Lung cancer (LC) is the leading cause of cancer-related death, with high incidence and mortality rate. Early diagnosis and treatment of LC are imperative to improve the 5-year survival rate for patients with LC. In recent years, miRNAs as promising biomarkers with high sensitivity and specificity for LC have been studied increasingly. In LC regulatory networks, miRNAs play crucial roles in the occurrence, development and metastasis of non-small cell lung cancer (NSCLC), such as oncogenic factors, tumor suppressors and regulators. Dysfunctional miRNAs perform tumor-suppressive or oncogenic functions in the regulation of cell proliferation, invasion, apoptosis, cell cycle disorder and angiogenesis by negatively regulating target genes. In the present review, the biological process of miRNAs was firstly summarized and recent advances in the mechanism of miRNAs involved in tumor formation and development were described. In addition, the present review concentrated on the latest findings on the miRNAs related with circulating free and extracellular vesicles in the early diagnosis of NSCLC. Additionally, the diagnostic performances of circulating free and extracellular vesicles-associated miRNAs in NSCLC were contrasted. Owing to the increased stability and wide-ranging practical applicability, miRNA may be one promising biomarker for NSCLC diagnosis.
non-small cell lung cancermicroRNAsbiomarkersearly diagnosisexosomesFunding: No funding was received.Introduction
Lung cancer (LC) is the most common cancer worldwide and the second largest cause of cancer morbidity and mortality, with 2.2 million new cases and 1.8 million deaths in 2020 (1). It is predicted that the number of incident cases of LC will reach 3.8 million by 2050 (2). LC is classified into two types based on pathological characteristics: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with the latter including lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC) and large cell carcinoma (LCC) (3). NSCLC is the most common pathological type of LC, which accounts for ~85% of all cases. The mechanism of leading to LC is the apoptosis of alveolar epithelial cells mediated by asbestos via mitochondrial and p53-regulated death pathways in the human body (4). Additional disorders associated with LC include chronic obstructive pulmonary disease, tuberculosis, emphysema and interstitial lung disease (5,6).
Due to the insidious nature of NSCLC, the illness is typically diagnosed at advanced stages and the 5-year survival rate is less than 15% (7). Patients with NSCLC who receive radical surgery at an early stage can have the 5-year survival rate of 40–70% (8). Therefore, early diagnosis of NSCLC could significantly reduce patient mortality. Currently, the main clinical strategy for diagnosing NSCLC is a low-dose computed tomography (LDCT) scan. However, LDCT has certain drawbacks, such as overdiagnosis, harmful radiation exposure from repeated detections, and elevated anxiety in patients. Researchers have studied certain new biomarkers with high specificity and sensitivity for NSCLC, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), circulating tumor cells and circulating tumor DNA (9–11). Particularly, miRNAs have attracted more attention in the field of high-quality biomarkers.
miRNAs are small and evolutionarily conserved class of non-coding RNAs (ncRNAs) with a size of ~19–25 nucleotides. miRNAs are key transcriptional regulators and can affect a variety of biological functions by targeting the 3′ untranslated region (UTR) of messenger RNA (mRNA) to induce mRNA degradation and inhibit translation (12). The first miRNA, lin4, was discovered in Caenorhabditis elegans in 1993 (13). At present, more than 2,000 miRNAs have been identified in the human genome, which are involved in the regulation of a variety of physiological and pathological processes. Therefore, miRNAs have been widely researched as potential biomarkers and therapeutic targets (14).
Exosomes are membrane-enclosed extracellular vesicles with a diameter of 30–150 nm. In addition to proteins and lipids, exosomes also contain a rich trove of nucleic acid metabolites such as miRNAs and lncRNAs (15). Tumor cells generate exosomes that contain abundant miRNAs, and tumor-specific exosomal miRNAs vanish when tumor tissue is removed. The expression profiles of exosomal miRNAs derived from plasma or serum are significantly different between NSCLC patients and healthy controls (16).
In the present review, a variety of serum and plasma miRNAs with high specificity and sensitivity that play an important role in the early diagnosis of NSCLC were summarized. Finally, the value of exosomal miRNAs as novel biomarkers for NSCLC diagnosis was emphasized.
miRNA biogenesis and function
The majority of miRNA genes are located in the intron and intergenic regions of protein-coding genes (17), which are transcribed by RNA polymerase II (Pol II) and RNA polymerase III (Pol III) (18). The typical biogenesis of miRNAs involves the beginning in the nucleus and the ending in the cytoplasm (Fig. 1), and comprises three main events: cropping, export and dicing (19). miRNA is typically generated from a primary miRNA (pri-miRNA) transcript through two consecutive cutting events. The pri-miRNA is usually added with a 5′ cap structure and a 3′ poly (A) tail, containing one or more long hairpin structures. Because the structural characteristics of these hairpins are unique, they can be distinguished from various RNA stem ring-like structures in the nucleus. Pri-miRNA hairpins typically have an imperfect 30 bp stem with flanking single-stranded RNA fragments at the base (20). Initially, pri-miRNAs are cleaved in the nucleus by a microprocessor complex, which is composed of the RNase III enzyme Drosha, the double-stranded RNA-binding protein (RBP) DiGeorge syndrome critical region gene 8 (DGCR8) and associated proteins (21). DGCR8 recognizes the connection between the stem and the flanking single-stranded RNA of the pri-miRNA hairpin, recruits Drosha, cuts the RNA double strand, and produces a 70-bp stem-loop structure known as precursor miRNA (pre-miRNA) (22,23). Methyltransferase-like 3 (METTL3) methylates pri-miRNA, which can be recognized and processed by DGCR8. METTL3 depletion reduces DGCR8 and pri-miRNA binding, resulting in a decrease in mature miRNA and an increase in unprocessed pri-miRNA accumulation (24). Pre-miRNA is transported to the cytoplasm by exportin-5, and cleaved by the cytoplasmic RNase III enzyme Dicer to produce mature double-stranded miRNA. Then the mature double-stranded miRNA binds to Argonaute (AGO) protein and forms a miRNA-induced silencing complex (miRISC). The mature chain is kept in miRISC, while the over-guest chain is released and degraded (25). By complementary pairing with the binding site of the 3′-UTR mRNAs, miRNAs lead to target mRNA degradation and/or translation inhibition of target genes (26). Under normal physiological conditions, miRNAs regulate cell biological processes such as proliferation, differentiation, apoptosis and protein synthesis. Therefore, its disturbance is involved in the regulation of tumor development and progression. In addition, a single miRNA can regulate multiple interaction networks and translation processes by targeting multiple mRNAs, whereas an mRNA can be regulated by multiple miRNAs (27).
miRNAs and the pathogenesis of NSCLC
miRNAs regulate cellular processes in both physiological and pathological conditions. A miRNA can bind to one or more mRNAs, affecting the expression of oncogenes and tumor suppressor genes, which is related to the pathogenesis of NSCLC. In NSCLC, various miRNAs are upregulated or downregulated and serve as either oncogenic miRNAs or tumor suppressor miRNAs. Several significant miRNAs implicated in the development of NSCLC are listed in Table I.
miR-224
miR-224 plays a dual function in various cancer cells. It plays an oncogenic role in the formation and progression of numerous kinds of malignant cancers, including NSCLC (28), breast cancer (41) and colorectal carcinogenesis (42). Otherwise, it functions as a tumor suppressor and is downregulated in certain patients with uveal melanoma (43).
Sirtuin3 (SIRT3) is a member of the sirtuin family of NAD+-dependent deacetylases. By controlling the acetylation of several mitochondrial proteins, it contributes to biological processes like energy metabolism and cell aging. It is also intimately associated to the formation and development of cancers (44). In comparison to paracancerous tissues and healthy controls, the expression levels of SIRT3 have significantly increased in NSCLC tissue and serum. SIRT3 may function as a tumor suppressor in NSCLC because its level was inversely related to tumor size, lymph node metastasis and TNM stage in individuals (45). miR-224 inhibits expression of SIRT3 and targets its 3′-UTR, contributing to the development of cancer. The overexpression of miR-224 may drastically reduce the degree of AMP-activated protein kinase (AMPK) phosphorylation in the co-culture model of cancer-associated fibroblasts (CAF) and NSCLC cells. Simultaneously, forced overexpression of SIRT3 may improve AMPK activation and counteract miR-224 mediated AMPK suppression. Additionally, miR-224 can stimulate the mammalian target of rapamycin/hypoxia inducible factor-1α (mTOR/HIF-1α) signal pathway to control the growth of NSCLC (28). mTOR is a serine-threonine kinase that acts as a crucial regulatory protein in typical cell physiology. The mTOR signaling pathway is crucial for regulating signals that promote cancer cell growth and survival and is a significant contributor to the development of NSCLC and other types of cancer (46). In addition, AMPK can inhibit mTOR (47). With the growth of NSCLC tumor, hypoxia aggravates the expression of HIF-1α. HIF-1α overexpression can activate downstream signaling molecules like vascular endothelial growth factor A (VEGFA) and accelerate the growth of tumors in NSCLC (48). Higher levels of HIF-1α stimulate the production of miR-224, producing the miR-224-SIRT3-AMPK-mTOR-HIF-1α positive feedback loop, which promotes tumor development, angiogenesis, and metastasis in NSCLC cells by targeting SIRT3 and inhibiting AMPK (28).
Phosphatase and tensin homolog (PTEN), as a prominent negative regulator of cell growth and phosphatidylinositol-3-kinase/v-akt murine thymoma viral oncogene homolog (PI3K/AKT) signaling pathway, plays a role as a tumor suppressor gene. Abnormal pathological features are caused by the loss of PTEN expression in numerous cancers (49). In serum-starved A549 cells, miR-224 negatively regulates PTEN through PI3K signal pathway to inhibit cell proliferation and induces apoptosis and autophagy due to the change of tumor microenvironment (50).
Angiopoietin-likeprotein1 (ANGPTL1) is another target gene of miR-224. ANGPTL1 prevents angiogenesis and the spread of cancer by acting as a tumor suppressor and an anti-angiogenic factor (51). Overexpression of snail family zinc finger 2 (SLUG) promotes tumor cell migration. By decreasing the expression of the SLUG, ANGPTL1 inhibits epithelial-mesenchymal transition (EMT) (52). The ectopic expression of miR-224 enhances NSCLC cell proliferation, migration, and lymph node metastasis by directly targeting ANGPTL1 mRNA (53).
miR-139-5p
miR-139-5p can function as tumor suppressor, which mainly regulates the translation of mRNA at the post-transcriptional level and plays an inhibitory role by mediating a variety of target genes and downstream signal pathways. The expression of miR-139-5p is decreased in multiple cancer tissues, such as pancreatic cancer, colorectal cancer and hepatocellular carcinoma. Therefore, miR-139-5p can be forcedly overexpressed in tumors to prevent the proliferation, invasion, and migration of tumor cells (54–56).
As the target gene of miR-139-5p, homeobox B2 (HOXB2) is a member of the homeobox (HOX) transcription factor family. The majority of the HOX proteins encoded by HOX gene function as transcription factors, regulating embryonic development, cell differentiation and carcinogenesis. HOXB2 is a crucial gene in the regulation of cell differentiation (57). miR-139-5p inhibits HOXB2 expression when it selectively binds to the 3′-UTR of HOXB2 and decreases tumor growth by promoting apoptosis in cells and inhibiting cell proliferation. In NSCLC cells treated with cisplatin (DDP), overexpression of miR-139-5p overcomes DDP resistance by regulating the PI3K/AKT/caspase-3 signaling pathway (31). The PI3K/AKT signaling pathway modulates diverse cellular processes, including cell proliferation. Caspase-3 is the key execution enzyme in cell survival and apoptosis (58). Therefore, overexpression of miR-139-5p inhibits cell proliferation and promotes cell apoptosis by downregulating the PI3K/AKT signaling pathway and increasing caspase-3 expression. Overexpression of miR-139-5p could attenuate paclitaxel (PTX) resistance of NSCLC cells. Integrin beta-8 (ITGB8) is an integrin family number. Integrins are located on the surface of cancer cells and promote tumor metastasis by mediating cell-to-cell adhesion and invasion. ITGB8 is typically upregulated in cancer and is associated with cancer metastasis (59). Delta/Notch-like epidermal growth factor-related receptor (DNER) is a transmembrane protein involved in the tumor development. CircDNER has been proved to function as a miRNA sponge to sequester miR-139-5p away from its target mRNA, thus reducing miRNA-mediated gene inhibition. ITGB8 is the target gene of miR-139-5p, and circDNER/miR-139-5p/ITGB8 forms a new regulatory axis. Enforced overexpression of miR-139-5p in PTX-resistant NSCLC cells reverses the tumor promoting functions of circDNER on NSCLC cell proliferation and invasion by targeting and inhibiting ITGB8, while also slows the growth of tumors and encourages the apoptosis of PTX-resistant cells (60).
Fine particulate matter (PM2.5) accelerates the development of NSCLC by suppressing the expression of miR-139-5p. High dose PM2.5 stimulation causes precancerous lesions such as bronchial epithelial dysplasia in mice, which promotes the EMT process and raises the risk of LC by lowering the level of E-cadherin protein and raising the level of vimentin protein. Meanwhile, PM2.5 regulates Notch1, the target of miR-139-5p (61). Notch1 is overexpressed in NSCLC, and that is associated with the disease's progression and poor prognosis (62). Overexpression of miR-139-5p can prevent NSCLC from developing by suppressing Notch1 expression and reversing PM2.5-induced EMT, indicating that miR-139-5p has the potential to be a therapeutic target in NSCLC.
miR-152
miR-152 is considered as a tumor suppressor and its expression is usually downregulated in different solid tumors. Tensin1 (TNS1), a member of the focal adhesion-associated proteins family, is essential for preserving normal tissue and structural stability. TNS1 is involved in cell proliferation, adhesion, migration, and regulation of signal transduction pathways (63). miR-152 could directly target and suppress the expression of TNS1. Therefore, inhibiting the expression of TNS1 could reduce metastasis and invasion of NSCLC cells (64). In addition, the core region of miR-152 is hypermethylated, and the hypermethylation level is regulated by the DNA methyltransferase 3B (DNMT3B), which leads to a reduction in miR-152 expression. Simultaneously, miR-152 directly targets and inhibits the expression of neural cell adhesion molecule 1 (NCAM1). As a highly expressed transmembrane protein in NSCLC, the NCAM1 gene may promote the proliferation and metastasis of NSCLC cells (65). This suggested that inhibiting DNMT3B can reduce the methylation level of miR-152. The overexpression of miR-152 inhibits NCAM1 and reduces NSCLC cell proliferation (66).
Fibroblast growth factor 2 (FGF2) is another target of miR-152, which is a multifunctional cytokine that expresses and influences multiple biological processes in a variety of cancers. The FGF/FGFR signaling pathway controls a number of biological functions, including cell proliferation, differentiation and migration (67). miR-152 specifically binds and inhibits the expression of FGF2 mRNA and protein, which participates in preventing NSCLC cell proliferation and migration (68).
LncRNA, a non-coding RNA, can bind to miRNA but cannot be transcribed into a protein. LncRNAs play crucial roles in a variety of biological processes, including cell proliferation, differentiation, apoptosis, and its dysregulation can lead to cancer. It is reported that lncRNA colon cancer-associated transcript 1 (CCAT1) sponge stimulates NSCLC cell growth and migration by suppressing the expression of miR-152. CCAT1 promotes EMT with the downregulation of E-cadherin (69). LncRNA prostate cancer gene expression marker-1 (PCGEM1) is correlated with lymph node metastasis and TNM stage in NSCLC. PCGEM1 targets and inhibits miR-152-3p to promote NSCLC proliferation and migration (70).
miRNAs as biomarkers for NSCLC
miRNAs have the potential to become high-quality biomarkers with the advantages of high stability, non-invasive, convenient, and efficient screening methods. In several studies, researchers used miRNA microarray or reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to analyze serum miRNA levels for patients with NSCLC, benign lung disease (BLD) and healthy subjects, to select specific miRNAs for routine examination to improve NSCLC sensitivity and specificity for early diagnosis (Table II).
In a previous study, Trakunram et al (71) used a TaqMan low-density array to compare the expression levels of 745 miRNAs in NSCLC, BLD and healthy subjects, and selected miR-339-3p through verification set and diagnostic evaluation. The area under the curve (AUC) of the miRNA is 0.616, indicating that it has guiding significance in the diagnosis of NSCLC. Chen et al (72) used RT-qPCR to profile miRNAs in 148 NSCLC patients and healthy controls. The high level of miR-762 was related to an advanced stage, poor tumor grade and positive lymph node metastasis. Combined detection of miR-762, carcinoembryonic antigen (CEA), and cytokeratin fragment antigen 21-1 (CYFRA21-1) could improve the diagnostic accuracy for NSCLC. Furthermore, miR-762 expression can be used as a predictive biomarker for gefitinib resistance, and high expression predicts poor therapeutic effect (73).
In addition, Yang et al (74) selected serum miRNAs for NSCLC early diagnosis, and 8 miRNAs were selected and validated by training set and validation set, ultimately obtaining the best predictive model composed of miR-146b, miR-205, miR-29c and miR-30b. The combination could be used not only in the diagnosis of NSCLC patients but also in NSCLC subtypes analysis and TNM staging. AUC of the combined training and verification sets was estimated to be 0.96 with 95.31% sensitivity and 82.98% specificity.
The researchers measured the expression of specific miRNAs in plasma, not just the serum sample. Dong et al (11) used a miRNA chip to examine the miRNAs in plasma from NSCLC patients and healthy volunteers. RT-qPCR was used to evaluate the expression of 11 upregulated miRNAs. Three plasma miRNAs (miR-1247-5p, miR-301b-3p and miR-105-5p) were selected and finally determined to distinguish between early NSCLC patients and healthy individuals, and their AUC are 0.769, 0.761 and 0.777, respectively. Reis et al (75) performed a study based on the NSCLC subtypes. They used Nanostring nCounter ®technology to evaluate the expression of miRNA in LUAD, LUSC and healthy controls, and identified a correlation between the expression of the majority of miRNAs in the two histological subtypes. A total of 12 differentially expressed miRNAs were selected for verification and the expression level of 11 miRNAs were consistent with the found set. Furthermore, 3 miRNAs (miR-16-5p, miR-92a-3p and miR-451a) with the best statistical performance were selected for pathway enrichment analysis, and it was found that the 3 miRNAs were related to the LC pathways such as epidermal growth factor receptor (EGFR) and PI3K/AKT. Concurrently, these 3 miRNAs can predict NSCLC with high specificity and sensitivity. Moreover, the researchers selected 12 previously reported aberrantly expressed miRNAs in NSCLC. A total of 4 miRNAs (miR-210, miR-1290, miR-150 and miR-21-5p) obtained from test set and verification set could distinguish NSCLC, BLD and healthy individuals. In the study of postoperative NSCLC patients, it was found that the significantly decreased expression of the 4 miRNAs were predictors of prolonged disease-free survival. A total of 2 miRNAs (miR-210 and miR-150) could predict patient's prognosis even if their expression levels do not significantly alter as NSCLC progresses (76). Based on miRNA chip, Lu et al (77) identified 6 miRNAs (miR-17, miR-190b, miR-19a, miR-19b, miR-26b and miR-375). These 6 miRNAs could distinguish between LC and asymptomatic high-risk patients through screening in three stages of discovery, training and verification. Further research showed that 3 miRNAs (miR-17, miR-190b and miR-375) could accurately differentiate SCLC from NSCLC.
Previous studies have indicated that combining different fluid biopsies could improve the accuracy of NSCLC detection. For example, Liao et al (78) used the Taqman miRNA assay to detect the expression of 2 miRNAs (miR-31-5p and miR-210p-3p) in sputum and 3 miRNAs (miR-21-5p, miR-210-3p and miR-486-5p) in plasma. The logical regression model with limited parameters in least absolute shrinkage and selection operator was used to optimize the miRNA detection panel. The detection of 2 sputum miRNAs (miR-31-5p and miR-210-3p) and 1 plasma miRNA (miR-21-5p) in the combined model had a synergistic effect on the diagnosis of NSCLC. The combination study proved that the analysis of 2 sputum miRNA biomarkers and 1 plasma miRNA biomarker had improved performance than a single class of miRNA biomarkers. Similarly, the study by Xie et al (79) revealed a positive correlation between the expression of miR-186 in serum and exhaled breath condensate, and the combination of decreased miR-186 and increased IL-1β were used for the diagnosis and severity evaluation of NSCLC.
Researchers typically assessed the effectiveness of the miRNA diagnostic model for the study of early diagnosis of miRNA by using logical regression analysis and receiver operating characteristic (ROC) curve (78,80). The majority of miRNAs have been studied to distinguish early NSCLC patients from BLD patients or healthy individuals, while certain miRNAs have been studied to identify NSCLC subtypes. Previous studies (11,74) revealed that miRNAs have high specificity and sensitivity, indicating that there is considerable potential for using miRNA in the early detection of NSCLC. However, it has poor repeatability for miRNA detection. The reasons may be the heterogeneity of NSCLC patients and the regulation of tumor formation by multiple genes. The selected miRNA should be validated in large-scale NSCLC patients utilizing standard operating procedures in the future. Based on understanding the pathway of miRNA mechanism, the best miRNAs combination for NSCLC diagnosis would be found.
In addition, miRNAs can serve as prognostic biomarkers. Higher levels of the serum miR-629 have been associated with poor differentiation, lymph node metastases and advanced clinical stage in patients with NSCLC compared with those with non-malignant lung disease and healthy controls (81). miRNAs differentially expressed in serum samples provide a novel basis for predicting the prognosis of NSCLC patients.
Exosomal miRNAs as potential biomarkers for NSCLC
Focus has been addressed on exosomal miRNAs as potential biomarkers since they are one of the major components of exosomes and play functional roles in cell-to-cell communication. Exosomal miRNAs may be used as prognostic and diagnostic biomarkers for NSCLC (Table III).
Exosomal miRNAs in blood have been extensively studied as biomarkers for the diagnosis of NSCLC. A novel immunomagnetic separation technique was used to selectively extract exosomes from serum of patients, which is more specific than traditional ultracentrifugation, and a multiplexed array sensor is used to simultaneously detect 4 exo-miRNAs (miR-21, miR-155, miR-205 and miR-let-7b) (82). A microarray-based study found that the combination of exosomal miR-5684 and miR-125b-5p had effective diagnostic value (AUC=0.744) for patients with NSCLC. Notably, in the tumor staging studies, it was found that exosomal miR-125b-5p is highly diagnostic in distinguishing between early and late stage, lymph node metastasis and distant metastasis (83). In comparison with traditional tumor markers, the level of miR-17-5p was significantly increased in NSCLC patients compared with healthy controls, and the detection performance of miR-17-5p was superior to CEA, CYFRA21-1 and squamous cell carcinoma antigen. The combination of these 4 tumor markers outperforms a single exosomal miR-17-5p in terms of diagnostic performance, indicating that the combination of exosomal miRNA and conventional tumor markers have significant clinical utility for the diagnosis of NSCLC (84).
Exosomes are circulating membrane-enclosed vesicles that contain miRNA, RNA, lipids, and proteins. By adhering to the target cell membrane, exosomes can transport miRNA and other contents from donor cells to recipient cells, which is relevant to the diagnosis and prognosis of NSCLC patients (85). For example, an increased level of miR-1246 isolated from serum exosomes was associated with a lower survival rate in patients with NSCLC (16). Plasma exosomal miR-4448 was shown to be decreased in patients with metastatic LUAD. Exosomal miR-4448 could be used as a diagnostic marker for patients with metastatic LUAD (86). In addition, elevated levels of exosomal miR-23b-3p, miR-10b-5p and miR-21-5p were independently associated with poor overall survival in patients with NSCLC (87). Plasma exosomal miR-451a was evaluated to be a reliable biomarker for predicting recurrence and prognosis in NSCLC patients with stage I, II or III cancer (88). Similarly, plasma exosomal miR-4257 and miR-21 have been identified as biomarkers of recurrence and TNM stage in NSCLC patients (89).
Comparison of circulating miRNAs with exosomal miRNAs
With the further development of miRNA research, circulating miRNAs and exosomal miRNAs may become the primary research forms in the early diagnosis and prognosis of NSCLC and other cancers. Few studies have simultaneously compared their detection performance. Exosomal miRNA may be more stable than circulating miRNA due to the protection of lipid bilayer. The distribution of miR-126 in the circulation of NSCLC patients at the early and advanced stages of the disease was evaluated, and it was found that miR-126 is primarily found in exosomes in the early and late stages of NSCLC. The levels of miR-126 increased in exosomes while they decreased in the exosome-free serum (90). Similarly, compared with whole plasma, the content of miR-21 in the exosomes of patients with hepatoblastoma was higher (91). The findings revealed a difference in the distribution of specific miRNAs between circulating miRNAs and exosomal miRNAs. The levels of miRNAs were higher in exosomes than serum or other bodily fluids.
Circulating miRNAs and exosomal miRNAs were distributed differentially in NSCLC patients. Several studies simultaneously investigated the changes in circulating miRNA and exosomal miRNA in cancer. In ovarian cancer, 5 miRNAs (miR-200c-3p, miR-346, miR-127-3p, miR-143-3p and miR-205-5p) were significantly upregulated in serum and exosomes (92). Wu et al (93) measured the expression levels of 8 serum miRNAs and their corresponding exosomal miRNAs in NSCLC, benign pulmonary lesions and healthy subjects. The AUC values of exosomal miR-146a-5p and miR-486-5p were found to be over 0.8, but the AUC values of 4 serum miRNAs (miR-21-5p, miR-141-3p, miR-222-3p and miR-486-5p) were all less than 0.8. The present study demonstrated that exosomal miRNA had an improved detection performance than circulating serum miRNA in identifying cancer samples from healthy control samples. The detection performance of the same miRNA in different studies was compared, and it was identified that the diagnostic value of exosomal miR-1246 (AUC=0.827) was greater than that of circulating plasma (AUC=0.641) (16,94). Exosomal miR-205-5p diagnostic value (AUC=0.806) was similar to that in circulating serum (AUC=0.8250) (95,96). To obtain more accurate detection results, it is necessary to detect circulating free and exosomal miRNA for one patient at the same time, and then identify which sample type is reasonable for miRNA detection.
Future prospects and conclusion
Numerous studies have shown that the dysregulation of miRNA is an important driver of NSCLC progression and plays crucial roles in the early diagnosis, treatment and prognosis of NSCLC (97,98). As there is a wide variety of miRNAs, there is also diversity in the roles of these miRNAs in NSCLC. The miRNAs in tissue or blood of patients with NSCLC, BLD, and healthy controls were examined using microarray, RT-qPCR, and next-generation sequencing (11,99,100). It has been found that a multitude of miRNAs have notable changes in NSCLC, suggesting that particular miRNAs can be used to diagnose NSCLC. Despite the existence of numerous studies on miRNAs, the mechanism of miRNAs in various tissue subtypes of NSCLC remains unknown due to the diversity of miRNA action mechanisms and the heterogeneity of NSCLC patients. The mechanisms of miRNAs should be studied more extensively and systematically in order to improve the use of miRNAs in clinical treatment. Additionally, the uniform operational procedure should be established for the repeatability of miRNAs detection in order to apply the miRNA detection with favorable performance for the clinical diagnosis of NSCLC.
In the present review, focus was addressed on the biological functions of miRNAs and their molecular mechanisms in the occurrence and progression of NSCLC, as well as the importance of various miRNAs in the diagnosis and prognosis of NSCLC. Although over 2,000 human miRNAs have been identified, most studies have focused on a single signaling pathway mechanism between a specific miRNA and its target gene. Future research should concentrate on the network of interactions between different miRNAs. In one word, miRNAs are well-known to exist in plasma and other bodily fluids and are one promising biomarker for NSCLC diagnosis.
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Authors' contributions
XL wrote the manuscript and revised it. QW designed and supervised the study. YW designed the tables and figure. SL edited and critically revised the article for intellectual content. All authors read and approved the final version of the manuscript.
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Competing interests
The authors declare that they have no competing interests.
ReferencesSungHFerlayJSiegelRLLaversanneMSoerjomataramIJemalABrayFGlobal cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countriesCA Cancer J Clin71209249202110.3322/caac.2166033538338PilleronSSoto-Perez-de-CelisEVignatJFerlayJSoerjomataramIBrayFSarfatiDEstimated global cancer incidence in the oldest adults in 2018 and projections to 2050Int J Cancer148601608202110.1002/ijc.3323232706917OsmaniLAskinFGabrielsonELiQKCurrent WHO guidelines and the critical role of immunohistochemical markers in the subclassification of non-small cell lung carcinoma (NSCLC): Moving from targeted therapy to immunotherapySemin Cancer Biol52103109201810.1016/j.semcancer.2017.11.01929183778LiuGChereshPKampDWMolecular basis of asbestos-induced lung diseaseAnnu Rev Pathol8161187201310.1146/annurev-pathol-020712-16394223347351ChoiWIParkSHParkBJLeeCWInterstitial lung disease and lung cancer development: A 5-year nationwide population-based studyCancer Res Treat50374381201810.4143/crt.2017.11928494537SeijoLMZuluetaJJUnderstanding the links between lung cancer, COPD, and emphysema: A Key to more effective treatment and screeningOncology (Williston Park)3193102201728205188Ben AmarJBen SaftaBZaibiHDhahriBBaccarMAAzzabiSPrognostic factors of advanced stage non-small-cell lung cancerTunis Med94360367201627801487NaylorECAdjuvant therapy for stage I and II non-small cell lung cancerSurg Oncol Clin N Am25585599201610.1016/j.soc.2016.03.00327261917LiXLiuLSongXWangKNiuLXieLSongXTEP linc-GTF2H2-1, RP3-466P17.2, and lnc-ST8SIA4-12 as novel biomarkers for lung cancer diagnosis and progression predictionJ Cancer Res Clin Oncol14716091622202110.1007/s00432-020-03502-533792796MalyVMalyOKolostovaKBobekVCirculating tumor cells in diagnosis and treatment of lung cancerIn Vivo3310271037201910.21873/invivo.1157131280190DongXChangMSongXDingSXieLSongXPlasma miR-1247-5p, miR-301b-3p and miR-105-5p as potential biomarkers for early diagnosis of non-small cell lung cancerThorac Cancer12539548202110.1111/1759-7714.1380033372399IqbalMAAroraSPrakasamGCalinGASyedMAMicroRNA in lung cancer: Role, mechanisms, pathways and therapeutic relevanceMol Aspects Med70320201910.1016/j.mam.2018.07.00330102929LeeRCFeinbaumRLAmbrosVThe C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14Cell75843854199310.1016/0092-8674(93)90529-Y8252621Griffiths-JonesSGrocockRJvan DongenSBatemanAEnrightAJmiRBase: microRNA sequences, targets and gene nomenclatureNucleic Acids Res34(Database Issue)D140D144200610.1093/nar/gkj11216381832LiuJRenLLiSLiWZhengXYangYFuWYiJWangJDuGThe biology, function, and applications of exosomes in cancerActa Pharm Sin B1127832797202110.1016/j.apsb.2021.01.00134589397HuangDQuDEarly diagnostic and prognostic value of serum exosomal miR-1246 in non-small cell lung cancerInt J Clin Exp Pathol1316011607202032782678de RieDAbugessaisaIAlamTArnerEArnerPAshoorHÅströmGBabinaMBertinNBurroughsAMAn integrated expression atlas of miRNAs and their promoters in human and mouseNat Biotechnol35872878201710.1038/nbt.394728829439SoléCLawrieCHMicroRNAs in metastasis and the tumour microenvironmentInt J Mol Sci224859202110.3390/ijms2209485934064331Di LevaGGarofaloMCroceCMMicroRNAs in cancerAnnu Rev Pathol9287314201410.1146/annurev-pathol-012513-10471524079833Starega-RoslanJKoscianskaEKozlowskiPKrzyzosiakWJThe role of the precursor structure in the biogenesis of microRNACell Mol Life Sci6828592871201110.1007/s00018-011-0726-221607569ShangRBaekSCKimKKimBKimVNLaiECGenomic clustering facilitates nuclear processing of suboptimal Pri-miRNA lociMol Cell78303316.e4202010.1016/j.molcel.2020.02.00932302542YeomKHLeeYHanJSuhMRKimVNCharacterization of DGCR8/Pasha, the essential cofactor for Drosha in primary miRNA processingNucleic Acids Res3446224629200610.1093/nar/gkl45816963499HeBZhaoZCaiQZhangYZhangPShiSXieHPengXYinWTaoYWangXmiRNA-based biomarkers, therapies, and resistance in cancerInt J Biol Sci1626282647202010.7150/ijbs.4720332792861AlarcónCRLeeHGoodarziHHalbergNTavazoieSFN6-methyladenosine marks primary microRNAs for processingNature519482485201510.1038/nature1428125799998ZhangYWangZGemeinhartRAProgress in microRNA deliveryJ Control Release172962974201310.1016/j.jconrel.2013.09.01524075926MatsuyamaHSuzukiHISystems and synthetic microRNA biology: From biogenesis to disease pathogenesisInt J Mol Sci21132201910.3390/ijms2101013231878193HaneklausMGerlicMO'NeillLAMastersSLmiR-223: Infection, inflammation and cancerJ Intern Med274215226201310.1111/joim.1209923772809ZhangJHanLYuJLiHLiQmiR-224 aggravates cancer-associated fibroblast-induced progression of non-small cell lung cancer by modulating a positive loop of the SIRT3/AMPK/mTOR/HIF-1α axisAging (Albany NY)131043110449202110.18632/aging.20280333819917ZhuLChenYLiuJNieKXiaoYYuHMicroRNA-629 promotes the tumorigenesis of non-small-cell lung cancer by targeting FOXO1 and activating PI3K/AKT pathwayCancer Biomark29347357202010.3233/CBM-20168532716350XiongJXingSDongZNiuLXuQLiYLiuPYangPmiR-654-3p suppresses cell viability and promotes apoptosis by targeting RASAL2 in non-small-cell lung cancerMol Med Rep23124202110.3892/mmr.2020.1176333300072DuHBaoYLiuCZhongANiuYTangXmiR-139-5p enhances cisplatin sensitivity in non-small cell lung cancer cells by inhibiting cell proliferation and promoting apoptosis via the targeting of homeobox protein Hox-B2Mol Med Rep23104202110.3892/mmr.2020.1174333300085PuRPuMHuangHCuiYMicroRNA 144 inhibits cell migration and invasion and regulates inflammatory cytokine secretion through targeting toll like receptor 2 in non-small cell lung cancerArch Med Sci1710281037202010.5114/aoms.2020.9308434336030YuanCBaiRGaoYJiangXLiSSunWLiYHuangZGongYXieCEffects of MicroRNA-195-5p on biological behaviors and radiosensitivity of lung adenocarcinoma cells via targeting HOXA10Oxid Med Cell Longev20214522210202110.1155/2021/452221034925694WuXWuGZhangHPengXHuangBHuangMDingJMaoCPengCMiR-196b promotes the invasion and migration of lung adenocarcinoma cells by targeting AQP4Technol Cancer Res Treat201533033820985868202110.1177/153303382098586833455522FangQYDengQFLuoJZhouCCMiRNA-20a-5p accelerates the proliferation and invasion of non-small cell lung cancer by targeting and downregulating KLF9Eur Rev Med Pharmacol Sci2425482556202032196605KordeAJinLZhangJGRamaswamyAHuBKolahianSGuardelaBJHerazo-MayaJSiegfriedJMStabileLLung endothelial MicroRNA-1 regulates tumor growth and angiogenesisAm J Respir Crit Care Med19614431455201710.1164/rccm.201610-2157OC28853613MaZWeiKYangFGuoZPanCHeYWangJLiZChenLChenYXiaYTumor-derived exosomal miR-3157-3p promotes angiogenesis, vascular permeability and metastasis by targeting TIMP/KLF2 in non-small cell lung cancerCell Death Dis12840202110.1038/s41419-021-04037-434497265WangDCaiLTianXLiWMiR-543 promotes tumorigenesis and angiogenesis in non-small cell lung cancer via modulating metastasis associated protein 1Mol Med2644202010.1186/s10020-020-00175-132410569ZhaoGZhangYZhaoZCaiHZhaoXYangTChenWYaoCWangZWangZMiR-153 reduces stem cell-like phenotype and tumor growth of lung adenocarcinoma by targeting Jagged1Stem Cell Res Ther11170202010.1186/s13287-020-01679-732375892FangLCaiJChenBWuSLiRXuXYangYGuanHZhuXZhangLAberrantly expressed miR-582-3p maintains lung cancer stem cell-like traits by activating Wnt/β-catenin signallingNat Commun68640201510.1038/ncomms964026468775ZhangLZhangXWangXHeMQiaoSMicroRNA-224 promotes tumorigenesis through downregulation of caspase-9 in triple-negative breast cancerDis Markers20197378967201930886656FassanMCuiRGaspariniPMescoliCGuzzardoVVicentiniCMunariGLoupakisFLonardiSBraconiCmiR-224 Is significantly upregulated and targets caspase-3 and caspase-7 during colorectal carcinogenesisTransl Oncol12282291201910.1016/j.tranon.2018.10.01330448733LiJLiuXLiCWangWmiR-224-5p inhibits proliferation, migration, and invasion by targeting PIK3R3/AKT3 in uveal melanomaJ Cell Biochem1201241212421201910.1002/jcb.2850730825222AlhazzaziTYKamarajanPVerdinEKapilaYLSIRT3 and cancer: Tumor promoter or suppressor?Biochim Biophys Acta18168088201121586315TaoFGuCLiNYingYFengYNiDZhangQXiaoQSIRT3 acts as a novel biomarker for the diagnosis of lung cancer: A retrospective studyMedicine (Baltimore)100e26580202110.1097/MD.000000000002658034232204MarinovMFischerBArcaroATargeting mTOR signaling in lung cancerCrit Rev Oncol Hematol63172182200710.1016/j.critrevonc.2007.04.00217540577ZhanPZhaoSYanHYinCXiaoYWangYNiRChenWWeiGZhangPα-enolase promotes tumorigenesis and metastasis via regulating AMPK/mTOR pathway in colorectal cancerMol Carcinog5614271437201710.1002/mc.2260327996156LuXKangYHypoxia and hypoxia-inducible factors: Master regulators of metastasisClin Cancer Res1659285935201010.1158/1078-0432.CCR-10-136020962028ChenCYChenJHeLStilesBLPTEN: Tumor suppressor and metabolic regulatorFront Endocrinol (Lausanne)9338201810.3389/fendo.2018.0033830038596WangGHanJZhuangLLiSGongQChenYSerum starvation induces cell death in NSCLC via miR-224Onco Targets Ther1239533962201931190892EndoMThe roles of ANGPTL families in cancer progressionJ UOEH41317325201910.7888/juoeh.41.31731548486KuoTCTanCTChangYWHongCCLeeWJChenMWJengYMChiouJYuPChenPSAngiopoietin-like protein 1 suppresses SLUG to inhibit cancer cell motilityJ Clin Invest12310821095201310.1172/JCI6404423434592HanHPanBLiangFWuLLiuXYangYChenJMiR-224 promotes lymphatic metastasis by targeting ANGPTL1 in non-small-cell lung carcinomaCancer Biomark34431441202210.3233/CBM-21037635275522ZhuJHDe MelloRAYanQLWangJWChenYYeQHWangZJTangHJHuangTMiR-139-5p/SLC7A11 inhibits the proliferation, invasion and metastasis of pancreatic carcinoma via PI3K/Akt signaling pathwayBiochim Biophys Acta Mol Basis Dis1866165747202010.1016/j.bbadis.2020.16574732109492SongMYinYZhangJZhangBBianZQuanCZhouLHuYWangQNiSMiR-139-5p inhibits migration and invasion of colorectal cancer by downregulating AMFR and NOTCH1Protein Cell5851861201410.1007/s13238-014-0093-525149074QiuGLinYZhangHWuDmiR-139-5p inhibits epithelial-mesenchymal transition, migration and invasion of hepatocellular carcinoma cells by targeting ZEB1 and ZEB2Biochem Biophys Res Commun463315321201510.1016/j.bbrc.2015.05.06226022123PanXLiuWChaiYWangJZhangYGenetic and clinical characterization of HOXB2 in gliomaOnco Targets Ther131046510473202010.2147/OTT.S26863533116626FaesSDormondOPI3K and AKT: Unfaithful partners in cancerInt J Mol Sci162113821152201510.3390/ijms16092113826404259HuangLCaiJLHuangPZKangLHuangMJWangLWangJPmiR19b-3p promotes the growth and metastasis of colorectal cancer via directly targeting ITGB8Am J Cancer Res719962008201729119049LiJZhuTWengYChengFSunQYangKSuZMaHExosomal circDNER enhances paclitaxel resistance and tumorigenicity of lung cancer via targeting miR-139-5p/ITGB8Thorac Cancer1313811390202210.1111/1759-7714.1440235396925WangYZhongYZhangCLiaoJWangGPM2.5 downregulates MicroRNA-139-5p and induces EMT in bronchiolar epithelium cells by targeting Notch1J Cancer1157585767202010.7150/jca.4697632913469DonnemTAndersenSAl-ShibliKAl-SaadSBusundLTBremnesRMPrognostic impact of Notch ligands and receptors in nonsmall cell lung cancer: Coexpression of Notch-1 and vascular endothelial growth factor-A predicts poor survivalCancer11656765685201010.1002/cncr.2555120737536LiaoYCLoSHTensins-emerging insights into their domain functions, biological roles and disease relevanceJ Cell Sci134jcs254029202110.1242/jcs.25402933597154DuanJWangLShangLYangSWuHHuangYMiaoYmiR-152/TNS1 axis inhibits non-small cell lung cancer progression through Akt/mTOR/RhoA pathwayBiosci Rep41BSR20201539202110.1042/BSR2020153933269380HinsbyAMBerezinVBockEMolecular mechanisms of NCAM functionFront Biosci922272244200410.2741/139315353284YangBHuangSChenHLiRHouSZhaoJLiYDNMT3B regulates proliferation of A549 cells through the microRNA-152-3p/NCAM1 pathwayOncol Lett2311202210.3892/ol.2021.1312934820010YangLZhouFZhengDWangDLiXZhaoCHuangXFGF/FGFR signaling: From lung development to respiratory diseasesCytokine Growth Factor Rev6294104202110.1016/j.cytogfr.2021.09.00234593304ChengZMaRTanWZhangLMiR-152 suppresses the proliferation and invasion of NSCLC cells by inhibiting FGF2Exp Mol Med46e112201410.1038/emm.2014.5125190353ZongDLiuXLiJLongYOuyangRChenYLncRNA-CCAT1/miR-152-3p is involved in CSE-induced inflammation in HBE cells via regulating ERK signaling pathwayInt Immunopharmacol109108818202210.1016/j.intimp.2022.10881835523108HuangJLouJLiuXXieYLncRNA PCGsEM1 contributes to the proliferation, migration and invasion of non-small cell lung cancer cells via acting as a sponge for miR-152-3pCurr Pharm Des2746634670202110.2174/138161282766621082710482834455968TrakunramKChaniadPGeaterSLKeeratichananontWChittithavornVUttayamakulSBuyaSRaungrutPThongsuksaiPSerum miR-339-3p as a potential diagnostic marker for non-small cell lung cancerCancer Biol Med17652663202010.20892/j.issn.2095-3941.2020.006332944397ChenLLiYLuJIdentification of circulating miR-762 as a novel diagnostic and prognostic biomarker for non-small cell lung cancerTechnol Cancer Res Treat191533033820964222202010.1177/153303382096422233317398GePCaoLChenXJingRYueWmiR-762 activation confers acquired resistance to gefitinib in non-small cell lung cancerBMC Cancer191203201910.1186/s12885-019-6416-431823748YangXZhangQZhangMSuWWangZLiYZhangJBeerDGYangSChenGSerum microRNA signature is capable of early diagnosis for non-small cell lung cancerInt J Biol Sci1517121722201910.7150/ijbs.3398631360113ReisPPDrigoSACarvalhoRFLopez LapaRMFelixTFPatelDChengDPintilieMLiuGTsaoMSCirculating miR-16-5p, miR-92a-3p, and miR-451a in plasma from lung cancer patients: Potential application in early detection and a regulatory role in tumorigenesis pathwaysCancers (Basel)122071202010.3390/cancers1208207132726984JiangHGDaiCHXuYPJiangQXiaXBShuYLiJFour plasma miRNAs act as biomarkers for diagnosis and prognosis of non-small cell lung cancerOncol Lett22792202110.3892/ol.2021.1305334630703LuSKongHHouYGeDHuangWOuJYangDZhangLWuGSongYTwo plasma microRNA panels for diagnosis and subtype discrimination of lung cancerLung Cancer1234451201810.1016/j.lungcan.2018.06.02730089594LiaoJShenJLengQQinMZhanMJiangFMicroRNA-based biomarkers for diagnosis of non-small cell lung cancer (NSCLC)Thorac Cancer11762768202010.1111/1759-7714.1333731994346XieHChenJLvXZhangLWuJGeXYangQZhangDChenJClinical value of serum and exhaled breath condensate miR-186 and IL-1β levels in non-small cell lung cancerTechnol Cancer Res Treat191533033820947490202010.1177/153303382094749032851926TulinskyLDzianAMatakovaTIhnatPOverexpression of the miR-143/145 and reduced expression of the let-7 and miR-126 for early lung cancer diagnosisJ Appl Biomed2016202210.32725/jab.2022.00435302725LiuFLiTHuPDaiLUpregulation of serum miR-629 predicts poor prognosis for non-small-cell lung cancerDis Markers20218819934202133763157MahmudunnabiRGUmerMSeoKDParkDSChungJHShiddikyMJAShimYBExosomal microRNAs array sensor with a bioconjugate composed of p53 protein and hydrazine for the specific lung cancer detectionBiosens Bioelectron207114149202210.1016/j.bios.2022.11414935290882ZhangZTangYSongXXieLZhaoSSongXTumor-derived exosomal miRNAs as diagnostic biomarkers in non-small cell lung cancerFront Oncol10560025202010.3389/fonc.2020.56002533178588ZhangYZhangYYinYLiSDetection of circulating exosomal miR-17-5p serves as a novel non-invasive diagnostic marker for non-small cell lung cancer patientsPathol Res Pract215152466201910.1016/j.prp.2019.15246631146974SunZShiKYangSLiuJZhouQWangGSongJLiZZhangZYuanWEffect of exosomal miRNA on cancer biology and clinical applicationsMol Cancer17147201810.1186/s12943-018-0897-730309355XuZWangZSunHXinHEvaluation of exosomal miRNA in Blood as a potential diagnostic biomarker for human non-small cell lung cancerMed Sci Monit26e924721202010.12659/MSM.92472132444593LiuQYuZYuanSXieWLiCHuZXiangYWuNWuLBaiLLiYCirculating exosomal microRNAs as prognostic biomarkers for non-small-cell lung cancerOncotarget81304813058201710.18632/oncotarget.1436928055956KanaokaRIinumaHDejimaHSakaiTUeharaHMatsutaniNKawamuraMUsefulness of plasma exosomal MicroRNA-451a as a noninvasive biomarker for early prediction of recurrence and prognosis of non-small cell lung cancerOncology94311323201810.1159/00048700629533963DejimaHIinumaHKanaokaRMatsutaniNKawamuraMExosomal microRNA in plasma as a non-invasive biomarker for the recurrence of non-small cell lung cancerOncol Lett1312561263201710.3892/ol.2017.556928454243GrimolizziFMonacoFLeoniFBracciMStaffolaniSBersaglieriCGaetaniSValentinoMAmatiMRubiniCExosomal miR-126 as a circulating biomarker in non-small-cell lung cancer regulating cancer progressionSci Rep715277201710.1038/s41598-017-15475-629127370LiuWChenSLiuBDiagnostic and prognostic values of serum exosomal microRNA-21 in children with hepatoblastoma: A Chinese population-based studyPediatr Surg Int3210591065201610.1007/s00383-016-3960-827601233WangWWuLRLiCZhouXLiuPJiaXChenYZhuWFive serum microRNAs for detection and predicting of ovarian cancerEur J Obstet Gynecol Reprod Biol X3100017201910.1016/j.eurox.2019.10001731404211WuQYuLLinXZhengQZhangSChenDPanXHuangYCombination of serum miRNAs with serum exosomal miRNAs in early diagnosis for non-small-cell lung cancerCancer Manag Res12485495202010.2147/CMAR.S23238332021461LiMShanWHongBZouJLiHHanDZhangYLiLLiDLinWCirculating miR-92b and miR-375 for monitoring the chemoresistance and prognosis of small cell lung cancerSci Rep1012705202010.1038/s41598-020-69615-632728103ZhaoYLZhangJXYangJJWeiYBPengJFFuCJHuangMHWangRWangPYSunGBXieSYMiR-205-5p promotes lung cancer progression and is valuable for the diagnosis of lung cancerThorac Cancer13832843202210.1111/1759-7714.1433135076182WangXJiangXLiJWangJBinangHShiSDuanWZhaoYZhangYSerum exosomal miR-1269a serves as a diagnostic marker and plays an oncogenic role in non-small cell lung cancerThorac Cancer1134363447202010.1111/1759-7714.1364433107700ZhouCChenZZhaoLZhaoWZhuYLiuJZhaoXA novel circulating miRNA-based signature for the early diagnosis and prognosis prediction of non-small-cell lung cancerJ Clin Lab Anal34e23505202010.1002/jcla.2350533463758YangYJiaYXiaoYHaoYZhangLChenXHeJZhaoYQianZTumor-targeting anti-MicroRNA-155 delivery based on biodegradable poly(ester amine) and hyaluronic acid shielding for lung cancer therapyChemphyschem1920582069201810.1002/cphc.20170137529488305JinXChenYChenHFeiSChenDCaiXLiuLLinBSuHZhaoLEvaluation of tumor-derived exosomal miRNA as potential diagnostic biomarkers for early-stage non-small cell lung cancer using next-generation sequencingClin Cancer Res2353115319201710.1158/1078-0432.CCR-17-057728606918Migdalska-SękMModrzewskaBKordiakJPastuszak-LewandoskaDKiszałkiewiczJMBielecFAntczakABrzeziańska-LasotaEDiagnostic value of PPARδ and miRNA-17 expression levels in patients with non-small cell lung cancerSci Rep1124136202110.1038/s41598-021-03312-w34921177
Schematic illustration of microRNA synthesis process.
Roles of miRNAs in the occurrence and progression of NSCLC.
miRNA
Target gene
Type of dysregulation
Function
(Refs.)
miR-224
Sirtuins3
Up
Promotes NSCLC cells proliferation, EMT and invasion
(28)
miR-629
FOXO1
Up
Promotes proliferation, migration and invasion in NSCLC cells
(29)
miR-654-3p
RASAL2
Down
Suppresses the viability and induce the apoptosis of NSCLC cells
(30)
miR-139-5p
HOXB2
Down
Inhibits proliferation and promotes apoptosis, enhances cisplatin sensitivity in NSCLC cells
(31)
miR-144
TLR2
Down
Inhibits NSCLC cells migration, invasion and release of inflammatory cytokines related to tumor chemical resistance
(32)
miR-195-5p
HOXA10
Down
Inhibits the growth, invasion and migration of LUAD, increases the proportion of cells in G1 phase in the cell cycle, promotes apoptosis and enhances radio sensitivity
(33)
miR-196b
AQP4
Up
Promotes the invasion and migration of LUAD cells, and the poor prognosis and low survival in patients with LUAD
(34)
miR-20a-5p
KLF9
Up
Promotes the proliferation and invasion of NSCLC cells
(35)
miR-1
Mpl
Down
Inhibits NSCLC growth and angiogenesis
(36)
miR-3157-3p
TIMP2/KLF2
Up
Promotes angiogenesis and increased vascular permeability
(37)
miR-543
MTA1
Up
Promotes proliferation and angiogenesis in NSCLC
(38)
miR-153
Jagged1/Notch1
Down
Inhibits stem cell properties and tumor growth of lung cancer cells
(39)
miR-582-3p
AXIN2, DKK3 and SFRP1
Up
Maintain stem cell-like characteristics and promote tumorigenesis, chemoresistance and relapse of NSCLC cells