Abstract
In spite of advances in the diagnosis and current molecular target therapies of lung cancer, this disease remains the most common cause of cancer-related death worldwide. Approximately 80% of lung cancers is non-small cell lung cancer (NSCLC), and 5-year survival rate of the disease is ~20%. On the other hand, idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology. IPF is refractory to treatment and has a very low survival rate. Moreover, IPF is frequently associated with lung cancer. However, the common mechanisms shared by these two diseases remain poorly understood. In the post-genome sequence era, the discovery of noncoding RNAs, particularly microRNAs (miRNAs), has had a major impact on most biomedical fields, and these small molecules have been shown to contribute to the pathogenesis of NSCLC and IPF. Investigation of novel RNA networks mediated by miRNAs has improved our understanding of the molecular mechanisms of these diseases. This review summarizes our current knowledge on aberrantly expressed miRNAs regulating NSCLC and IPF based on miRNA expression signatures.
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Introduction
In spite of advances in diagnosis and current developing treatment, lung cancer remains the most common cause of cancer-related death worldwide, accounting for 1.59 million deaths in 2012.1 Lung cancers are classified into two subtypes, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), according to the pathological features of the disease. NSCLC can be categorized into three histological subtypes according to the pathological characteristics: adenocarcinoma, squamous cell carcinoma and large cell carcinoma.2 The 2015 World Health Organization Classification of Lung Tumors was published last year as the fourth edition. In this edition, with certain drugs approved for specific subgroups of NSCLC patients, the decision of more exact histopathological subtyping is required. Recently, several therapeutic agents have been designed for the treatment of adenocarcinoma; these target epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements.3, 4, 5, 6, 7, 8 However, such a molecular-targeted treatment has not been yet approved for squamous cell carcinoma, large cell carcinoma and neuroendocrine cancer.9, 10, 11, 12
Idiopathic pulmonary fibrosis (IPF) is a type of chronic progressive interstitial lung disease of unknown etiology. IPF is characterized by aberrant accumulation of extracellular matrix (ECM) proteins, activation of fibroblast proliferation and scarring of the lung epithelium.13, 14 IPF is associated with a very low survival rate, and effective treatment methods are limited.15, 16, 17
Many studies indicated that NSCLC and IPF share common risk factors.14, 18, 19, 20, 21 In the clinical setting, NSCLC is often associated with IPF. Indeed, concurrent IPF was found in 7.5% of surgically resected lung cancer cases.22 Furthermore, several reports have described a high incidence of lung cancer (4.4–13%) in patients with IPF.23, 24, 25 These epidemiological studies linked the presence of IPF to the development of lung cancer. Moreover, the development of lung cancer in patients with IPF is markedly poorer prognosis.26, 27, 28 Thus, these studies have shown that there are common pathogenic pathways activated in both lung cancer and IPF; investigation of the molecular pathogenesis of these diseases may lead to the development of new treatments for lung cancer and IPF.
Biogenesis and functional significance of microRNAs
Post-genome sequence era, the discovery of noncoding RNAs in the human genome has provided a conceptual breakthrough in the investigation of molecular pathologies. Noncoding RNAs affect every stage of gene expression, from RNA transcription to RNA degradation.29, 30 Among the various types of noncoding RNAs, microRNAs (miRNAs) are small RNA molecules (18–25 nucleotides in length) that control the expression of protein-coding/non-protein-coding genes by repressing translation or degradation of RNA transcripts in a sequence-specific manner.31, 32, 33 To date, the miRNA database (Release 21) contains 35 828 mature miRNA products in 223 species (http://www.mirbase.org/). With advancements in analytical methods, it is expected that the number of known miRNAs will continue to increase.
The miRNA-regulatory pathway involves a multistep process. First, miRNA genes are transcribed by RNA polymerase-II or -III using a gene-specific or shared promoter. Next, transcribed pri-miRNAs are modified by the double-stranded RNA-binding proteins DGCR8 and Drosha and processed to 60–100-nucleotide hairpin RNAs called pre-miRNAs.34, 35, 36 Pre-miRNAs are then transported to the cytoplasm by exportin 5 and further processed by the endonucleases Dicer and TRBP into 19–22-nucleotide mature miRNAs.34, 35, 37 Mature miRNA duplexes contain the mature miRNA (guide-strand miRNA) and the miRNA* (passenger-strand miRNA). This duplex is recruited to the RNA-induced silencing complex, which includes Ago2, a critical factor in the miRNA biogenesis pathway.34, 35
In general, the guide-strand RNA from duplex miRNA is retained to direct recruitment of RNA-induced silencing complex to target mRNAs and repress RNA expression, whereas the passenger-strand RNA is degraded.35, 38 Several recent studies have shown that both guide and passenger strands of the miRNA duplex are functional in cancer cells.39, 40 Moreover, some miRNAs bind to the promoter region of the genes and activate the transcription of target genes.33, 41
miRNA expression signatures in NSCLC
Current advanced proteomic and genomic analyses lead to understanding the etiology of lung cancer.42, 43, 44, 45 Through basic genome analysis, several therapeutic agents have been designed—gefitinib, erlotinib and afatinib—which target epidermal growth factor receptor (EGFR), and crizotinib and alectinib, which targets the EML4-ALK fusion gene.3, 5, 6, 7, 8
To date, many reports have shown that a number of miRNAs contribute to lung cancer.46, 47, 48, 49, 50, 51 Expression levels of the let-7 family were reduced in NSCLC tissues.46 Overexpression of let-7 suppresses the growth of cancer cells through targeting of RAS.52
Aberrantly expressed miRNAs disrupt the normally controlled RNA networks, and these events may trigger cancer cell initiation, development, metastasis and drug resistance.33, 53, 54 Therefore, identification of dysregulated miRNAs in cancer cells is the pivotal step in the study of miRNA-mediated cancer networks. In this chapter, we focused on the downregulated miRNAs and described the functional significance of miRNAs and miRNA-regulated oncogenic genes in NSCLC and IPF. Upregulated miRNAs are described at length in other review articles. In this review, we describe four miRNA expression signatures of NSCLC clinical tissues from previous studies (Table 1a).
Among them, miR-143 and miR-145 form an miRNA cluster in the human chromosome 5q32 region and are frequently downregulated in several cancers, including lung cancer.47, 55, 56, 57, 58, 59 These miRNAs have been shown to function as tumor suppressors. The p53 gene is a master of antitumor gene in the human genome and regulates a diverse set of anticancer cellular pathways.60, 61, 62 The p53 gene induces the expression of miR-145 by direct binding to the miR-145 promoter region.63, 64 miR-145 has been shown to suppress the oncogenic c-MYC gene.65, 66, 67 Interestingly, the EGFR and Ras oncogenes are therapeutic targets in lung cancers, and miR-145 and miR-143 have been shown to inhibit EGFR and Ras expression, respectively, in cancer cells.59 Low expression of miR-145 is associated with poor prognosis in NSCLC, and aberrant expression of miR-145 mediates chemoresistance and brain metastasis.67, 68, 69 Cisplatin is a key drug used to treat advanced NSCLCs, and miR-145 is associated with the potential mechanism of cisplatin chemoresistance by regulation of CDK6.70 In addition, downregulation of miR-145 contributes to brain metastasis in NSCLC, which is associated with high mortality rates via upregulation of target genes, such as OCT-4, EGFR, c-MYC, MUC-1 and TPD52.67, 71 Stromal expression of miR-145-5p also promotes neoangiogenesis in NSCLC development.72
Downregulation of miR-126 has been reported in various cancers.73, 74, 75, 76 In the human genome, miR-126 is mapped on chromosome 9q34.3 and within the intron of the epidermal growth factor-like domain 7 (EGFL7) gene. The miR-126 host gene EGFL7 has pivotal roles in angiogenesis and cancer cell progression and development.77 The mature miR-126 binds to the host gene EGFL7, resulting in a decrease in EGFL7 expression; this creates a negative feedback loop.78 Similar to miR-126 downregulation in cancer cells, miR-126* (miR-126-5p) expression has reduced in several types of cancer.79 The sequence of mature miR-126* is complementary to that of miR-126. Downregulation of miR-126/miR-126* was reported in NSCLC.80 Overexpression of miR-126 inhibits the expression of vascular endothelial growth factor (VEGF)-A and impairs cancer cell growth.75 VEGF enhances angiogenesis and upregulated VEGF-A in many cancers.81 In miRNA biogenesis, the passenger strand of the miRNA is degraded; however, in the case of miR-126/miR-126*, both miRNAs are stable and mediate characteristic functions. However, the role of miR-126/miR-126* in the complex process of cancer formation remains largely unknown. The expression of miR-126 is relatively low in SCLC, and miR-126 functions as a negative regulator of SCLC cell growth.82
Downregulation of miR-26 family members and the tumor-suppressive roles of these miRNAs have been reported in several cancers.47, 83 The miR-26 family includes three subtypes in human cells: miR-26a-1 (located on chromosome 3p22.2), miR-26a-2 (located on chromosome 12q14.1) and miR-26b (located on chromosome 2q35). The seed sequences of these miRNAs are identical, suggesting that the miR-26 family members regulate the same genes in human cells (miRBase, release 21; http://www.mirbase.org/). Ectopic expression of miR-26a in A549 cells inhibits the G1–S transition and enhances cell death in response to CDDP (cisplatin) treatment.84 In addition, high mobility group A2 (HMGA2) was previously investigated as a target of miR-26a in A549 cells.85 miR-26b has been reported to exhibit anticancer functions in NSCLC cells through targeting COX2 and MIEN1.86 Another study showed that low expression of miR-26b was a risk factor for poor prognosis in patients with NSCLC.87
Downregulation of miR-1 is frequently observed in many cancers, including lung cancer.88 miR-1 is highly conserved in the muscles of flies, mice and humans, and has been extensively investigated in various human diseases.89 In human genome, miR-1-1/miR-133a-2 (chromosome 20q13.33), miR-1-2/miR-133a-1 (18q11.2) and miR-206/miR-133b (6p12.1) form clusters in three different chromosomal regions.90 To investigate the functional roles of the miR-1/miR-133a cluster in cancer cells, we sequentially identified novel cancer pathways regulated by the miR-1/miR-133a cluster in several cancers, including NSCLC.91 Restoration of both mature miR-1 and miR-133a markedly inhibits cancer cell aggressiveness in NSCLC cells. In addition, the gene encoding coronin-1C is a common target of the miR-1/miR-133a cluster.91 Activation of EGFR and MET oncogenic signaling enhances cancer cell aggressiveness and promotes lung cancer.92 Overexpression of miR-206 inhibits the dual signaling networks activated by MET and EGFR in lung squamous cell carcinoma cells.93
miRNA expression signatures in IPF
IPF is a chronic fibrosing interstitial lung disease of unknown etiology.14, 16, 94 One of the main characteristics of fibrosis is excess accumulation of ECM components, such as collagen, fibronectins, elastin and fibrillins.95, 96, 97 Accumulated ECM components replace functional tissue and disrupt organ architecture. During the process of fibrosis development, several genes and pathways are activated. In particular, matrix metalloproteinases (MMPs) and connective tissue growth factor (CTGF) are upregulated in fibrotic lesions.98, 99, 100 The activation of Wnt/β-catenin signaling regulates the expression of several pro-oncogenic molecules in cancer cells.101 Activation of the Wnt/β-catenin pathway has reported in fibrotic disease, including IPF.102 The Wnt pathway may also be activated by the fibrogenic cytokine transforming growth factor (TGF)-β.99 Therefore, further studies are needed to investigate the regulation of the genes involved in these pathways by miRNAs.
The miRNA signature of human IPF lung specimens compared with controls has revealed the differential expression of 46 miRNAs.103 Of these, let-7d was found to be abundantly expressed in normal lung epithelial cells and markedly reduced in IPF.103 The expression level of let-7d was reduced by TGF-β, resulting in overexpression of its target gene HMGA2 in IPF lesions.104
Expression of the CTGF gene is induced by TGF-β in a SMAD3/SMAD4-dependent manner, and CTGF enhances the synthesis of ECM proteins.105, 106, 107 The downregulation of miR-26a, which targets CTGF, is involved in IPF pathogenesis, and miR-26a expression has been shown to be reduced by TGF-β.100 In addition, studies have reported that CTGF expression is regulated by miR-145, miR-30 and miR-133.108
Downregulation of miR-18a, miR-19a and miR-19b, members of the miR-17-92 cluster, has also been reported in human IPF lung tissue.109 The miR-17-92 cluster is a proto-oncogenic cluster consisting of six miRNAs.110, 111 Recent studies have shown that miR-18a, miR-19a and miR-19b regulate CTGF in liver and cardiac fibrosis.112, 113
The expression levels of miR-21 and miR-155 have also been shown to differ in lung tissues from patients with IPF and healthy controls (Table 1b). Upregulation of miR-21 and miR-155 has been reported by profiling of circulating serum miRNAs in patients with IPF and is associated with various clinical features of the disease.114, 115 Similar to the miR-17-92 cluster, miR-21 is regarded as an oncomiR in cancer cells.116, 117 Moreover, miR-21 has been shown to have profibrotic activity in human IPF and murine bleomycin-induced lung fibrosis.118 miR-21 expression is induced by TGF-β and suppresses smad-7, a negative regulator of TGF-β signaling.118 In addition, a recent study showed that miR-155-knockout mice are resistant to bleomycin-induced skin fibrosis.119 Silencing of miR-155 inhibits collagen synthesis function and blocks signaling through two profibrotic pathways, that is, the Wnt/β-catenin and Akt signaling pathways.119
Aberrantly expressed miRNAs in NSCLC and IPF
Previous studies have shown that IPF and lung cancer share common risk factors, such as smoking, viral infection and chronic tissue injury.14, 18, 19, 20, 120 These risk factors may lead to induction of critical genetic and epigenetic alterations in the human genome.121 A previous study showed that p53 and p21 are upregulated in bronchial and alveolar epithelial cells in patients with IPF.122 Moreover, constitutive chronic DNA damage may lead to mutation of the p53 gene and could contribute to tumorigenesis in IPF.123 Tumor-suppressor fragile histidine triad (FHIT) is a pivotal factor in lung cancer, and mutations in this gene have been detected in patients with IPF.124 Using microsatellite DNA analysis, loss of heterozygosity was found in MYCL1, FHIT, SPARC, p16Ink4 and TP53 genomic loci in IPF.125 Currently available sequence-based analyses may be used to identify genomic alterations common to lung cancer and IPF pathogenesis. Recent studies have indicated that constitutive chronic damage to the alveolar epithelium predisposes individuals to IPF and lung cancer.126 During the process of repair and scar formation, alveolar epithelial cells undergo a transition to a mesenchymal phenotype, giving rise to fibroblasts and myofibroblasts.126 Many studies have shown that TGF-β induces the epithelial–mesenchymal transition in alveolar epithelial cells.126 Moreover, activation of TGF-β signaling and excessive accumulation of ECM proteins are observed in IPF and lung cancer, suggesting the presence of common molecular mechanisms in both diseases.107, 126, 127 Thus, a large number of genes are commonly involved in the molecular pathogenesis of both diseases. Moreover, recent studies have demonstrated that miRNAs contribute to the pathogenesis of both NSCLC and IPF.46, 47, 103, 109, 128 We focused on aberrantly expressed miRNAs in both diseases and elucidated the common molecular pathways based on miRNA expression signatures. miRNAs showing aberrant expression in lung cancer and IPF are shown in Tables 2a and 2b. For example, miR-29 and miR-30 are both downregulated in NSCLC and IPF. We will describe each of these miRNAs below.129
The miR-29 family consists of three members (miR-29a, miR-29b and miR-29c) and forms clustered miRNA in human genome on different chromosome regions (miR-29a and miR-29b-1 are 7q32, whereas miR-29b-2 and miR-29c are 1q32).130 Recent studies have shown that all members of miR-29 family abnormally expressed in NCSLC and IPF.47, 85, 103, 131 The mechanisms regulating the expressions of miR-29 family members have also been elucidated in previous studies.132, 133, 134 Specifically, the promoter regions of miR-29a and miR-29b-1 contain c-Myc and nuclear factor of kappaB (NF-κB)-binding sites, and the expression of miR-29 family members can be repressed by c-Myc and NF-κB.135 A previous study showed that low expression of miR-29b is more common in NSCLC, exhibiting high c-Myc expression.136 Moreover, high c-Myc expression in NSCLC is associated with low miR-29b expression and shorter survival durations than those in patients with low c-Myc expression (and high miR-29b expression).136 The expression of miR-29 family is suppressed by growth factors or cytokines, such as the TGF-β/Smad pathway. Interestingly, researchers have demonstrated the presence of a regulatory loop feedback between TGF-β and the miR-29 family.130 The miR-29 family involves in multiple profibrotic and inflammatory pathways, and its expression is markedly reduced in fibrotic lungs.103, 109, 131 In addition, members of the miR-29 family inhibit TGF-β-induced ECM synthesis through activation of the phosphoinositol 3-kinase/AKT pathway in human lung fibroblasts.133 According to previous studies, members of the miR-29 family inhibits antifibrotic activity through regulation of the ECM and epithelial–mesenchymal transition involved genes.134 Moreover, in the initial stage of fibrosis, inflammatory cytokines inhibit the expression of miR-29 family members in fibroblasts or myofibroblasts, subsequently resulting in decreased miR-29 family members, which enhances the expression of collagens and ECM-related genes that are associated with the development of IPF.134
The expression levels of miR-29 family members are also downregulated in lung cancer and various types of cancer.47, 137, 138 Indeed, miR-29 family members regulate several common pathways involved in carcinogenesis and cancer progression and act as antitumor miRNAs in many types of cancer.130, 139, 140 We demonstrated that miR-29 family members exert antitumor effects by directly targeting lysyl oxidase-like protein 2, which modifies ECM components and promotes cancer progression.141 The miR-29 family is an important regulator of the ECM and epithelial–mesenchymal transition, which are both involved in the pathogenesis of IPF and progression of lung cancer. The relationship between IPF and lung cancer still remains unclear; however, studying common molecular pathways regulated by miR-29 family members may lead to the elucidation of common pathogenic pathways involved in the development of both diseases.
The miR-30 family has five isoforms (miR-30a, miR-30b, miR-30c, miR-30d and miR-30e); miR-30a and miR-30c are located on chromosome 6q13, miR-30b and miR-30d are located on chromosome 8q24.22, and miR-30e is located on chromosome 1p34.2. (Entrez Gene, http://www.ncbi.nlm.nih.gov/gene/, accessed 4 April 2016). These miRNAs are involved in various types of cancer, including breast cancer, glioma, osteoblastic tumor and pancreatic cancer.142, 143, 144, 145 In lung cancer, miR-30b and miR-30c inhibit NSCLC cell proliferation by targeting Rab18, which belongs to the RAS superfamily.146 The expression of miR-30 family was reduced in lung cancer tissues and caused the dysregulation of MMP19 expression.147 Profibrotic mediator WISP1 (WNT1-inducible signaling pathway protein 1) is upregulated in IPF tissues.99, 102 WISP1 is associated with the epithelial–mesenchymal transition in alveolar epithelial type II (ATII) cells and ECM synthesis by fibroblasts.148 Alterations in miR-30a expression reverse TGF-β1-induced expression of WISP1 in lung fibroblasts, including experimental lung fibrosis and primary IPF fibroblasts.149 Activation of WISP1 signaling may result in various pathologies, including fibrosis and cancer.
Conclusions
IPF and lung cancer may share a similar etiology and that there may be a common course contributing to the development of lung cancer and IPF in this context. Various signals and molecules transmit individual signaling pathways, and the general pathway can converge and may promote inflammatory processes in IPF and cancer development. These phenomena may lead to a high incidence of complications in lung cancer and IPF. Consequently, attempts have been made to develop effective treatment strategies for both diseases, including the use of tyrosine kinase receptor inhibitors, such as nintedanib,150 which was initially developed for the treatment of cancer and has recently been approved for the treatment of IPF. In this review, we highlight the miRNA-mediated pathways and molecules that can be associated with both of these diseases. However, there are still several unresolved questions regarding the possible links between lung cancer and IPF. For example, how do diffuse fibrotic lesions confer local development of lung cancer? Furthermore, the mechanistic possibilities discussed here have mostly been generated in the study of cultured cells in vitro. We believe that a better understanding of the detailed mechanisms linking IPF and lung cancer will lead to identification of novel therapeutic targets and new therapies for the prevention of cancer development.
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Mizuno, K., Mataki, H., Seki, N. et al. MicroRNAs in non-small cell lung cancer and idiopathic pulmonary fibrosis. J Hum Genet 62, 57–65 (2017). https://doi.org/10.1038/jhg.2016.98
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DOI: https://doi.org/10.1038/jhg.2016.98
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