www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No.

46), pp: 81679-81685

Review

MicroRNAs in lung cancer

Diana Castro1, Márcia Moreira1, Alexandra Monteiro Gouveia1,2,3, Daniel Humberto
Pozza1,3 and Ramon Andrade De Mello4,5,6
1
Department of Experimental Biology, Faculty of Medicine, University of Porto, Porto, Portugal
2
Institute for Cellular and Molecular Biology (IBMC), Institute for Health Innovation, University of Porto, Porto, Portugal
3
Faculty of Nutrition and Food Sciences, University of Porto, Porto, Portugal
4
Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal
5
Department of Medicine, Faculty of Medicine, University of Porto, Porto, Portugal
6
Cearense School of Oncology, Ceará Cancer Institute, Fortaleza, Brazil
Correspondence to: Ramon Andrade De Mello, email: ramondemello@doctors.org.uk
Keywords: microRNAs, lung cancer, inflammation, epithelial mesenchymal transition, interleukin 1
Received: April 12, 2017     Accepted: August 26, 2017     Published: September 16, 2017
Copyright: Castro et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY
3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

Lung cancer (LC) is a serious public health problem responsible for the majority
of cancer deaths and comorbidities in developed countries. Tobacco smoking is
considered the main risk factor for LC; however, only a few smokers will be affected
by this cancer. Current screening methods are focused on identifying the early stages
of this malignancy. Thus, new data concerning the roles of microRNA alterations in
inflammation, epithelial-mesenchymal transition and lung disease have increased
hope about LC pathogenesis, diagnosis, treatment and prognosis. MicroRNA
mechanisms include angiogenesis promotion, cell cycle regulation by modulating
cellular proliferation and apoptosis, and migration and invasion inhibition. In this
context, this manuscript reviews the current information about many important
microRNAs as they relate to the initiation and progression of LC.

INTRODUCTION These mechanisms include regulation of genes that

mediate processes such as inflammation, the cell cycle,
Lung cancer (LC) is the most common cause of stress responses, differentiation, apoptosis and invasion.
cancer death, with a high incidence and mortality in both In this context, research regarding the involvement
genders. Despite progress in research regarding new of microRNAs in LC tumorigenesis is increasing as
targets, therapeutics, and strategies for LC screening and the search for new biomarkers and therapeutic targets
early diagnosis, prognosis is still poor, and overall survival continues [1, 2]. Thus, the main objective of this brief
rates remain low [1, 2]. LC can be divided in two types: review is to summarize the current information about the
small cell lung cancer (SCLC) with a neuroendocrine role of microRNAs in inflammation associated with the
origin and non-small cell lung cancer (NSCLC). NSCLC initiation and progression of LC.
accounts for approximately 80% of all LC and includes
both squamous cell cancer and adenocarcinoma [2]. MicroRNAs
The main risk factor for LC is tobacco use; however,
only a small percentage of smokers will develop LC MicroRNAs are small, noncoding RNA molecules,
(approximately 10% of all smokers), suggesting that 20-25 nucleotides in length, that negatively regulate
other factors are also involved, such as individual genetic gene expression at the post-transcriptional level. These
variations [3]. molecules are encoded by specific genes and function
Recent data demonstrated the importance of in repressing mRNA translation or promoting mRNA
regulatory mechanisms at the transcriptional level, such as degradation. MicroRNAs play an important role in many
gene regulation by small non-coding RNAs (microRNAs). biological processes, such as inflammation, cell growth,

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 apoptosis, development, differentiation, endocrine ultimately assuming a mesenchymal cell phenotype. These
homeostasis and even cancer [4]. changes increase cell migratory capacity, invasiveness,
It is known that microRNAs are involved in lung resistance to apoptosis and production of extracellular
inflammatory mechanisms, epithelial-mesenchymal matrix components. Thus, EMT is crucial for epithelial
transition, and, consequently, in LC development and cancer invasion and metastasis [25]. A strong correlation
therapy response. The potential applications of microRNAs between EMT and the migratory and invasive capacity of
in cancer diagnostics and prognostics, and as therapeutic tumor cells has been demonstrated. These mesenchymal-
targets have led to an increased interest in this research area like cancer cells and TGF-β-induced EMT cells are
[5]. The effects of microRNAs on cytokine signaling are characterized by increased invasive abilities compared to
based on transcription factors, cytokines and modulators of epithelial-like cancer cells. Thus, EMT is a key factor in
cytokine signaling. In addition, cytokine signaling is crucial the facilitation of tumor migration and invasion [26].
in the differentiation of many immune cells. Thus, the role Several microRNAs have been described as
of microRNAs in immune cell differentiation is based on the important regulators of EMT, and their dynamic roles
regulation of cytokine expression and the regulation of their in the balance between EMT and the reverse process,
downstream signaling components. Several studies have termed mesenchymal to epithelial transition (MET), are
shown that microRNAs, including miR-21, have an important recognized. One of these microRNAs is miR-153, which
role in balancing Th1 and Th2 responses to antigens is downregulated in the TGF-β-induced mesenchymal
[6, 7]. At present, the most studied microRNAs are miR-494, phenotype of epithelial cancer cells [25].
let-7, miR-155, miR-135b, miR-21, miR-125b, miR-196 and Additionally, ectopic expression or targeted
miR-210 [5]. ‘knockdown’ of miR-153 resulted in downregulation
miR-494 can be produced by lung cancer cells or increased expression of SNAI1 (Snail Family Zinc
leading to tumor angiogenesis. In a hypoxic environment, Finger 1) and ZEB2 (Zinc Finger E-Box Binding
this angiogenic process promotes tumor development Homeobox 2) protein levels, respectively. These two
through HIF-1α-induced upregulation of miR-494 [8]. transcription factors promote the repression of the
On the other hand, miR-494 downregulates cellular adhesion molecule E-cadherin to regulate EMT during
proliferation in LC. It was demonstrated that constitutive embryonic development. In fact, SNAI1 and ZEB2 are
expression of miR-494 in A549 lung cancer cells leads considered critical pro-metastatic factors for their EMT-
to the suppression of cell proliferation and induction of inducing capabilities [26, 27]. These studies also defined
senescence. It was also demonstrated that insulin-like SNAI1 and ZEB2, both of which serve as transcriptional
growth factor 2 mRNA-binding protein 1 (IGF2BP1) repressors of E-cadherin through binding with E-box
could be a target of miR-494. It was demonstrated that elements in the E-cadherin promoter, as direct targets of
IGFBP1 has a role in carcinogenesis development and miR-153. Therefore, E-cadherin is a key factor in EMT
regulation by binding to mRNAs coding IGF2 (Insulin- since its expression is decreased in the cells that undergo
like growth factor 2) and c-Myc [9]. In the A549 lung EMT in the presence of miR-153 inhibitors. Thus, the
cancer cell line, miR-155 modulates cellular apoptosis and downregulation of miR-153 is crucial for the acquisition
DNA damage through an Apaf-1-mediated pathway [10]. or maintenance of mesenchymal cell morphology and
miR-153 inhibits the migration and invasion of human contributes to the EMT-associated carcinoma cell invasion
NSCLC by targeting ADAM19 and producing anti-tumor induced by TGF-β [26].
activity in LC through AKT suppression (Table 1) [11, 12]. Regarding the miRNAs that are related to
Another microRNA involved in cell proliferation the promotion of EMT and development of LC, the
and survival pathways, which is frequently altered in downregulated miR-200 family controls transcriptional
tumors, is Let-7. This microRNA is overexpressed during factors such as Zinc Finger E-Box-Binding Homeobox
cell cycle progression and functions as a key regulator (ZEB), E-cadherin and vimentin [20]. miR-218 also has an
of several genes involved in cell proliferation. It is also important role in the regulation of EMT-related traits and
known that reduced expression of the Let-7 family the metastasis of LC, in part by modulating Slug/ZEB2
molecules in LC is associated with a poor survival rate. signals [23] (Table 1). Increasing evidence has shown
Furthermore, Let-7 directly regulates several proto- other miRNAs, including miR-124, miR-135a, miR-148a
oncogenes involved in cell cycle regulation, such as RAS, and miR-193a-3p/5p, to be powerful suppressors of EMT
CDC25A, CDK6 and cyclin D [13]. Thus, Let-7 controls that are often downregulated in LC (for review see [28]).
cell proliferation by impairing the G1 to S transition [4].
Cytokines and inflammatory cells, inflammation
MicroRNAs and epithelial-mesenchymal and lung cancer
transition (EMT)
Chronic inflammation, a key promoting factor of
EMT is a complex process that allows a polarized lung tumorigenesis, is associated with the secretion of
epithelial cell to go through several biochemical changes, cytokines, including tumor necrosis factor α (TNF-α),

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 Table 1: Key microRNAs in lung cancer
miRNAs Gene targets Biological mechanisms References
miR-494 IGF2BP1 Promotes angiogenesis and decreases cellular [8, 9]
proliferation
Let-7 RAS, CDC25A, CDK6, cyclin D, LIN28, Represses cell proliferation and regulates the [4, 13]
MYC, HMGA2, HOXA9, TGFBR1, cell cycle
BCL-XL, MAP4K3
miR-155 hexokinase 2, APAf-1 Promotes glucose metabolism, modulates [10, 14]
cellular apoptosis and DNA damage response
miR-153 ADAM19, AKT Inhibits the migration and invasion of human [11, 12]
non-small cell lung cancer, inhibits proliferation
and migration, and promotes the apoptosis of
cultured lung cancer cells
miR-101 COX-2, Lin28B, EZH2 Inhibits cell proliferation, inflammation, and [15–18]
dysregulation of the cell cycle
miR-135b IL-1R1 Mediates the inflammatory response [19]
miR-200 ZEB, E-cadherin, vimentin Promotes EMT [20, 21]
miR-218 Slug/ZEB2, tumor protein D52 Inhibits cell migration, invasion and EMT [22, 23]
miR-487b SUZ12, BMI1, WNT5A, MYC, KRAS Represses the proliferation and invasion of LC [24]
cells

interleukin (IL) 1, IL-6, IL-8, and molecules such of COX-2 in the initiation and progression of NSCLC is
as cyclooxygenase-2 (COX-2), that are defined as already recognized. It was demonstrated that knockdown
“alarm cytokines” due to their roles in the initiation of of COX-2 significantly increased miR-101 expression,
inflammation. These cytokines are produced by normal showing that COX-2 negatively controls miR-101
cells, tumor cells and cellular components of the tumor expression in NSCLC cells. Previous studies also showed
microenvironment [5, 29]. TNF-α serves as an important that IL-1β activates HIF1α through the NF-κB/COX-2
factor in the initiation and regulation of the cytokine pathway. HIF1α is a transcriptional repressor for miR-101
signaling cascade by triggering the release of IL-1β and via IL-1β interactions in NSCLC. It was demonstrated
IL-6 [29]. IL-1β is a pro-inflammatory cytokine that that IL-1β promotes the activation of NF-κB, which
belongs to the interleukin-1 family, which is composed of transcriptionally activates Lin28B. This protein coding
several members, including IL-1α and IL-1R antagonist gene represents a key link the inflammation associated
(IL-1Ra), an inhibitor of preformed IL-1β. It was with cancer cell transformation and is a novel target of
demonstrated that a variable number of the IL-1Ra gene is miR-101. Thus, Lin28B is upregulated by repression of
not an independent risk factor for NSCLC, but it can play miR-101 (IL-1β). It was concluded that downregulation
a role in prognosis when combined with polymorphisms of of miR-101 by IL-1β is a key mechanism in the promotion
the IL-1β gene [3]. IL-6 and IL-8 play different roles at the of carcinogenesis and the development of malignant
systemic level, and both are inducible by IL-1β [30]. IL-6 processes [5, 18].
stimulates secretion of C-reactive protein, an important miR-101 is also related to IL-1β via Enhancer of
inflammatory biomarker (Figure 1). Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2),
IL-1β is also directly involved in the regulation of a member of the polycomb-group family that form
plasma levels of C-reactive protein by gene regulation multimeric protein complexes, including the complex
and indirectly involved through the production of several involved in the methylation of histone H3. Several
pro-inflammatory molecules, including COX-2, inducible studies demonstrated the upregulation of EZH2 in LC,
nitric oxide synthase, and IL-6, among other cytokines. and it is postulated that this upregulation promotes tumor
High levels of IL-1β in the tumor microenvironment are development and progression by dysregulation of the cell
directly associated with a poor prognosis mainly because cycle [15]. The first study that proposed the role of the
IL-1β promotes tumor invasiveness by angiogenesis IL-1β/miR-101/EZH2 axis in LC found that autocrine
induction and the activation of myeloid-derived suppressor and paracrine IL-1β stimulated the downregulation
cells and M2 macrophages [29, 31]. of miR-101 in a Xuanwei LC cell line (XWLC-05),
IL-1β inhibits miR-101, a tumor-suppressive leading to EZH2 upregulation, which in turn triggered
microRNA, via the COX-2-HIF1α pathway [17]. The role tumorigenesis [16].

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 miR-135b expression is regulated by IL-1R1, an important marker for therapeutic intervention. For
a direct target of miR-135b, during IL-1R1/IL-1α- example, in a specific smoking status group, miR-
mediated inflammation. By using IL-1R1 knockout 195, miR-138 and miR-150 demonstrated aberrant and
mice, it was demonstrated that miR-135b expression is recurrent expression, and were significantly associated
IL-1R1 dependent. Furthermore, in vitro activation of the with the survival rate of this group [32].
IL-1R1 pathway in mouse embryonic fibroblasts and lung Experimental data provided evidence that exposure
epithelial cells resulted in increased miR-135b levels. to various environmental or lifestyle factors, such as
Thus, there is a negative feedback loop in which IL-1R1 environmental cigarette smoke, result in extensive
and miR-135b self-regulate one another. In addition, to alterations to miRNA expression in the lung. The
decrease the inflammation induced by cigarette smoke, expression of 484 miRNAs was analyzed in rat lungs
miR-135b regulates IL-1R1 expression by targeting its after exposure to environmental cigarette smoke for
downstream mediators, Caspase-1 and IL-1β [19]. 28 days, which led to the downregulation of 126 of
these miRNAs [33]. Most miRNAs are downregulated
Cigarette smoke: alterations on microRNAs in tumors when compared to normal tissues because of
the association between microRNA levels and cellular
The identification of differentially expressed differentiation. Thus, the reduction of microRNA
microRNAs between the non-malignant tissues of current expression in cancer cells is associated with their degree
smokers and the non-malignant tissues of individuals of cellular differentiation, and consequently, the reduction
who had never smoked suggests that smoking history is greater in differentiated tumors [34]. The most notably
plays an important role in microRNA expression. It was downregulated microRNAs belong to the families of let-
hypothesized that the altered expression of microRNAs 7, miR-10, miR-26, miR-30, miR-34, miR-99, miR-122,
in the non-malignant tissues of current smokers affects miR-123, miR-124, miR-125, miR-140, miR-146, miR-
distinct cellular pathways and may be an early event in 191, mi-192, miR-219, miR-222 and miR-223. These
smoking-associated tumorigenesis [32]. Finding the microRNAs are responsible for a variety of cell functions,
same pattern of differentially expressed microRNAs may including apoptosis, proliferation, angiogenesis, gene
differentially influence LC prognosis and may represent expression and stress response.

Figure 1: Chronic inflammation, a key promoting factor of lung tumorigenesis, is associated to secretion of cytokines
including tumour necrosis factor α (TNF-α), interleukin 1 (IL-1), IL-6 and IL-8, and molecules such as cyclooxygenase-2
(COX-2) that are defined as “alarm cytokines”. TNF-α is determinant to initiate and regulate the cytokine cascade by triggering
the release of IL-1β and IL-6. IL-6 and IL-8 play different roles at a systemic level, being both inducible by IL-1β. IL-6 stimulates
secretion of C-reactive protein that is an important inflammatory biomarker. High levels of IL-1β in the tumour microenvironment is
directly associated with bad prognosis, mainly because IL-1β promotes tumour invasiveness by angiogenesis induction, activation of
myeloid-derived suppressor cells and macrophages type M2.

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 It was demonstrated that increasing or decreasing clinical outcomes. Consequently, there is an urgent need
the expression of miR-218, one of the microRNAs in to identify minimally invasive biomarkers to facilitate
human airway epithelium most commonly affected by early diagnosis. Interestingly, microRNAs can be found
smoking, was sufficient to induce a respective change in in the nucleus of the cells and in blood. The discovery of
the expression of predicted miR-218 mRNA targets in microRNAs, namely, circulating miRNAs, sheds new light
both primary bronchial epithelial cells and H1299 cells. on tumor diagnosis and prognosis [36, 37].
On the other hand, the alteration of miR-218 expression Plasma samples from 100 early stage NSCLC
may influence the expression of MAFG gene targets patients and 100 non-cancer controls were screened for
since binding sites for MAFG are overrepresented in the 754 circulating microRNAs via qRT-PCR using TaqMan
epithelial cells of smokers [34]. miR-294, an inhibitor of microRNA arrays. The results revealed that a group of 24
transcriptional repressors, is also affected; it is upregulated miRNAs were significantly and independently associated
in an environment with cigarette smoke [33]. with LC development and with predicting and establishing
When human airway epithelial cells are exposed to risk factors [38]. However, it was shown that a group of
cigarette smoke condensate, epigenetic repression of miR- six microRNAs (miR-30c, miR-616, miR-146b-3p, mi-
487b expression occurs. This downregulation, together 566, miR-550 and miR-939) were substantially increased,
with increased expression of miR-487b oncogenic targets and another two miRNAs (miR-339-5p and miR-656)
(SUZ12, BMI1, WNT5A, MYC and KRAS), leads to were substantially diminished in the serum of LC patients.
increased proliferation and invasion in LC cells. Thus, The increased miRNAs are particularly relevant in the
the repression of miR-487b increases tumorigenesis, earlier stages of disease, suggesting their importance for
proliferation and invasion, and the expression of this early diagnosis [37].
microRNA inhibits the growth and metastatic potential Plasma miR-195 could be used as a biomarker for
of LC [24]. Furthermore, tobacco smoke carcinogens the early detection and as an independent unfavorable
can also generate epigenetic silencing, for example, prognostic factor for NSCLC since it is downregulated in
the downregulation of miR-200 and miR-205 through patients with this pathology when compared with healthy
epigenetic mechanisms, to induce EMT; in these cases, controls [39]. It was also observed that 10 miRNAs had a
EMT was strongly associated with LC [21]. significantly different expression level in serum of cases
Recently, it has been thought that the downregulation with NSCLC when 400 NSCLC cases and 220 controls
of microRNAs induced by cigarette smoke could be were analyzed. Thus, the combination of multiple serum
reversed by the oral administration of chemopreventive miRNAs allows a more accurate cancer diagnosis [36].
agents (e.g. N-acetylcysteine, oltipraz, indole-3-carbinol, It was reported that increased plasma levels of miR-
5,6-benzoflavone and phenethyl isothiocyanate) [33]. let-7b can be an indicator of survival. Therefore, decreases
According to the authors, these agents could modulate in the plasma expression of let-7b were associated with
proliferation, apoptosis, differentiation, angiogenesis or worse prognosis and poorer survival. The reduction in
p53 functions. Furthermore, some human polymorphic serum miR-223 expression was also associated with poor
microRNAs that are downregulated by cigarette smoke survival outcomes in TNM stage I patients. These findings
can be protected by these chemopreventive agents. showed that LC patients with epigenetic alterations were
For example, phenethyl isothiocyanate can affect the predisposed to more aggressive disease [40]. Considering
downregulation of some of the miRNAs that participate in that Let-7 can clinically increase the postoperative survival
a variety of functions, including the stress response (miR- of patients with LC by suppressing tumor proliferation and
125b), NF-kB activation (miR-146-prec), TGF-β expression survival through the mediation of oncogenes and other cell
(miR-26a), Ras activation (let-7a, let-7c and miR-192), functions, it has been one of the main potential therapeutic
cell apoptosis (miR-99b), cell proliferation (let-7a, targets studied in cancer therapy. Inflammation is one of the
let-7c and miR-222-prec) and angiogenesis (let-7a, let-7c, mechanism clinically affected by Let-7 expression in cancer.
miR-123-prec and miR-222-prec). The efficacy of these Molecules related to inflammation, such as NFκB, have are
agents may be influenced by genetic polymorphisms in involved in the regulatory feedback loop controlling Let-7
these miRNAs. The optimal chemopreventive agents expression in inflammation and cancer. Positive feedback
should not modify the baseline expression of genes and occurs when NFκB reduces let-7 levels, inhibiting IL-6
should be able to counteract the molecular alterations expression and consequently activating NFκB [13].
induced by carcinogens, re-establishing a normal Additionally, microRNAs can also be used to
physiologic situation [35]. predict the risk of radiation-induced esophageal toxicity
in patients receiving radiochemotherapy for NSCLC. High
MicroRNAs: a brief reference to diagnosis and serum miR-155 and miR-221 levels during the first two
prognosis weeks of radiochemotherapy were associated with the
development of severe radiation esophagitis. Thus, these
Early diagnosis and the adequate treatment of miRNAs may be useful as important predictors for this
each patient with LC are essential in order to improve form of toxicity [41].

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 CONCLUSIONS Baumgaertner P, Devevre E, Ramesh A, Braun M, Speiser
D, et al. Differentiation associated regulation of microRNA
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LC screening. The new data about the roles of microRNA   7. O'Connell RM, Rao DS, Baltimore D. microRNA regulation
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for the pathogenesis, diagnosis, treatment and prognosis 30:295–312.
of this cancer. Although tobacco smoking is the main risk   8. Mao G, Liu Y, Fang X, Liu Y, Fang L, Lin L, Liu X, Wang
factor, there are some cases of LC in non-smokers, and only N. Tumor-derived microRNA-494 promotes angiogenesis in
a small percentage of smokers will develop LC. Thus, there non-small cell lung cancer. Angiogenesis. 2015; 18:373–82.
is likely an association of both environmental and genetic  9. Ohdaira H, Sekiguchi M, Miyata K, Yoshida K.
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lung inflammation and epithelial-mesenchymal transition. senescence in A549 lung cancer cells. Cell Prolif. 2012;
The levels of serum microRNAs could be employed as 45:32–8.
cancer markers and used in the diagnosis of early stages of 10. Zang YS, Zhong YF, Fang Z, Li B, An J. MiR-155 inhibits
the disease; they could also be used to predict prognosis, the sensitivity of lung cancer cells to cisplatin via negative
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12. Yuan Y, Du W, Wang Y, Xu C, Wang J, Zhang Y, Wang H,
Ju J, Zhao L, Wang Z, Lu Y, Cai B, Pan Z. Suppression of
CONFLICTS OF INTEREST AKT expression by miR-153 produced anti-tumor activity
in lung cancer. Int J Cancer. 2015; 136:1333–40.
R.A. De Mello is on the advisory board for Pfizer 13. Wang X, Cao L, Wang Y, Wang X, Liu N, You Y. Regulation
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The authors declare that they have no conflicts of 2012; 3:955–60.
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14. Lv X, Yao L, Zhang J, Han P, Li C. Inhibition of
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