Arch Toxicol DOI 10.1007/s00204-015-1462-4


MicroRNAs as regulators of airborne pollution‑induced lung inflammation and carcinogenesis Jun Wei · Feng Li · Jiali Yang · Xiaoming Liu · William C. Cho 

Received: 18 December 2014 / Accepted: 8 January 2015 © Springer-Verlag Berlin Heidelberg 2015

Abstract  The increasing incidence of pulmonary inflammation and lung cancer, as well as exacerbation of preexisting chronic lung diseases by exposure to airborne pollutants, e.g., particulate matter and cigarette smoke, is becoming a major public health concern in the world. However, the exact mechanisms of pulmonary injury from exposure to these airborne insults have not been fully elucidated. Nevertheless, accumulating evidence suggests that microRNAs (miRNAs) may play a unique role in the regulation of airborne agent-induced lung inflammation and carcinogenesis. Since epigenetic modifications are heritable and reversible, this may provide a new insight into the relationship of miRNAs and environmental pollution-related lung disorders. The aim of this review was to update our existing knowledge regarding the mechanisms

Jun Wei and Feng Li have contributed equally in this work. J. Wei · J. Yang · X. Liu (*)  Center of Medical Research, General Hospital, Ningxia Medical University, Yinchuan, Ningxia 750004, People’s Republic of China e-mail: [email protected] J. Wei · F. Li · X. Liu  College of Laboratory Medicine, Ningxia Medical University, Yinchuan, Ningxia 750021, People’s Republic of China X. Liu  Key Laboratory of the Ministry of Education for Conservation and Utilization of Special Biological Resources in Western China, Ningxia University, Yinchuan 750021, People’s Republic of China W. C. Cho (*)  Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong e-mail: [email protected]

by which airborne pollutants altering miRNA profiles in the lung, specifically for cigarette smoke and airborne particulate matter, and the potential biological roles of miRNAs in the initiation of pulmonary inflammation and lung cancer, as well as the regulation of underlying genetic susceptibility to these environmental stressors. Keywords  Air pollution · Epigenetic modification · Lung cancer · Lung inflammation · MicroRNA

Introduction Environmental air is composed of a complex mixture of particulate matter (PM) of varied sizes and compositions, inorganic gases, volatile organic compounds (VOC), and biological agents (Moller et al. 2008). Both epidemiological and clinical studies have demonstrated the exposure to airborne pollutants links with adverse cardiopulmonary disorders, increased hospital admissions, susceptibility to respiratory infections and lung cancer, as well as exacerbation of asthma and chronic obstructive pulmonary diseases (COPD), especially in people with pre-existing medical conditions (Cao et al. 2009; Cui et al. 2014; Guo et al. 2014; Jie et al. 2014; Song et al. 2014; Wang et al. 2010). Both the World Health Organization and the International Agency for Research on Cancer (IARC) have officially classified outdoor air pollution and PM as IARC Group 1 carcinogens to humans, acknowledging the importance and global impact of air pollution in cancer deaths worldwide (IARC 2013). Therefore, understanding the mechanisms of lung injury from airborne pollutants has significant implications for reducing the susceptibility to chronic pulmonary diseases, such as asthma and COPD, lung cancer, and other pulmonary disorders.


Accumulating evidence has suggested that genetic mutations are only found in a small portion of environmentalrelated diseases that may extend well beyond the interaction with DNA sequence (Hamra et al. 2014; Song et al. 2014; Wong et al. 2014). In this regard, the epigenome is amenable to environmental pollutants which are evidenced by the importance of epigenetics as a functional modifier of the genome and a critical determinant of disease risk and etiology, since epigenetic mechanisms are flexible genomic parameters that can alter genome function in response to exogenous stimuli (Feil and Fraga 2011). DNA methylation, histone modification, and microRNAs (miRNAs) are three main epigenetic regulatory mechanisms that can regulate gene expression without altering DNA sequence, among which miRNAs are newly emerged gene expression modifier that links to environmental insults and their related diseases (Izzotti and Pulliero 2014) (Fig. 1) (Lobanenkov et al. 2011). miRNAs are a class of small noncoding RNAs with biological functions that regulate biological processes by repressing the expression of their target genes at the posttranscriptional level. To date, miRNAs have been recognized as novel modifiers that play a unique role in the modification of cellular functions. Similar to other epigenetic mechanisms, miRNAs have been implicated in the regulation of a board range of biological processes including development, cell fate determination, immunity, inflammation, and tumorigenesis (Cho 2007; Cho et al. 2011; Feil and Fraga 2011). Recent studies in both humans and

Fig. 1  A schematic representation of potential mechanisms of environmental insults in disease risks. The environmental pollutants may modify multiple biological processes via a genetic mechanism by targeting susceptible genes, and/or epigenetic mechanisms by alterations of DNA methylation, histone codes, and microRNA expression. These alterations may in turn change the expression of target genes and sequentially affect disease risk


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animals have demonstrated that the exposure to airborne pollutants, including cigarette smoke (CS), environmental chemicals, and PMs can lead to the alterations of miRNA expression profiles in lung tissues and cells (Bollati et al. 2010; Izzotti et al. 2009a; Jardim 2011; Jardim et al. 2009; Schembri et al. 2009). More importantly, such altered miRNA profiles have recently been linked to the exposure to airborne pollutants in emerging human epidemiological diseases, including pulmonary inflammation and lung cancer (Bollati et al. 2010, 2014). Of note, a study on miRNA profiling analysis of the brain and liver of mice exposed to hexahydro-1,3,5-trinitro-1,2,3-triazine further demonstrated an environmental pollutant-induced tissue type-specific alteration of miRNAs (Zhang and Pan 2009). In this review, we overview the alteration of miRNA profiles in the lung exposed to several airborne pollutants and discuss the potential role of miRNAs in pulmonary inflammation and lung cancer in response to these environmental insults. The correlation of miRNAs to environmental pollutants and their role as potential biomarkers for environmental diseases are also discussed.

Alterations of miRNA profile in the lung exposed to CS Recently, miRNA profiling studies in both the CS models and ambient air pollutant exposure have shown alterations of miRNA expression in the lung (Izzotti et al. 2009a, b, 2010b; Jardim et al. 2009; Schembri et al. 2009) or peripheral blood leukocytes (Bollati et al. 2010). Of interest, CS exposure has been used as models in the studies of air pollution, not only because of its detrimental health effects that cause over five million people die annually (Wong et al. 2010), but also due to an overlap in the chemical composition between samples from CS and ambient air, particularly in air samples from heavily polluted areas (See et al. 2007). The effects of exposure to CS on miRNA profiles in the respiratory tract had previously been investigated in the lungs of mouse and rats exposed to CS (Izzotti et al. 2009a, b), as well as in the bronchial epithelium of smokers (Schembri et al. 2009). In these studies, Izzotti et al. first reported that 484 miRNAs were altered in the lung of rats exposed to CS (Izzotti et al. 2009a), and the dysregulation of miRNA expression was gender- and age-dependent in the lung of mice (Izzotti et al. 2009b). Of great interest, the majority of the altered miRNAs (126 out of 484) were down-regulated, only seven miRNAs were up-regulated in the rat lungs exposed to CS (Izzotti et al. 2009a). Among them, the most significantly down-regulated miRNAs were those involved in the regulation of genes related to stress responses, apoptosis, proliferation, and angiogenesis, such as let-7, miR-34, miR-99, miR-122, miR-124, miR125, miR-140, miR-146, miR-219, and miR-222 (Table 1)

Human serum Mouse lung



NA Not defined yet

Non-human primate nasal epithelial cells

Human lung tumor tissues

Ozone (O3)


Human sputum samples

Metal-rich PM

Human bronchial epithelial cells

Mouse lung fibroblasts Human airway epithelium and lung cancer cells

Murine lung A549 alveolar epithelial cells Human blood

Diesel exhaust/PM

Primary human bronchial epithelial cells

Cigarette smoke

Rat and mouse lung

Species tissue/cell type


miR-145, miR-142-3p, miR-203, miR-125b, miR-152

miR-494, miR-513, miR-923 miR-96, miR-26b, miR-27a, miR-31, miR-135b, miR-374a miR-375 miR-200c miR-135b miR-128, miR-302c let-7 g miR-29a miR-146a miR-421 miR-21 miR-222 miR-132, miR-143, miR-145, miR-199a*, miR-199b-5p, miR-222, miR-223, miR-25, miR-424, miR-582-5p miR-148b, miR-374a, miR-24, let-7d, let-7e, miR-199b-5p, miR-331-3p, miR-96 miR-939, miR-671-5p, miR-605, miR-1224-5p, miR-202 miR-133b, miR-206 miR-125a, miR466 miR-125b Genes in apoptosis signaling pathway


Down Up


Multiple targets

Down Up Up

Multiple targets

Up Down Up Up Up Up Up Up Up Up Up


Aryl hydrocarbon receptor (AhR) NF-κB ND ND HMGA2 PETN Multiple targets SMAD4 ND ND Multiple targets

Up Down

MAFG (miR-218) ND NF-κB pathway. Erg, Bcl-2

Potential target protein or pathway

RelB Dickkopf-1 (Dkk-1) and DACT-3 SUZ12, BMI1, WNT5A, MYC, and KRAS Inflammatory signaling Undefined inflammatory signaling

Up Down

miR-181d let-7c, let-7f, miR-34b, miR-34c, miR-222 miR-146a miR-31 miR-487b Up Up Down



miR-128b, miR-218, miR-500

Altered microRNAs

Table 1  Airborne pollutants induced alterations of microRNAs

Rager et al. (2013)

Izzotti et al. (2009a); Wang et al. (2014)

Wu et al. (2013) Wang et al. (2014)

Nymark et al. (2011)

Nymark et al. (2011)

Bleck et al. (2013) Zhao et al. (2013) Bourdon et al. (2012) Bollati et al. (2014) Motta et al. (2013) Motta et al. (2013) Motta et al. (2013) Motta et al. (2013) Bollati et al. (2010) Bollati et al. (2010) Fry et al. (2014)

Jardim et al. (2009) Jardim et al. (2009)

Schembri et al. (2009) Izzotti et al. (2005, 2009a, b); Liu et al. (2010) Zago et al. (2014) Xi et al. (2010) Xi et al. (2013)

Schembri et al. (2009)


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(Izzotti et al. 2009a). Similar to the findings in the rat lungs, all the identified smoke-related miRNAs were also downregulated in the lung of mice exposed to CS; no miRNA was up-regulated (Izzotti et al. 2009b). Such down-regulation of miRNAs in airway epithelium of smokers was also observed by Schembri et al. (2009) in which the authors identified 28 miRNAs that were differentially expressed in bronchial airway epithelium by comparing miRNA profiles in 10 smokers and 10 never smokers using a battery of 467 miRNAs analyzed microarray, and 23 out of 28 miRNAs were down-regulated (the most down-regulated miRNA was miR-218), only 5 miRNAs were up-regulated (Table 1). Importantly, the downregulated miRNAs were overlapped between the species, particularly in mice and rats; 13 down-regulated miRNAs in mouse lung were also found in rat lung (such as miR30, miR-99, and miR-125); miR-146 and miR-223 were down-regulated in the lung of both rats and humans (Izzotti et al. 2009a; Schembri et al. 2009). The prevailing trend of global down-regulation of miRNAs in lungs upon CS exposure was in line with another study by the same group that a mainly up-regulated mRNA and protein expression were found in CS-exposed lungs (Izzotti et al. 2005).

The alteration of miRNA profiles in the lung exposed to PMs Environmental PM is a mixture of chemicals and particles, among which particulates with an aerodynamic diameter of

MicroRNAs as regulators of airborne pollution-induced lung inflammation and carcinogenesis.

The increasing incidence of pulmonary inflammation and lung cancer, as well as exacerbation of pre-existing chronic lung diseases by exposure to airbo...
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