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. 2017 Oct 8;50(6):e12394. doi: 10.1111/cpr.12394

MicroRNAs: A novel potential biomarker for diagnosis and therapy in patients with non‐small cell lung cancer

Qun Zhou 1,†, Shao‐Xin Huang 2,†, Feng Zhang 1,†, Shu‐Jun Li 3,†, Cong Liu 1, Yong‐Yong Xi 1, Liang Wang 1, Xin Wang 2, Qi‐Qiang He 4, Cheng‐Cao Sun 1,✉, De‐Jia Li 1,✉
PMCID: PMC6529072  PMID: 28990243

Abstract

Background

Lung cancer is still one of the most serious causes of cancer‐related deaths all over the world. MicroRNAs (miRNAs) are defined as small non‐coding RNAs which could play a pivotal role in post‐transcriptional regulation of gene expression. Increasing evidence demonstrated dysregulation of miRNA expression associates with the development and progression of NSCLC.

Aims

To emphasize a variety of tissue‐specific miRNAs, circulating miRNAs and miRNA‐derived exosomes could be used as potential diagnostic and therapeutic biomarkers in NSCLC patients.

Materials & Methods

In the current review, we paid attention to the significant discoveries of preclinical and clinical studies, which performed on tissue‐specific miRNA, circulating miRNA and exosomal miRNA. The related studies were obtained through a systematic search of Pubmed, Web of Science, Embase.

Results

A variety of tissue‐specific miRNAs and circulating miRNAs with high sensitivity and specificity which could be used as potential diagnostic and therapeutic biomarkers in NSCLC patients. In addition, we emphasize that the miRNA‐derived exosomes become novel diagnostic biomarkers potentially in these patients with NSCLC.

Conclusion

MiRNAs have emerged as non‐coding RNAs, which have potential to be candidates for the diagnosis and therapy of NSCLC.

Abbreviations

NSCLC

Non‐small cell lung cancer

SCC

squamous cell carcinoma

ZEB1

zinc finger E‐box‐binding homeobox 1

TGFBR2

transforming growth factor beta receptor 2

BMPR2

bone morphogenetic protein receptor type 2

CDK4

cyclin‐dependent kinase 4

EZH2

enhancer of zeste 2 polycomb repressive complex 2 subunit

DNMT1

DNA methyltransferase 1

PTEN

tensin homologue deleted on chromosome 10

HOXA9

homeobox A9

FoxO1

forkhead box O1

AKT

serine/threonine kinase 1

CYP1B1

cytochrome P450 family 1 subfamily B member 1

MAP3K2

mitogen‐activated protein kinase kinase kinase 2

STAT3

signal transducer and activator of transcription 3

ITGB1

integrin subunit beta 1

ECM

extracellular matrix

EMT

epithelial‐mesenchymal transition

VIM

vimentin

CX3CR1

chemokine (C‐X3‐C motif) receptor 1

FYCO1

FYVE and coiled‐coil domain containing 1

E2F2

E2F transcription factor 2

TCGA

The Cancer Genome Altas

MT1G

metallothionein 1G

TICs

tumour‐initiating cells

qPCR

quantitative polymerase chain reaction

MSCs

mesenchymal stem cells

HSP70

heat shock protein 70

MCP‐1

macrophage cationic peptide 1

TLR2

toll‐like receptor 2

TLR7

toll‐like receptor 7

TLR8

toll‐like receptor 8

1. BACKGROUND

Lung cancer is one of the most harmful diseases which associates with cancer deaths around the world, with more than 220 000 new diagnoses and nearly 158 000 deaths occurring in the United States in 2016.1 Non‐small cell lung cancer occupied nearly 85% of lung cancer cases; it was composed primarily of squamous cell carcinoma (SCC) and adenocarcinoma.2 In spite of advances in the diagnosis and current molecular targeted therapies, the overall 5‐year survival rate is only 18%.1 Consequently, there is an urgent assignment to investigate the potential molecular mechanisms of lung tumorigenesis and identify novel therapeutic targets, which can enhance the survival probability for patients with lung cancer.

MicroRNAs (miRNAs) are defined as small non‐coding RNAs with a length of about 20‐25 nucleotides, which exert pivotal effects in various biological processes.3 miRNAs can regulate gene expression at post‐transcriptional level through 3′‐untranslated region (3′UTR) pairing with target gene mRNAs.4 miRNAs regulate various targets which have critical roles in a wide spectrum of biological processes, including tumorigenesis and development, cell proliferation, metastasis, invasion and apoptosis.5 In addition, miRNA participated in almost all of the essential signalling pathways, including the expression of many important tumour‐associated genes such as oncogenes and tumour suppressors.6 The identification of alteration in miRNA levels is associated with various human cancers including NSCLC.7 A large number of studies have shown that the identification of various risk factors and biomarkers could help to better comprehend the cellular and molecular alterations involved in the cancer progress including NSCLC. In addition, it would be a better monitor of NSCLC patients for therapy by using a powerful diagnostic and prognostic biomarker.8 miRNAs have appeared to be novel diagnostic, therapeutic and prognostic biomarkers in NSCLC patients among various recommended biomarkers such as DNAs, RNAs, proteins, epigenetic changes and glycoproteins.9 Several lines of evidence have confirmed that miRNAs were related to molecular pathological changes and signalling cascades of lung cancer.10 Additionally, dysregulation of these molecules could be associated with inhibition and/or activation of several cellular and molecular therapy targets, which have functions in tumorigenesis and development of NSCLC.11 miRNAs were considered to be novel candidates for the diagnosis and therapy of NSCLC, as it could be detected with non‐invasive and comparatively easy assay methods.

Moreover, the discovery of miRNA in exosomes opened an attractive world that they could play an important role in diagnosing patients with NSCLC as significant biomarkers.12 Exosomes were drivers as small vesicles (50‐150 nm) of endocytic initially, which released from many different cell types, such as tumour cells, stem cells, mesenchymal cells, thrombocytes and some normal cells.13 There is emerging evidence that suggest that vesicles could carry various cargos such as DNA, mRNAs, miRNAs and proteins. It has been reported that secretion of exosomes could result in alteration in the behaviour of cancer cells or tumours.14, 15 As a proof concept, exosomes might be applied as significant diagnostic and therapeutic biomarkers in NSCLC patients. In this paper, we summarize a variety of tissue‐specific miRNAs and circulating miRNAs with high sensitivity and specificity which could be used as potential diagnostic and therapeutic biomarkers in NSCLC patients. In addition, we emphasize that the miRNA‐derived exosomes become novel diagnostic biomarkers potentially in these patients with NSCLC.

2. FEATURES OF MIRNA

The miRNAs are endogenous small (19‐22 nucleotides), non‐coding RNAs which play pivotal roles in various biological processes.3 The miRNA genes are typically transcribed from RNA polymerase II into long primary transcripts, which are up to several kilobases (pri‐miRNA).16 Then they undergo a further step that processes it into shorter hairpin sequences of approximately 70 nucleotides (pre‐miRNA) by the nuclear microprocessor complex formed by the RNase III Drosha17 and DiGeorge syndrome critical region gene 8 (DGCR8).18 Next, these pre‐miRNA are transported into the cytoplasm carried out by RNase III Dicer to form a double‐stranded RNA.19 Generally, one of the chains is chosen to act as the mature miRNA through the Argonaut proteins to enter the RNA‐induced silencing complex (RISC), while the remaining complementary chain is degraded. The miRNA recognizes target genes based on sequence complementarity, primarily to the 3′‐UTR of the target mRNAs. Moreover, miRNA modulates the translation of proteins through binding to their target mRNA.4, 20, 21, 22 So miRNA mediates translational repression or degradation of mRNAs depending on the degree of homology to their 3′‐UTR target sequence, and miRNA could regulate gene expression emerged in multiple signalling participating in carcinoma growth, dissemination, metastatic and even rejection to therapy.23 Accordingly, dysregulated miRNA will contribute to a variety of pathological events, including cancer initiation and progression.

3. MECHANISMS OF MIRNA IN CANCER

It is essential to maintain normal cellular homeostasis through controlling of miRNA levels precisely. During the past years, it is a critical task to determine the mechanisms of how the miRNA was dysregulated in cancer.

Several miRNA genes are located in cancer‐related genomic regions or in fragile sites; miRNA is highly susceptible to genomic alterations of solid tumours and haematological malignancies.24 Calin et al25 suggested that the loss or down‐regulation of miR‐15a and miR‐16‐1 located at a 30‐kb region on chromosome 13q14 is caused by frequent deletions or down‐regulations of B‐cell chronic lymphocytic leukaemia. Follow‐up studies demonstrated that a large number of miRNA genes are in cancer‐related genomic regions or in fragile sites. For example, there is a loss of heterozygosity region of 17p13 aligning with the hsa‐miR‐22 cluster in lung cancer.26

Aberrant epigenetic changes such as DNA hypermethylation, extensive genomic DNA hypomethylation and alteration of histone modification patterns appear frequently in cancer cells.27 Actually, epigenetic modifications represent a widespread mechanism associated with the changes of miRNA expression in cancer.28 For example, miR‐145 was demonstrated to be induced after DNA methylation in patients with lung adenocarcinoma.29 As for histone modifications of miRNA, Seol et al30 suggested that miR‐373 was silenced by histone modification in lung cancer cells and it functioned as a tumour suppressor through down‐regulating IRAK2 and LAMP1. In addition, deregulation of the miR‐101 could increase the expression of EZH2 during cancer progression, which contributed to the epigenetic silencing of target genes and regulated the metastasis of cancer cells.31

Most miRNA are transcribed by the RNA polymerase II; moreover, numerous PolII‐related factors are involved in this process, which exert critical effect regulating miRNA genes transcription in cells.16 It is the first reported that miR‐17/92 cluster mediated transcriptional activation through the c‐Myc oncogene. c‐Myc increases the expression of the miR‐17/92 cluster, which is able to balance the apoptotic activity of E2F1.32 miR‐34 family was identified to be transcriptionally regulated by the fundamental tumour suppressor p53 and played pivotal roles controlling p53‐mediated cell cycle arrest and apoptosis.33

In brief, dysregulation of miRNA in cancer can occur at genetic and epigenetic, transcriptional and post‐transcriptional levels via miRNA genomic localization, epigenetic changes such as DNA methylation and histone modifications.

4. MIRNA FUNCTION IN CANCER

The development of cancer is a multi‐step process that involves multiple alterations in oncogenes and tumour suppressor genes over a period of time, generally over several years. Cancer‐associated miRNA have been known as ‘onco‐miRs’, which play critical roles as oncogenes and/or tumour suppressors. A variety of studies suggested that miRNA would play a critical role as tumour suppressors or oncogenes. Valuably, they modulate almost all cell functions including apoptosis, proliferation, cell cycle, differentiation, stem cell maintenance and metabolism.23 Selected functional miRNAs and their targets in NSCLC are summarized in Figure 1.

Figure 1.

Figure 1

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Dysregulated miRNA participating in biological processes of lung cancer. The schematic representation depicting a variety of miRNA would emerge in cell proliferation, migration, invasion and apoptosis when down‐regulated or up‐regulated. It is known to us that miRNA play tumour suppressor and/or oncogenic roles in NSCLC by negatively modulating the target genes which exert tumour suppressor and/or oncogenic effect involved in cell proliferation, metastasis, invasion and apoptosis

4.1. Tumour suppressor

It is reported that the miR‐34 family was down‐regulated in cancer tissues compared with normal tissues, and decreased expression of miR‐34a was associated with a worse prognosis of cancer.34 Bommer et al35 confirmed that miR‐34 expression was significantly decreased in NSCLC and their data also suggested that the miR‐34 family might be the key effectors of p53 tumour suppressor to inhibit NSCLC cells growth. Young Hun Kim et al36 identified the combined effect of miR‐34b/c methylation on the prognosis of NSCLC. These results suggest that methylation of the miR‐34 families may serve as an inhibitor of tumour metastasis and as prognostic biomarkers for patients with NSCLC.

The miRNA encoded by the let‐7 family (including 12 human homologues) are considered to be tumour inhibitors because they map to brittle sites associated with lung, breast, urothelial and cervical cancers.26 It has been shown that the inhibition of oncogenes, such as rat sarcoma (RAS), myelocytomatosis oncogene (Myc), the high mobility group AThook 2 (HMGA2), cyclin D2, cyclin‐dependent kinase 6 (CDK6) and cell division cycle 25A (CDC25A) in cellular growth and proliferation, led to suppression of cancer cell proliferation and cell cycle distribution.37 Takamizawa et al38 observed that the expression of let‐7 frequently decreased in lung cancer both in vitro and in vivo; in addition, the down‐regulated let‐7 was significantly associated with poor post‐operative survival, independently with the state of disease.

miR‐200 family (miR‐200a, miR‐200b, miR‐200c, miR‐141 and miR‐429) are demonstrated to be down‐regulated in human cancer cells and tumours due to aberrant epigenetic gene silencing. In addition, these miRNAs exert pivotal effect inhibiting epithelial‐to‐mesenchymal transition (EMT), tumour cell metastasis and invasion through targeting key mRNAs involved in EMT.39 In lung cancer cells, miR‐200c overexpression led to reduced expression of zinc finger E‐box‐binding homeobox 1 (ZEB1) and increased expression of E‐cadherin.40

4.2. Oncogenic miRNA

Apart from their roles as tumour suppressors, some miRNAs function as tumour promoters by targeting tumour suppressor genes have been proved to having important regulatory effects on cell proliferation in a variety of human cancers, including lung cancer.41 Members of this cluster could directly target the tumour suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which participated in the cell‐survival signalling pathway phosphoinositide 3‐kinase (PI3K)/Akt in lung cancer.42 Genetic mutation of p53 and inhibition of the miR‐17~92 cluster are synthetic lethal in NSCLC due to up‐regulation of vitamin D signalling.43

miR‐155 gene was found to be one of the miRNA most consistently in several solid tumours, where it was considered to be a marker of poor prognosis.44, 45, 46, 47, 48, 49, 50 The results suggested that miR‐21 and miR‐155 could promote the cell growth of NSCLC through down‐regulating SOCS1, SOCS6 and PTEN.51

5. CLINICAL APPLICATIONS OF MIRNA IN NSCLC

Early diagnosis of NSCLC is important for prognosis and can lead to reducing mortality rate in patients.52 After describing these examples of how miRNA target specific pathways that are important for NSCLC, an important and compelling application is to concern miRNA to be used as biomarkers in the clinic. The discovery of sensitive and specific biomarkers for NSCLC will improve current treatment of malignant disease and early detection of cancer.

Another important task is how to detect the miRNA in panels of different haematological and solid cancer types. Quantitative real‐time reverse transcription PCR (qRT‐PCR) is a quantitative gold standard for gene expression and it is one of the most common methods for detecting low levels of miRNA with high sensitivity and specificity.53, 54 Recently, enzymatic luminescence miRNA assay, for example, quantitative bioluminescence assay, has been proposed as suitable for clinical diagnostic. This assay is designed for rapid and sensitive miRNA expression analysis based on isothermal rolling circle amplification.55 Over the years, hybridization based‐methods have improved such as in situ hybridization (ISH) with locked nucleic acid probes.56 Microarray method57 is widely used to screen large numbers of miRNAs simultaneously. Moreover, the appearance of deep‐sequencing methods consider to be a new star which depend on next‐generation sequencing machines that can process millions of sequence reads in parallel in just a few days, has driven to detect most of the miRNA.58 Circulating miRNA, which presented in serum, plasma, urine, saliva and other human body fluids, is often detected by high‐throughput profiling techniques, sequencing and miRNA microarray combined with qRT‐PCR.59, 60, 61

Shen et al62 identified that miR‐145 was down‐regulated in poorly differentiated NSCLC specimens; moreover, the relative expression levels of miR‐145 in stage II and III were significantly lower than those in stage I. In terms of miR‐126, it was associated with tumour stage and lymph nodes metastasis, suggesting that miR‐126 might play a key role in the progression and metastasis of NSCLC.63 Stenvold et al64 also found that miR‐182 has tumour suppressor properties in stage II and in SCC patients, suggesting miR‐182 tended to be a favourable prognostic factor in the total NSCLC cohorts. In addition, the expression of miR‐451 in NSCLC tissues was also associated with poor degree of tumour differentiation, advanced pathological stage, lymph node metastasis and poor prognosis.65 These clinical data suggested that miRNA could act as pivotal part for the detection of novel diagnostic, prognostic and therapeutic biomarkers in patients with NSCLC.

5.1. Tissue‐specific miRNA as diagnostic, prognostic and therapeutic biomarkers in NSCLC

miRNAs appeared to become a novel valuable diagnostic candidates, and would be more advanced than other various biomarkers, which are employed for the diagnosis of NSCLC in early stages.66 It has been shown that significantly different miRNA expression profiles emerged in human tumours,7 and the dysregulated expression patterns of miRNA were detected with high sensitivity and specificity.67 Moreover, miRNA has an advantage with high stability.68 These evidences speculated that miRNA may have potential to play a crucial role in cancer.

Recently, there were a large number of studies identifying up‐regulation or down‐regulation of a variety of tissue‐specific miRNAs in NSCLC.69 Surgical resection remains the most effective treatment of early‐stage NSCLC.36 Up to this point, many patients with NSCLC still develop tumour metastasis and recurrence after receiving pulmonary resection procedure, due to lack of promising biomarkers for the diagnosis, prognosis, and therapy of lung cancer.70 Gao et al71 identified a 7‐miRNA signature, including miR‐139, miR‐326, miR‐944, miR‐190, miR‐183, miR‐182 and miR‐101, as potential outcome predictor for SCC patients from clinical characteristics of Kaplan‐Meier and ROC curves. miR‐139 was suppressed frequently in primary NSCLCs; in addition, H3K27me3‐mediated silencing of miR‐139 significantly enhances invasiveness and lymph node metastasis of NSCLC.72 Mao et al73 showed that miR‐187‐5p is down‐regulated in NSCLC, which plays pivotal roles in promoting the growth and metastasis of NSCLC cells by directly targeting the oncogenic CYP1B1 gene.

miRNA appeared appropriately to become valuable therapeutic targets reversing cancer phenotypes or sensitizing tumours to chemotherapy. It is the fact that each miRNA simultaneously targets various genes, and a single miRNA is potential to regulate the activity of a molecular signalling pathway, or coordinately regulate multiple targets in different pathways.23, 74 Several lines of evidences identified that molecular/cellular targets could mediate tumorigenesis and development such as angiogenesis, apoptosis, survival, cell cycle and differentiation.74 Therefore, in a global sense, dysregulation of miRNA would make some changes in the behaviour of cells and have a tendency to cancerous conditions. A variety of dysregulated miRNAs, which could act as potential diagnostic and therapeutic biomarkers in NSCLC patients, including let‐7c,75 miR‐138,76, 77, 78 miR‐145,79 miR‐183,80 miR‐29 family,81 miR‐34a,82 miR‐34c‐3p,83 miR‐101‐3p,84 miR‐129,85 miR‐200b,86 miR‐212,87 miR‐218,88 miR‐449a89 and miR‐45165 were down‐regulated, while miR‐21/155,51 miR‐25,90 miR‐31,91 miR‐221/222,92 miR‐224,93 miR‐191,94 miR‐494,95 miR‐19a96 and miR‐34697 were up‐regulated in NSCLC samples. These results indicated that the different expression profile of miRNA could be applied as diagnostic and therapeutic biomarkers in patients with NSCLC.98

Huang et al99 indicated that miR‐186 played a key role as a tumour suppressor in NSCLC cells and its overexpression could inhibit cell proliferation, invasion, migration and induce cell apoptosis of NSCLC cells via targeting mitogen‐activated protein kinase kinase kinase 2 (MAP3K2). Hence, miR‐186 might represent a novel therapeutic candidate in patients with NSCLC. Mitogen‐activated protein kinase kinase kinase 2 is one of great potential targets for NSCLC and plays critical roles in the tumorigenesis and development of NSCLC.99

In other studies, Sun et al100 confirmed that miR‐9600 could be used as tumour suppressor and a negative controller for NSCLC patients to inhabit metastasis through signal transducer and activator of transcription 3 (STAT3) signalling pathway. In addition, miR‐9600 is deregulated in NSCLC lung tissues and cell lines, which would be a favourable factor for prognosis. It has been observed that miR‐9600 is capable to repress cell motility, metastasis, invasive and cell proliferation in vitro. This molecule exerts its effect via downstream genes expression of the STAT3 signalling pathway, which was relative to cell cycle. miR‐9600 could also have a certain function on the protein expression of MMP‐2, MMP‐7 and MMP‐9 in A549 and SPC‐A‐1 cells. These results suggested that miR‐9600 could play an important role as potential therapeutic biomarkers in NSCLC patients.100

Integrin subunit beta 1 (ITGB1) is an essential subgroup of the integrin family, which plays an important role in regulating cell‐extracellular matrix (ECM) adhesion and signalling, affecting various of cellular processes, including cell proliferation, apoptosis, metastasis, invasion and survival.101 It has been observed that positive expression or activation of ITGB1 signalling was associated with poor prognosis in lung cancer.102 Epithelial‐mesenchymal transition is a pivotal process that promotes tumour cells to obtain a more migratory and invasive mesenchymal phenotype, during which tumour cells exert down‐regulation of the expression of epithelial proteins such as E‐cadherin, while up‐regulation of the expression of mesenchymal proteins such as N‐cadherin and vimentin (VIM; Figure 2).103 Qin et al104 demonstrated that miR‐134 down‐regulated ITGB1 expression and inhibited EMT, resulting in suppressed migration and invasion of NSCLC both in vitro and in vivo. These researches indicated that miR‐134 might be applied as a novel therapeutic biomarkers in patients with NSCLC.104 Table 1 illustrates a large number of miRNAs and their targets that are involved in lung cancer pathogenesis and could be used as diagnostic, prognostic and therapeutic biomarkers in this disease.

Figure 2.

Figure 2

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miRNA involved in epithelial‐to‐mesenchymal transition (EMT) in NSCLC. The schematic representation depicting EMT is a pivotal process to promote tumour cells. miR‐134 inhibits EMT evidenced by up‐regulation of E‐cadherin expression and down‐regulation of vimentin and integrin subunit beta 1 (ITGB1) expression. miR‐206 inhibits EMT through decreased expression of c‐Met and Bcl2 in lung cancer cells. Slug is a potent trigger for EMT, and miR‐124 inhibits EMT by down‐regulating Slug protein. FHIT inhibits EMT through transcriptional repression of EMT‐related genes. A FHIT:Fragile histidine triad‐activated miRNA, miR‐30c, inhibits EMT via targeting metastasis‐related genes (MTDH) and high mobility group AThook 2 (HMGA2)

Table 1.

Tissue‐specific miRNAs up‐/down‐regulated in lung cancer

miRNA Expression Target genes or pathways Function of NSCLC References
miR‐139 Down‐regulation PDE2A Enhance invasiveness and metastasis 72
miR‐187‐5p Down‐regulation CYP1B1 Promote growth and metastasis 73
Let‐7c Down‐regulation ITGB3, MAP4K3 Suppress metastasis and invasion 75
miR‐138 Down‐regulation Sirt1, GIT1, SEMA4C, EZH2 Suppresses the proliferation, metastasis 76, 77, 78
miR‐145 Down‐regulation FSCN1 inhibits migration and invasion 79
miR‐183 Down‐regulation FoxO1 Promotes growth 80
miR‐29 family Down‐regulation WIF‐1 Inhibits proliferation and induce apoptosis 81
miR‐34a Down‐regulation TGFβR2 Inhibits proliferation and promotes apoptosis 82
miR‐34c Down‐regulation PAC1/MAPK Suppresses proliferation and invasion 83
miR‐101‐3p Down‐regulation MALAT‐1 Inhibits growth and metastasis 84
miR‐129 Down‐regulation MMP9 Prevent the metastasis 85
miR‐200b Down‐regulation FSCN1 Inhibits migration and invasion 86
miR‐212 Down‐regulation SOX4/EMT Inhibited cell migration, invasion and EMT 87
miR‐218 Down‐regulation HMGB1 Suppresses cell migration and invasion 88
miR‐449a Down‐regulation c‐Met Inhibits migration and invasion 89
miR‐451 Down‐regulation RAB14 Inhibits proliferation and promotes apoptosis 65
miR‐9600 Down‐regulation STAT3 Inhibits proliferation, migration, invasion and promotes apoptosis 100
miR‐186 Down‐regulation MAP3K2 Inhibit cell proliferation, invasion, migration and induce apoptosis 99
miR‐134 Down‐regulation ITGB1 Suppress migration and invasion 104
miR‐21/155 Up‐regulation SOCS1, SOCS6, PTEN Promote cell growth 51
miR‐25 Up‐regulation FBXW7 Promotes cell proliferation and motility 90
miR‐31 Up‐regulation ABCB9 Inhibits apoptosis 91
miR‐221/222 Up‐regulation EMT Inhibits cell growth and apoptosis 92
miR‐224 Up‐regulation RASSF8: RAS association domain family 8 Promotes cell proliferation 93
miR‐191 Up‐regulation NIFA: transcription factor, nuclear factor 1α Promotes cell proliferation and migration 94
miR‐494 Up‐regulation BIM: also called BCL2‐like 11 Promotes cell proliferation and Inhibits apoptosis 95
miR‐346 Up‐regulation XPC, ERK, E‐cadherin Promotes cell growth and metastasis, and suppresses cell apoptosis 97
miR‐19a Up‐regulation SOCS1 Promotes cell growth metastasis and inhabits invasion 96
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ITGB1, integrin subunit beta 1; MAP3K2, mitogen‐activated protein kinase kinase kinase 2; PTEN, tensin homologue deleted on chromosome 10; STAT3, signal transducer and activator of transcription 3; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; FoxO1, forkhead box O1

6. CIRCULATING MIRNAS AS DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC BIOMARKERS IN NSCLC

A large number of studies have suggested circulating miRNA was known as a miRNA released into bloodstream.105 Chen et al and Mitchell et al106, 107 revealed that large amounts of circulating miRNA were detected stably in serum and plasma, which could be used as non‐invasive serological markers of tumours concurrently in 2008. Circulating miRNA could be a novel attractive option for the diagnosis and treatment of several diseases including lung cancer. Multiple lines of evidence has revealed that dysregulation of circulating miRNA could be used as potential diagnostic and therapeutic biomarkers in NSCLC.108, 109, 110, 111, 112, 113, 114, 115, 116

Circulating miR‐422a may provide a potential target for therapeutic approaches in management of lung cancer.117 Wu et al117 suggested that miR‐422a would play the most crucial diagnostic roles in lymphatic metastasis through miRNA microarray (AUC, 0.744; 95% CI, 0.570‐0.918). They conducted a group of 51 lung cancers and found that miR‐422a could act as a potential diagnose in the lung cancer patients with AUC (0.880; 95% CI, 0.787‐0.972). In addition, they suggested that a series of target genes, such as CX3CR1, FYCO1, E2F2, exerted their unique effects contributing to the biological processes of transport, apoptosis and protein phosphorylation significantly through analysing GEO: The Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) and The Cancer Genome Altas (TCGA). These findings highlight that circulating miR‐422a could emerge as a non‐invasive biomarker with sufficient accuracy in predicting lymph node metastasis in lung cancer patients.

Nadal et al118 identified circulating miRNA expression profile in NSCLC patients. They revealed some differentially expressed miRNAs, such as miR‐141, miR‐193b, miR‐301 and miR‐200b in the serum of NSCLC patients. Their results indicated that the expression of these miRNAs could have high specificity for detecting the NSCLC patients. These findings suggested that these circulating miRNA could exert effects as attractive option to diagnose patients with NSCLC.118

Dinh et al119 showed from an unbiased screen that miR‐29a and miR‐150 were decreased in the circulation of NSCLC patients undergoing thoracic RT: thoracic radiotherapy. Franchina et al120 investigated that miR‐22, miR‐24, and miR‐34a were found up‐regulated (P < .05) in NSCLC patients vs healthy controls. In addition, these up‐regulated miR‐22, miR‐24 and miR‐34a in lung cancer patients could be represented as significant biomarkers in the follow‐up of early‐stage NSCLC and for innovative approaches to early diagnosis in healthy heavy smokers. Ma et al measured serum levels of miR‐125b in NSCLC and determined the relationship of miR‐125b expression to diagnosis, stratification and patient prognosis. They observed that circulating miR‐125b levels can distinguish patients with NSCLC from healthy controls. The concentration of circulating miR‐125b may be a valuable blood biomarker for NSCLC to screen, which could represent a potential biomarker for disease progression.121

In other studies, Zhang et al122 confirmed that miR‐1246 and miR‐1290 could drive tumour initiation and cancer progression, due to a high specificity with the tumour‐initiating cell (TIC) in NSCLC. Significantly, they suggested that miR‐1246 and miR‐1290 played pivotal roles in regulating the spontaneous metastasis of primary tumour cells. Metallothionein 1G (MT1G) is a great gene that represses tumour. Moreover, it could mediate the function of lung cancer cells through targeting both miR‐1246 and miR‐1290 together. It has been observed that miR‐1246 and miR‐1290, which were enriched in TICs, exerted great effects in regulating tumour growth and metastasis through the repression of metallothioneins, especially MT1G. These results highlight that miR‐1246 and miR‐1290 might be a valuable therapeutic modality for NSCLC patients by directly targeting MT1G.122

Dou et al123 used plasma miRNA for the diagnosis of NSCLC in the early stages. They assessed miRNA expression in 120 NSCLC patients and 360 healthy controls. They have observed down‐regulated expression of let‐7c and miR‐152 in plasma in NSCLC. These findings identified that circulating let‐7c and miR‐152 could play an important role in detecting NSCLC with an advantage of non‐invasive and valuable diagnosis. In addition, in order to determine the effects of let‐7c and miR‐152 expression as a significant potential biomarker for NSCLC, they have screened a large number of plasma samples. Table 2 illustrates a number of circulating miRNA which might be applied as diagnostic and therapeutic biomarkers for lung cancer patients.

Table 2.

Circulating miRNAs up‐/down‐regulated in lung cancer

miRNA Expression Materials Stages Samples References
miR‐422a Up‐regulation Serum I‐IV 77 117
miR‐22 Up‐regulation Blood ΙΙΙ‐IV 54 120
miR‐24 Up‐regulation Blood ΙΙΙ‐IV 54 120
miR‐34a Up‐regulation Blood ΙΙΙ‐IV 54 120
miR‐125b Up‐regulation Serum I‐IV 193 121
miR‐1246 Up‐regulation Serum I‐ ΙΙΙ 143 122
miR‐1290 Up‐regulation Serum I‐ ΙΙΙ 143 122
Let‐7c Down‐regulation Plasma I‐IV 120 123
miR‐152 Down‐regulation Plasma I‐IV 120 123
miR‐574‐5p Up‐regulation Serum I‐IV 75 109
miR‐874 Up‐regulation Serum I‐IV 75 109
miR‐21 Up‐regulation Serum I‐II 85 110
miR‐126 Down‐regulation Serum I‐II 85 110, 111
Let‐7a Down‐regulation Serum I‐II 85 110
miR‐125b Up‐regulation Serum I‐IV 100 112
miR‐200b Up‐regulation Serum I‐IV 100 112
miR‐34b Up‐regulation Serum I‐IV 100 112
miR‐203 Up‐regulation Serum I‐IV 100 112
miR‐205 Up‐regulation Serum I‐IV 100 112
miR‐429 Up‐regulation Serum I‐IV 100 112
miR‐448 Up‐regulation Plasma I‐IV 90 113
miR‐4478 Up‐regulation Plasma I‐IV 90 113
miR‐506 Down‐regulation Plasma I‐IV 90 113
miR‐182 Up‐regulation Serum I‐III 112 111
miR‐183 Up‐regulation Serum I‐III 112 111
miR‐210 Up‐regulation Serum I‐III 112 111
miR‐15b‐5p Down‐regulation Serum I‐III 164 114
miR‐16‐5p Up‐regulation Serum I‐III 164 114
miR‐20a‐5p Up‐regulation Serum I‐III 164 114
miR‐324‐3p Up‐regulation Plasma I 395 115
miR‐1285 Down‐regulation Plasma I 395 115
miR‐98‐5p Up‐regulation Plasma III‐IV 15 116
miR‐302e Up‐regulation Plasma III‐IV 15 116
miR‐495‐3p Up‐regulation Plasma III‐IV 15 116
miR‐613 Up‐regulation Plasma III‐IV 15 116
miR‐1246 Up‐regulation Serum I‐III 59 122
miR‐1290 Up‐regulation Serum I‐III 59 122
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7. EXOSOMAL MIRNA AS DIAGNOSTIC BIOMARKERS IN NSCLC

Exosomes were microvesicles containing 5′‐nucleotidase activity released from different types of cells such as tumour cells, stem cells and some normal cells, which could play a crucial role in contributing to intercellular communication.13, 124 Exosomes can take along a series of different functional molecules such as DNAs, mRNAs, miRNAs and proteins to receipt cells. Hence, exosomes and their bioactive cargos altered the recipient cells' behaviour differently such as re‐programming the recipient cells through transferring particular message to these cells in the microenvironment.125 A wide range number of studies have indicated that exosomes released from cancer cells play great roles in tumour progression in several diseases such as cancer.14, 15, 126 Several lines of studies have identified that exosomal miRNA performed different expression profiles between lung cancer patients and controls, suggesting exosomal miRNA might be as a novel screening modality for patients with lung cancer.127, 128, 129, 130 Thus, it has opened the window to a new world of possibilities to diagnose NSCLC in early stage.

Munagala et al125 evaluated miRNA expressed profile of lung cancer and normal bronchial epithelial cells as well as in exosomes, which secreted from these cells in culture media. The results identified that miR‐132, miR‐155, miR‐21, miR‐331‐5p and miR‐483‐5p were significantly up‐regulated in lung cancer cells and exosomes, while let‐7e, miR‐26a, miR‐193b, miR‐345, miR‐16 and miR‐423‐5p were down‐regulated, suggesting exosomal miRNA can be requisition as valuable biomarkers for diagnosis in lung cancer.125

Liu et al131 assessed exosomal miRNA as novel biomarker for early diagnosis and prognosis in lung cancer patients through quantitative polymerase chain reaction (qPCR) array panel. Their results indicated that the expression of exosomal miR‐23b‐3p, miR‐10b‐5p and miR‐21‐5p were associated with the prognostic significance of NSCLC. Moreover, the expression of exosomal miR‐21‐5p and miR‐10b‐5p were up‐regulated, while miR‐23b‐3p was observed down‐regulated in NSCLC patients compared with the control group. As a consequence, the expression of exosomal miR‐23b‐3p, miR‐10b‐5p and miR‐21‐5p provided a significantly survival prediction for NSCLC and suggested these exosomal miRNA could be used as prognostic biomarkers independently.131

Li et al132 indicated that exosomes released from lung cancer mesenchymal stem cells (MSCs) could carry various cargos such as some proteins and RNAs which could be used as biomarkers in lung cancer cells. They showed that exosomal proteins, including CD63, heat shock protein 70 (HSP70), P65 and macrophage cationic peptide 1 (MCP‐1), are useful biomarkers for the identification of lung cancer cells. Moreover, they detected other cargos such as mRNA (TLR2, TLR7 and TLR8) and miRNA (miR‐142‐5p, miR‐203, miR‐21 and miR‐29a) in exosomes released from lung cancer MSCs. In addition, they identified that lung cancer cell‐derived exosomes could educate naive MSCs into a novel kind of pro‐inflammatory MSCs (P‐MSCs) by activating TLR2/NF‐kB signalling through exosomal surface HSP70. Finally, these results confirmed that exosomal RNAs and miRNAs, and proteins might exert effects as potential diagnosis biomarkers in lung cancer patient.132 Table 3 indicates a number of exosomal miRNA released from lung cancer cell.

Table 3.

Exosomal miRNA biomarkers in lung cancer

miRNAs Detection method Samples (human/cell lines) Stages References
miR‐29a, miR‐150 qRT‐PCR 5 ΙΙΙ 119
miR‐182, miR‐185, miR‐21, miR‐127, miR‐142, miR‐155, miR‐138, miR‐125‐5p, let‐7e, miR‐193b, miR‐16, miR‐26a, miR‐345, miR‐423‐5p, qRT‐PCR H1299 125
miR‐1228‐3p, miR‐30b, miR‐30c, miR‐103, miR‐122, miR‐195, miR‐203, miR‐221, miR‐222 qRT‐PCR 12 128
miR‐197‐5p, miR‐4443, miR‐642a‐3p, miR‐27b‐3p, miR‐100‐5p qRT‐PCR A549 129
miR‐98, miR‐133b, miR‐138, miR‐181a, miR‐200c qRT‐PCR A549 130
miR‐23b‐3p, miR‐10b‐5p, miR‐21‐5p qRT‐PCR 196 I‐IV 131
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8. CONCLUSION AND PERSPECTIVE

Non‐small cell lung cancer is the most common serious cancer and a leading cause of cancer‐related death worldwide. Early diagnosis of NSCLC is a prerequisite for proper management and increasing survival. Several lines of evidence have indicated that NSCLC patients have a poor prognosis, due to the lack of simple, reliable and non‐invasive diagnostic tools for the early stage. At present, according to the clinical stage of lung cancer treatment options, surgical treatment has been recognized as the preferred method of treatment for lung cancer. But lung cancer patients transfer rate and mortality rate has not been significantly improved due to lack of effective diagnostic tools in the early stage. miRNAs have emerged as non‐coding RNAs, which have potential to be candidates for the diagnosis and therapy of NSCLC. Moreover, exosomal biomarkers such as miRNA, proteins and mRNAs could open new horizons for the diagnosis of NSCLC.

9. AUTHORS' CONTRIBUTIONS

Q Z, S‐X H and F Z drafted the manuscript. C‐C S revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.

COMPETING INTERESTS

The authors declare that they have no competing interests.

Zhou Q, Huang S‐X, Zhang F, et al. MicroRNAs: A novel potential biomarker for diagnosis and therapy in patients with non‐small cell lung cancer. Cell Prolif. 2017;50:e12394 10.1111/cpr.12394

Funding information

This study is funded by the National Natural Science Foundation of China (No. 81360447), the National Natural Science Foundation of China (No.81372973), the National Natural Science Foundation of China (No. 81660535), the Fundamental Research Funds for the Central Universities (No. 2015305020202) to Cheng‐Cao Sun and the National Postdoctoral Program for Innovative Talents (No. BX201700178) to Cheng‐Cao Sun

Contributor Information

Cheng‐Cao Sun, Email: lodjlwhu@sina.com.

De‐Jia Li, Email: chengcaosun@whu.edu.cn.

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