As we all know, breast cancer is the most common malignant tumor in female reproductive system. According to the global cancer statistics in 2018, there are about 2.1 million newly diagnosed cases of female breast cancer, accounting for 1/4 of female cancer, which is a serious threat to the health of women around the world (34).

Fortunately, many of the recent and upcoming anticancer drugs are attempted to treat breast cancer. It has been reported that paclitaxel (PTX) is a first-line drug for the treatment of breast cancer. However, due to the resistance of breast cancer to PTX, the application of PTX is limited (35). Recently, a study by Xiang et al. revealed that ursolic acid (UA), a pentacyclic triterpenoid existing widely in plant, can reverse the resistance of MDA-MB-231, one breast cancer cell line, to PTX. The expression of miR-149-5p in 231/PTX cells treated with UA was remarkably higher compared to untreated 231/PTX cells. Intriguingly, the reverse effect of UA disappeared after miR-149-5p inhibitors treatment, indicating that UA has a reversal effect by up-regulating the expression of miR-149-5p. Bioinformatics analysis showed that there was a binding site of miR-149-5p in the 3’-UTR of MyD88. Furthermore, the reversal effect of UA in 231/PTX cell disappeared after overexpression of MyD88, suggesting that miR-149-5p negatively regulate the expression of MyD88 by binding to its 3’-UTR, thereby reversing drug resistance of breast cancer (36). The protective effect of miR-149-5p was also proved in trastuzumab resistance (Tr-R). At present, trastuzumab is the first choice for treating HER2-overexpressing breast cancer by restraining HER2 expression, but its drug resistance is gradually increasing (37). Tian and coworkers found that propofol, a common intravenous anesthetic, has anti-cancer effects in breast cancer via epigenetically upregulating miR-149-5p expression in HER2-overexpressing cell with Tr-R (38). In short, miR-149-5p might be a target for reversing drug resistance in breast cancer, and finding an upstream regulator of miR-149-5p is also important for comprehending the intrinsic mechanism. Qi and collaborators found that circ_0072995 promotes breast cancer cell progression by acting as a sponge for miR-149-5p, thereby upregulating serine hydroxymethyltransferase 2 (SHMT2), an oncogene in breast cancer (39). Later, Temiz et al. found that in breast cancer, overexpression of miR-149-5p reduces the expression of Chaperonin Containing TCP1 Subunit 3 (CCT3), which leads to the destruction of intracellular reactive oxygen species (ROS) homeostasis and the distribution of free amino acids in energy metabolism, and promotes tumor cell apoptosis (14).

Collectively, miR-149-5p may act as a tumor suppressor and restoring the expression of miR-149-5p in breast cancer may be an effective strategy for breast cancer treatment ( Figure 1 ).

Ovarian cancer is the third most common gynecological malignant tumor in the world, but it has the highest mortality among these cancers. Globally, there are 239000 new cases and 152000 deaths each year (40). The treatment of ovarian cancer, especially advanced and recurrent ovarian cancer, has always been the biggest challenge in clinical work.

Xu et al. found that the expression of miR-149-5p in chemotherapy-resistant ovarian cancer tissues is abnormally higher than that in chemotherapy-sensitive ovarian cancer tissues and non-cancer tissues. Functionally, silencing of miR-149-5p enhanced the sensitivity of ovarian cancer cells to cisplatin in vivo and in vitro. On the contrary, overexpression of miR-149-5p increased the chemotherapy resistance of ovarian cancer cells. Mechanistical studies showed that miR-149-5p directly inhibits MST1 and SAV1, two key proteins in Hippo pathway, thereby leading to inactivation of Hippo signals and promoting chemotherapy resistance of ovarian cancer cells to cisplatin (41).

Paradoxically, Sun et al. found that the expression of miR-149-5p is down-regulated in chemotherapy-resistant ovarian cancer tissues and cells, and the overexpression of miR-149-5p inhibited the growth of ovarian cancer cells and promoted apoptosis and cisplatin sensitivity (42). Consistently, Wei et al. found that compared with PTX-sensitive ovarian cancer tissues and cells, the expression of miR-149-5p was down-regulated in PTX-resistant ovarian cancer tissues and cells. And overexpression of miR-149-5p could enhance the sensitivity of PTX, inhibit cell viability and clone formation, block cell cycle, and induce apoptosis of PTX-resistant cells. In addition, inhibition of miR-149-5p could effectively reverse the effects of circ_CELSR1 deficiency on PTX resistance, cell survival, colony formation, cell cycle and apoptosis of PTX-resistant cells, indicating that circ_CELSR1 increased PTX resistance of PTX-resistant cells through acting sponges for miR-149-5p. The up-regulation of salt inducible kinase 2 (SIK2) reversed the inhibitory effect of miR-149-5p on PTX resistance and cell progression in PTX-resistant ovarian cancer cells, indicating that miR-149-5p enhanced PTX sensitivity by targeting SIK2. In summary, they found that circ_CELSR1 can act as a sponge for miR-149-5p, thus regulating the expression of SIK2 (43). Moreover, Li et al. found that the expression of PVT1 increased in ovarian cancer, and circular PVT1 regulated miR-149-5p in the form of ceRNA, and then up-regulated Forkhead Box M1 (FOXM1), subsequently promoting the occurrence of ovarian cancer (44).

Conclusively, the emerging role of miR-149-5p is gradually investigated ( Figure 1 ), but due to the contrary opinions, the function of miR-149-5p in ovarian cancer needs to be further studied.

Cervical cancer is a growing global burden for both developing and developed countries. It is estimated that there were 570000 cases and 311000 deaths worldwide in 2018, making it the fourth most commonly diagnosed cancer among women and the fourth leading cause of cancer death among women (34).

Based on microRNA sequencing and bioinformatics analysis, miR-149-5p was found as a potential regulatory factor in HPV-positive cervical squamous cell carcinoma (45). Recently, Shao et al. found that the expression of hsa_circ_0075341 is aberrantly up-regulated in patients with cervical cancer, which was related to tumor size, FIGO stage progression and lymph node metastasis. Inhibition of hsa_circ_0075341 in vitro weakened the proliferation and invasion of cervical cancer cells. Circinteractome analysis confirmed that hsa_circ_0075341 may have a target site for miR-149-5p, which was further verified by luciferase report experiment and qRT-PCR. Their study found that the expression of miR-149-5p is down-regulated in cervical cancer, which is related to poor prognosis. Rescue assay showed that inhibition of miR-149-5p can block the effect of circ_0075341 siRNA on the proliferation of cervical cancer cells. Therefore, hsa_circ_0075341 may act as a sponge for miR-149-5p in cervical cancer. In addition, they found that increased expression of Aurora kinase A (AURKA) was associated with poor prognosis in patients with cervical cancer. Functional analysis showed that inhibition of AURKA could reduce the proliferation and invasion of cervical cancer cells in vitro. In terms of mechanism, they further confirmed that AURKA is the target for miR-149-5p. Therefore, miR-149-5p may act as key modulator in the oncogenic role of hsa_circ_0075341 in cervical cancer, by binding 3’-UTR region of AURKA (23) ( Figure 1 ). Besides, Liu et al. found that hsa_circ_0061140 may play a role in promoting tumorigenesis in endometrial carcinoma by inducing the expression of STAT3 as a molecular sponge for miR-149-5p (46). Collectively, miR-149-5p may be a tumor suppressor in cervical cancer progression and further studies are needed to confirm its therapeutic effect.

Prostate cancer (PCa) is the most common non-skin cancer in men in the world. It is estimated that there are nearly 1.3 million new cases of PCa and 359000 related deaths worldwide in 2018, making it the second most common cause of cancer and the fifth leading cause of cancer death among men (34).

In 2019, Fu et al. found the anticancer effect of Fuzheng Yiliu decoction (FZYL), a Chinese medicinal formulae, combined with docetaxel (Doc) was enhanced in PCa, compared with one of them in a castration-resistant prostate cancer (CRPC) mouse model. By analyzing the differential miRNA in tumor tissues treated with Doc + FZYL, there were 10 specific miRNAs, in which miR-149-5p sharply decreased. The enrichment analysis of speculated target genes by KEGG and GO showed that Doc + FZYL-specific miRNAs may be involved in PI3K-Akt signal pathway to enhance the therapeutic effect (47).

Subsequently, Ma et al. found that the expression of miR-149-5p is down-regulated in PCa, and overexpression of miR-149-5p weakened the malignant degree of PCa cells by regulating Regulator of G Protein Signaling 17 (RGS17). Mechanistically, silencing of miR-149-5p upregulated the expression of RGS17 in PCa tissues and cells, while overexpression of miR-149-5p showed an opposite effect (48). Besides, Temiz et al. found that in PCa cell lines, overexpression of miR-149-5p can downregulate the expression of CCT3, which leads to the destruction of intracellular ROS homeostasis and the distribution of free amino acids in energy metabolism, and promotes tumor cell apoptosis (14).

Overall, miR-149-5p may be a vital tumor suppressor in reproductive system cancers ( Figure 1 ), but its function in ovarian cancer is controversial. To explore the diagnostic role in reproductive system cancers, essential studies are needed to perform.

Gastric cancer is a dangerous disease in the world, which threatens human lives. It is estimated that there are more than 1 million new cases of GC every year, making it the fifth largest disease diagnosed as a malignant tumor in the world. Because GC is often diagnosed at an advanced stage and has a high mortality rate, it ranked the third most common cause of cancer-related deaths, with 784000 deaths worldwide in 2018 (49).

The discovery of the role of miR-149-5p in GC is attributed to the studies on circRNA and lncRNA. Recently, the next-generation sequencing method was used to detect the differentially expressed circRNA in GC tissues. It was found that CircNRIP1 was up-regulated exponentially in GC tissues compared with adjacent normal gastric tissues, and the levels of CircNRIP1 were significantly correlated with the size of GC, lymphatic invasion, disease-free survival and overall survival. Functionally, CircNRIP1 knockdown successfully blocked the proliferation, migration, invasion and AKT1 expression of GC cells. Interestingly, miR-149-5p inhibited the oncogenic role of CircNRIP1 in GC cells, and the overexpression of miR-149-5p blocked the malignant behavior of CircNRIP1. Experiments in vitro suggested that CircNRIP1, as a sponge for miR-149-5p, promotes the progression of GC through AKT/mTOR-mediated metabolism and EMT pathway. In addition, CircNRIP1 can be transmitted between GC cells through exosome communication, and CircNRIP1 in exosomes can also promote tumor metastasis in vivo. Further studies on the mechanism show that RNA binding protein QKI can promote the cyclic transcription of NRIP1 gene. Finally, the tumor promoting effect of CircNRIP1 was verified in patient-derived xenograft (PDX) model (13).

Moreover, another study demonstrated that lncRNA BLACAT1 promotes the proliferation, migration and invasion of GC cells by regulating the miR-149-5p/KIF2A axis (50). CircNHSL1 can affect the expression of YWHAZ through sponging miR-149-5p, thereby regulating the progression of GC (51). Circ_0044516 could promote the expression of HuR through sponging miR-149-5p, thereby regulating the progression of GC (52). Importantly, Chen et al. reported low serum levels of miR-149-5p, combined with miR-1-3p, miR-125b-5p and miR-196a-5p, may be used as a noninvasive biomarker for gastric adenocarcinoma diagnosis (53). Given the crucial role of miRNA in cellular communication through exosome, it is necessary to explore whether miR-149-5p exists in exosome in GC.

Collectively, as a tumor suppressor in GC, miR-149-5p expression was imprisoned by a variety of lncRNAs and circRNAs ( Figure 2 ). Therefore, targeting some upstream non-coding RNAs is a good choice to rescue the normal levels of miR-149-5p.

Liver cancer is predicted to be the fourth leading cancer-related deaths and the sixth most commonly diagnosed cancer worldwide in 2018, posing a serious threat to human quality of life (34). Based on annual data, the World Health Organization estimates that more than 1 million people will die of liver cancer in 2030 (54). Hepatocellular carcinoma is the most common tumor in all primary liver cancer, accounting for 80% of the total number of cases (55).

In HCC, miR-149-5p was also regarded as tumor suppressor, and was regulated by several important lncRNAs. For example, Ji et al. found that LINC00461 was a ceRNA by directly sponging miR-149-5p in liver cancer cells, and then regulated LRIG2, to play a carcinogenic role (56). Zhou et al. found that lncRNA PART1 promotes the proliferation, migration and invasion of HCC cells by regulating the miR-149-5p/MAP2K1 axis (57). Moreover, Chen et al. confirmed that miR-149-5p was associated with lung metastasis in patients with liver cancer (58).

Niu et al. found that the expression of NEAT1 in HCC tissues was significantly higher than that in adjacent tissues. Functional analysis showed that NEAT1 could directly bind to miR-149-5p, leading to suppression of miR-149-5p/AKT1 axis, thereby promoting the drug resistance of HCC cells to sorafenib (59).

It is widely acknowledged that tumor microenvironment (TME) plays a crucial role in tumor growth, development and metastasis, among which inflammation is one of the most important factors, and macrophages are class of the most common immune-related cells in it. Macrophages can be classified into two types, classical macrophages (M1) and alternative (M2) macrophages, in microenvironment. In general, M1 macrophages play a pro-inflammatory role by expressing nitric oxide synthase (INOS), while M2 macrophages express anti-inflammatory cytokines, such as IL-10, to promote tumor progression and metastasis (60). Liu et al. found that M2 macrophages may increase the expression of MMP9 by reducing the level of miR-149-5p in HCC cells and promote the progression of HCC (15), further confirmed the tumor suppressive role of miR-149-5p in HCC. Interestingly, increasing evidences revealed that hypoxia can regulate the status of tumor immune microenvironment, such as promoting the release of inflammation factors, enhancing the recruitment of innate immune cells (61). Thus, it is meaningful for researchers to study whether hypoxia alters the level of miR-149-5p and whether miR-149-5p is involved in the changes of immune microenvironment induced by hypoxia in HCC.

In order to accurately predict the prognosis of HCC patients, many teams have constructed a model containing miRNAs (62–64). Inconsistent with above mentioned studies ( Figure 2 ), they reported that miR-149-5p was one of the elements, and its high expression was associated with poor prognosis. Therefore, further studies should pay more attention on clinical samples, and analyze the correlation between miR-149-5p with HCC.

A few decades ago, CRC was rarely diagnosed. According to 2018 GLOBOCAN, CRC ranks third in terms of incidence, but second in terms of mortality. Over 1.8 million new CRC cases and 881,000 deaths are estimated to occur in 2018, accounting for about 1 in 10 cancer cases and deaths (34). The incidence and mortality of CRC vary geographically, with the highest rates in developed countries, but with the continuous progress of developing countries, the global incidence of CRC is expected to increase to 2.5 million new cases by 2035 (65).

By analyzing TCGA RNA sequencing data and other publicly available microarray data, Lian et al. found a new lncRNA, LINC00460, whose expression in CRC tissues is significantly higher than that in adjacent normal tissues. Importantly, the high levels of LINC00460 in CRC were associated with larger tumor, advanced tumor stage, lymph node metastasis and shorter overall survival. Functional studies indicated LINC00460 can promote proliferation and inhibit apoptosis of CRC cells in vitro and in vivo. Mechanistical studies demonstrated that LINC00460 can be served as a molecular sponge for miR-149-5p, antagonizing its capacity to inhibit cullin 4A (CUL4A) protein translation, which suggests a tumor suppressive role of miR-149-5p, in contrast to the oncogenic function of LINC00460 in CRC (16). Consistently, Ruan et al. confirmed that LINC00460 can be used as the ceRNA for miR-149-5p to up-regulate BGN, thus promotes the metastasis of CRC cells (22).

It has been reported that oxaliplatin resistance was a major challenge in clinical treatment of advanced CRC (66). Meng et al. reported that LINC00460-miR-149-5p/miR-150-5p-mutant p53 feedback loop was associated with oxaliplatin resistance in CRC. LINC00460 was exhibited a high level in oxaliplatin-resistant CRC (CRC/OxR) cells than that in oxaliplatin-sensitive CRC cells, and this expression pattern depends on mutant p53 (SW480/OxR) rather than wild-type p53 (HCT116/OxR). Further studies suggested that LINC00460 promotes oxaliplatin resistance by inhibiting miR-149-5p/miR-150-5p, and improving the expression of miRNA-targeted p53 (21). Moreover, Qu et al. found that lncRNA DLGAP1-AS1 knockdown inhibits the occurrence of CRC by regulating miR-149-5p/TGFB2/Smad2 signal pathway in vivo and in vitro, and improves the sensitivity of 5-FU (67). These studies highlighted an important role of miR-149-5p in CRC, and the intimate regulatory relation between miRNA-149-5p and lncRNAs.

It is worth mentioning that the levels of miR-149-5p are also regulated by two newly discovered circRNAs, Circ5615 and CircCTNNA1. The study by Ma et al. first explored the expression profile of circRNA in 5 pairs of CRC tissues by microarray, and found that one CircRNA, hsa_CIRC_0005615 (Circ5615) was remarkably up-regulated in CRC tissues. The upregulation is closely related to the high T stage and poor prognosis of patients with CRC. Studies in vitro and in vivo have shown that in CRC cells, Circ5615 gene knockdown inhibited cell proliferation and cell cycle acceleration, while overexpression promoted malignant phenotype. Mechanism studies have shown that Circ5615, as a sponge for miR-149-5p, inhibits miRNA-mediated inhibition of target gene TNKS. The increase of TNKs level can stabilize β-catenin by stimulating the degradation of AXIN2. Promote the proliferation of CRC cells through Wnt/β-catenin pathway (68).

Similarly, Chen et al. used CircRNA and mRNA microarray techniques to analyze the colon cancer tissues and paracancerous normal tissues of 3 patients with colon cancer. The most related mRNA (FOXM1) and CircRNA (CircCTNNA1, a new CircRNA) were significantly up-regulated in colon cancer, and their levels were related to the stage of lymph node metastasis, poor prognosis and poor survival in patients with colon cancer. CircCTNNA1 can promote the proliferation, migration and invasion of colon cancer cells in vitro and in vivo. Functional analysis showed that CircCTNNA1 could be used as a ceRNA of miR-149-5p to counteract the inhibitory effect of miR-149-5p on downstream target gene FOXM1 (69).

Collectively, miR-149-5p exerts a tumor suppressive role in CRC, and is usually regulated by some crucial lncRNAs and circRNAs ( Figure 2 ).

In addition to GC, HCC and CRC, miR-149-5p has also been studied in other digestive system cancers, including oral cancer, esophageal cancer and ductal adenocarcinoma of the pancreas (70–76).

According to statistics, more than 140000 people die of oral cancer every year. More than 300000 people are diagnosed with oral cancer each year (77). Studies reported that the expression of miR-149-5p was decreased in oral carcinoma, including tongue squamous cell carcinoma (71) and oral squamous cell carcinoma (OSCC) (75). Luo et al. found that the expression of miR-149-5p in cisplatin-resistant cell line (CAL-27/CDDP) was lower than that in normal OSCC cell line (CAL-27). Functional analysis showed that miR-149-5p could enhance the chemosensitivity of OSCC cells to cisplatin by targeting TGF β2, inhibit cell proliferation, migration and invasion, and promote apoptosis (75). Notably, Qiu et al. confirmed that CircBICD2 knockdown could inhibit the proliferation, migration, invasion, glutamine degradation and increase apoptosis of OSCC cells by regulating the miR-149-5p/IGF2BP1 axis (70). Similarly, down-regulation of lncRNA DLEU1 could inhibit the occurrence of OSCC by regulating the miR-149-5p/CDK6 axis (76).

Esophageal cancer is a global problem and the sixth most common cause of cancer death every year. In 2018, an estimated 572000 people worldwide were diagnosed with esophageal cancer and 509000 died of the disease, indicating a high mortality rate from esophageal cancer (34). The expression of miR-149-5p was low, while LincDRAIC and NFIB were highly expressed in esophageal cancer cells. Down-regulation of DRAIC, NFIB and up-regulation of miR-149-5p can inhibit the proliferation, invasion, and promote apoptosis and autophagy of esophageal cancer cells at the meanwhile. Further studies suggested that DRAIC could act as a sponge for miR-149-5p (72). Consistently, Xu et al. found that miR-149-5p was remarkably down-regulated in esophageal squamous cell carcinoma tissues and cell lines. CIRC_0000654 can be used as a sponge for miR-149-5p to promote the progression of esophageal cancer by indirectly activating IL-6/STAT3 signal pathway (73).

Compared with healthy people and patients with benign pancreatic lesions, the expression of miR-149-5p in serum exosome of patients with pancreatic ductal adenocarcinoma (PDAC) was up-regulated (74). But no further studies elucidated the role of miR-149-5p in PDAC, thus to explore the prognostic and diagnostic role of miR-149-5p, more researches should focus on its function in tumor initiation and progression rather than merely examining its expression level.

Lung cancer remains the most common cancer (11.6% of all cancers) and the leading cause of cancer deaths, with about 1.8 million deaths worldwide in 2018 (78). Histologically, lung cancer is divided into two categories: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), in which NSCLC accounts for more than 80% of lung cancer (79).

The role of miR-149-5p in lung cancer is still controversial ( Figure 3 ). In 2016, Yang et al. made a comprehensive analysis of the expression profiles of miRNA and mRNA in NSCLC tissues for the first time, and found that the expression of miR-149-5p in cancer tissues was up-regulated compared with that in paracancerous tissues (80). On the contrary, Li et al. found that the expression of miR-149-5p was down-regulated in NSCLC tissues and cell lines. LncRNA PCAT-1 promoted the growth of NSCLC cells by up-regulating LRIG2 through acting as a ceRNA for miR-149-5p, indicating tumor suppressive role of miR-149-5p (81). Consistently, Liu et al. also found that the expression of miR-149-5p was relatively down-regulated in NSCLC. LncRNA HNF1A-AS1, a newly found “oncogene”, was reported to promote the proliferation, migration and invasion of NSCLC cells through sponging with miR-149-5p and targeting CDK6 (82). Zhou et al. found that MIAT can directly bind to miR-149-5p, and then act as a sponge to improve the expression level of FOXM1 and promote the process of NSCLC (83). Li et al. found that HOTAIR can be used as the endogenous ceRNA of miR-149-5p to promote the expression of HNRNPA1, and then promote the proliferation, migration and invasion of NSCLC cells (84). Similarly, Wei et al. found that CircFOXM1 promotes the development of NSCLC by regulating the miR-149-5p/ATG5 axis (85).

Besides, β1, 3-N-acetylglucosaminyltransferase-3(B3GNT3) was reported be abnormally expressed in lung cancer, and the overexpression of B3GNT3 is related to the poor prognosis of patients with lung cancer. Further studies indicated miR-149-5p had a negative regulatory effect on lung cancer progression, and downregulating the expression of B3GNT3 by directly targeting 3’-UTR of B3GNT3. Overexpression of miR-149-5p can antagonize the tumorigenicity of B3GNT3 in vitro (86).

Platinum-based chemotherapy after surgical resection has become the standard strategy for the treatment of NSCLC (87). However, the clinical results of patients with NSCLC are still disappointing, mainly due to acquired clinical drug resistance (88). Therefore, reducing drug resistance may be a promising method for the treatment of cisplatin-resistant NSCLC patients.

Zhan et al. found that the expression of lncRNA HOTAIR was up-regulated in DDP-resistant NSCLC tumor tissues and cell lines (A549/DDP and H1299/DDP). The knockdown of HOTAIR decreased the acquired resistance of A549/DDP and H1299/DDP cells to cisplatin, which was characterized by the decrease of 50% inhibitory concentration (IC50) of DDP, the weakening of cell proliferation, migration and invasion in vitro, and the inhibition of tumor growth in vivo. Functionally, miR-149-5p deletion counteracted the inhibitory effect of HOTAIR gene knockdown on cisplatin resistance; on the contrary, restoring miR-149-5p showed a similar inhibitory effect on cisplatin resistance in vitro, and up-regulation of DCLK1 weakened this inhibitory effect. In conclusion, HOTAIR gene knockdown can enhance the cisplatin sensitivity of cisplatin-resistant NSCLC cells partly by regulating the miR-149-5p/DCLK1 axis (89).

Non-small cell lung cancer is a heterogeneous tumor, that can be divided into lung adenocarcinoma(LUAD) and lung squamous cell carcinoma (LUSC) (90). It has been reported that epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) is the first choice for the treatment of LUAD with EGFR activation mutation. However, although the initial response to EGFR-TKI treatment was good, most patients eventually developed EGFR-TKI resistance and relapsed within 1 year.

In LUAD cells, LINC00460 promotes EGFR-TKI resistance as a competitive bait for miR-149-5p, thus promoting the expression of IL-6 and inducing EMT-like phenotype. In LUAD cells resistant to gefitinib, the knockdown of LINC00460 restored the response to EGFR-TKI. In addition, compared to patients with low expression of LINC00460 in tumors, patients with high expression of LINC00460 had significantly shorter progression-free survival and shorter overall survival after gefitinib treatment. The discovery of the importance of LINC00460 may lead to its application as a prognostic factor, a diagnostic index of EGFR-TKIs and a molecular target of drugs (91).

Conversely, miR-149-5p was reported be highly expressed in peripheral blood exosome of patients with LUAD. The upregulation of miR-149-5p in exosomes promoted the growth of tumor cells and inhibited the apoptosis of tumor cells. The results of ROC curve analysis showed that exosome miR-149-5p was of good value in the diagnosis of LUAD. Exosome miR-149-5p can directly bind to AMOTL2 and mediate tumor cell proliferation and apoptosis, suggesting that exosome miR-149-5p may be a reliable biomarker of TME in LUAD (17).

Collectively, miR-149-5p may play a tumor suppressive role in NSCLC, and its low expression is usually caused by some oncogenic ceRNAs. However, in LUAD, miR-149-5p is highly expressed in exosome, displaying a tumor promotive role. Therefore, it is important to clarify the role of miR-149-5p in lung cancer, and to detect the exosome miR-149-5p will be more effective to estimate the disease stage.

Nasopharyngeal carcinoma (NPC) is a type of epithelial carcinoma originating from the lining of nasopharyngeal mucosa. According to the International Agency for Research on Cancer, there were about 129000 new cases of NPC in 2018, accounting for only 0.7 percent of all cancers diagnosed in January 2018. However, its global geographical distribution is extremely uneven, with more than 70% of new cases occurring in East and Southeast Asia (92). At present, radiotherapy, chemotherapy and radiotherapy are the main methods for the treatment of NPC, but some patients always grow to the neck and/or distant metastasis, because of their high metastasis, the prognosis is still very poor (93). Therefore, it is necessary to further study the molecular mechanism of NPC and more effective treatment strategies.

Kong et al. identified a new lncRNA, LINC00460, that is located on chromosome 13q33.2 and is transcribed into a 935nt transcript. The expression of LINC00460 in NPC is significantly higher than that in non-tumor tissues. The overexpression of LINC00460 is closely related to the poor prognosis of patients with NPC. Silencing LINC00460 can inhibit the proliferation of NPC cells in vivo and in vitro. Mechanistic studies showed that LINC00460 may play an oncogenic role partly by up-regulating the target gene IL-6, acting as a sponge for miR-149-5p in NPC (94). Therefore, the tumor suppressive role of miR-149-5p may be inhibited by LINC00460 in NPC.

Renal cell carcinoma (RCC) affects more than 400,000 people worldwide every year. The age of diagnosis is about 60 years old, and the number of males is twice as high as that of females (95).

Jin et al. clarified the expression and function of miR-149-5p in RCC for the first time. Compared with normal renal tissue, the expression of miR-149-5p was significantly down-regulated in RCC. Restoring the expression of miR-149-5p with synthetic mimics could inhibit the proliferation and migration and promote apoptosis of RCC cells (96).

The most common subtype of RCC is clear cell renal cell carcinoma(ccRCC) with high morbidity and poor prognosis (97). Okato’s team studied the role of pre-miR-149’s dual strands in ccRCC. The expression level of miR-149-5p in cancer tissues was significantly lower than that in normal tissues, but there was no significant difference in the expression level of miR-149-3p between cancer tissues and non-cancer tissues. The overexpression of miR-149-5p and miR-149-3p could inhibit the proliferation, migration and invasion of renal cancer cells, showing anti-tumor effect. After screening, FOXM1 was the downstream gene of miR-149-5p and miR-149-3p. Compared with normal tissues, the expression of FOXM1 in cancer tissues was significantly up-regulated. In this study, they speculated that miR-149-5p and miR-149-3p jointly regulate the progression and metastasis of ccRCC by acting on FOXM1 (98). These results suggest that miR-149-5p may be a tumor suppressor in RCC.

In addition, Xie et al. constructed a signature containing four-miRNA (miR-21-5p, miR-9-5p, miR-149-5p, and miR-30b-5p), which was related to the survival of ccRCC and can be used as a prognostic biomarker of ccRCC (99). In short, it is crucial for researchers to detect serum miR-149-5p and study whether exosome miR-149-5p is involved in progression of RCC.

Bladder cancer (BC) brings a huge social burden, with more than 500000 new diagnoses and 200000 deaths worldwide every year. The impact of the disease on men (3:1 ratio) is disproportionate to that of the elderly, with a median age of 69 years for men and 71 years for women at the time of diagnosis (100, 101).

CircRNA_100146 was highly expressed in BC, and the increase of circRNA_100146 indicated a poor prognosis of patients with BC. CircRNA_100146 promoted the proliferation, migration and invasion of BC cells through sponging miR-149-5p and promoting the expression of RNF2 (102).

In addition, Lin and other researchers found that the expression level of miR-149-5p in urine of patients with BC were significantly higher than that of healthy controls. The high expression of miR-149-5p was significantly correlated with the overall survival rate of patients with BC, suggesting that urinary miR-149-5p may be a potential biomarker for non-invasive BC detection (103).