive oxygen species levels by reducing H2AX foci, which in turn decreased apoptosis following ionizing radiation. In addition, H1270 and A549 NSCLC cells with high expression of miR-409-3p exhibited enhanced sensitivity to irradiation by direct targeting of AQP4 (21).

To meet their energy needs for proliferation and metastasis, cancer cells mostly rely on glycolysis. Aerobic glycolysis is an abnormal process of energy metabolism in cancer (110). Rate-limiting enzymes HK2, LDHA and GLUT1 are the key components of the glycolysis pathway. In NSCLC, DUXAP8 served as an miR-409-3p sponge to promote HK2 and LDHA expression. By regulating the miR-409-3p/HK2/LDHA axis, DUXAP8 promoted glycolysis (16). In addition, Chen et al (51) demonstrated that LINC00630 controlled glycolysis primarily by targeting the miR-409-3p/HK2 axis, which may explain the development of CRC and offer a possible target for its treatment. Likewise, ATF1, an miR-409-3p target, conspicuously reduced the extracellular acidification rate, glucose uptake and lactic acid generation in CC (33). A study by Wang et al (58) indicated that miR-409-3p served as a suppressor in glycolysis. In the A-498 and 769-P ccRCC cell lines, HIF-1α, an important molecule for cancer cells to respond to a hypoxic microenvironment (111), could induce the decrease of miR-409-3p expression and weaken the inhibitory effect of miR-409-3p on 3-phosphoinositide dependent kinase 1, a molecule required for metabolic activation. In osteosarcoma, miR-409-3p decreased LDH2 expression, which was associated with a decrease in glucose absorption, lactate generation and extracellular acidification rate (112).

Angiogenesis refers to the process of producing new blood vessels from pre-existing posterior venules of capillaries and has a critical role in embryonic development, wound healing and inflammation (113). In addition, the growth and metastasis of tumors largely depend on angiogenesis (114). MiR-409-3p appears to have a significant role in tumor angiogenesis, according to new research. The capacity of HT1080 fibrosarcoma cells to form tubular structures on Matrigel^® was significantly diminished when miR-409-3p was overexpressed compared with control cells, according to in vitro investigations. However, this inhibition could be reversed by ANG overexpression (81).

The incidence and progression of malignancies are linked to the Wnt/β-Catenin signaling pathway, which enhances tumor stem cell proliferation, survival and differentiation (115). NLK is an evolutionarily conserved MAPK, highly expressed in nerve tissues (116,117). When NLK phosphorylation is activated, it can phosphorylate substrates that participate in the Wnt/β-Catenin signaling pathway (118). Hence, in CRC, miR-409-3p downregulation could boost NLK expression and increase the expression of the Wnt/β-Catenin signaling pathway, regulating CRC cell proliferation and metastasis (45). In addition, using functional enrichment analysis, Zhang et al (55) demonstrated that the targeted genes of miR-409-3p are implicated in the pathway, and the negative regulatory association between miR-409-3p and C-terminal binding protein 1 (CTBP1) was verified using OC data in The Cancer Genome Atlas (TCGA). A study by Deng et al (119) indicated that CTBP1 activates the expression gene of Wnt genes, thereby regulating the signaling pathway. Chang et al (83) found that miR-409-3p regulated BRF2, which enhanced invasion and metastasis in HCC via the Wnt/β-catenin signaling pathway.

According to a vast number of studies, miR-409-3p is found in most oncogenic signaling pathways. One of the many signaling pathways involved in cell growth and survival is the PI3K/AKT/mTOR signaling pathway. MET is a tyrosine kinase protein in response to a hepatocyte growth factor that plays an essential part in cancer progression, including in morphogenesis, mitogenesis, metastasis, proliferation and survival (120). In vitro experiments confirmed that miR-409-3p has MET as its direct target; it inactivated AKT signaling and achieved the effect of inhibiting cancer proliferation, invasion and migration, as well as promoting apoptosis in NSCLC (12). Another group also found that, by inhibiting the expression of SPIN1, miR-409-3p could inhibit components of PI3K/AKT, including the expression of BCL2, cAMP responsive element binding protein 1, p-AKT and cyclin D, thereby blocking the progression of NSCLC (14). Besides, as previously mentioned, AKT1 is a crucial downstream target kinase in the PI3K signaling cascade (121). In GC, miR-409-3p/AKT1 axis could influence GC cell lines, including MDA-ZMB-231, MDA-MB-468 and T47D cell proliferation and metastasis in vivo and vitro (26). In addition, in DLBCL, Leivonen et al (64) demonstrated that PIK3R1 was a targeted gene of miR-409-3p in SU-DHL-4 DLBCL cells by using lentiviral vectors. Most importantly, the PI3K/AKT pathway has been found to be involved in the progression of DLBCL, which exerts an obviously significant contribution to cellular processes and is expected to become a promising therapeutic target. Besides, in PCa, Yu et al (74) indicated that PCa cells subjected to CIRT delivered exosomal miR-409-3p, inhibiting AKT in the PI3K/AKT pathways in recipient cells, which is the main signaling pathway linked to apoptosis induction and proliferation inhibition, and which may be involved in the mechanism of action of CIRT.

MAPK cascade pathways are highly conserved and modulate cell proliferation, differentiation and migration by phosphorylating specific target protein substrates. MAPK consists of the following subfamilies, including extracellular signal-regulated kinases, c-Jun N-terminal kinase, p38 protein kinases and extracellular-signal-regulated kinase 5 (122). Furthermore, circFAT1 promoted cancer progression in the C-33A and CaSki CC cell lines, stimulating proliferation and metastasis, as well as inhibiting their apoptosis by activating the ERK1/2 and p38 MAPK pathway (34). Of note, in malignant hematological diseases such as DLBCL, miR-409-3p has been indicated to suppress MAPK1 mRNA and ERK1/2 protein levels and improve the chemosensitivity of cells in vitro, indicating that the MAPK pathway is involved in the progression of DLBCL (64).