Researchers have identified lung cancer as one of the most significant causes of cancer-associated mortality, and non-small cell lung cancer (NSCLC) has been reported to account for 80% lung cancer (28). NSCLC has a low 5-year survival rate (29). Previous epidemiological studies have indicated that ambient PM2.5 is carcinogenic (30), and may increase the morbidity and mortality rates associated with lung cancer (31,32), and PM2.5 has been suggested to decrease the survival time of patients with lung cancer (33). A short-term decrease in PM2.5 exposure has been demonstrated to decrease the population risk of lung cancer (34).

miRs are a class of small non-coding single-stranded RNA molecules which participate in the regulation of post-transcriptional gene expression and RNA silencing (35). It has been established that miRs regulate 50% of protein-coding genes and cell metabolic processes (36). However, the pathogenesis of PM2.5 induction of lung cancer remains to be elucidated. A previous study indicated that exposing human bronchial epithelial (HBE) cells to ambient PM2.5 resulted in downregulation of miR-182 and miR-185 expression compared with non-exposed cells (37). The expression of three target oncogenes, solute carrier family 30 member 1, serpin family B member 2 and aldo-keto reductase family 1 member C1, which are markedly expressed in human lung adenocarcinoma cells and squamous carcinoma cells, may cause neoplastic transformation in NIH3T3 cells (37). However, whether this is translatable to humans remains unknown. Another study investigated the association between PM2.5 exposure and the miR-802/Rho family GTPase 3 (Rnd3) pathway in lung cancer in vivo and in vitro. PM2.5 was demonstrated to enhance the growth and metastasis of lung cancer (38). These results warrant further investigation of PM2.5-induced miR changes in lung cancer.

In one study, following exposure of HBE cells to 200 and 500 µg/ml PM2.5, 970 and 492 gene alterations were detected, respectively (39). Furthermore, an in vivo study demonstrated that, in PM2.5-treated mice, 57 genes were demonstrated to be mutated, including 14 upregulated genes and 43 downregulated genes (40). It has been suggested that these mutations occur in response to an exogenous stimulus, metabolic processing and an inflammatory immune pathway, possibly involving the MAPK signaling pathway (41). These studies provide a preliminary basis to direct further investigation of the function of miRs in oncogene activation in lung cancer following PM2.5 exposure. Furthermore, the interaction between PM2.5-induced long non-coding RNA (lncRNA) alteration and lung cancer has been studied, indicating that PM2.5 is able to induce lncRNA loc146880 via reactive oxygen species (ROS), promoting autophagy and malignancy of lung cancer cells (42).

p53 is an important regulatory gene in cell proliferation, apoptosis and damage repair (43). Mutation of p53 contributes to the pathogenesis of lung cancer (44,45). A previous study sought to identify PM2.5-induced p53 mutations using human alveolar epithelial BEAS-2B cells constantly exposed to low-dose PM2.5 for 10 days. It was demonstrated that PM2.5 was able to trigger p53 promoter methylation by increasing DNA (cytosine-5-)-methyltransferase 3β (DNMT3B) methylation levels, resulting in p53 inactivation. The same study indicated that the ROS/protein kinase B (Akt) signaling pathway was involved in the process of DNMT3B methylation (46). Notably, these cells were exposed long term to ‘safe’ concentrations of PM2.5 (120 µg/m³). Furthermore, a previous study established that the expression of DNMT was different when cells were acutely exposed to high-dose PM2.5 (data not shown) (46). To the best of our knowledge, inactivation of other PM2.5-induced tumor suppressor genes via DNA methylation has not been demonstrated. However, a recent analysis of the methylome and transcriptome of PM2.5-induced (100 µg/ml) BEAS-2B cells identified 66 differentially expressed genes, which were either hyper- or hypo-methylated, involved in lung diseases, particularly lung cancer (47). A number of the genes were identified to be involved in tumor suppression, including deleted in malignant brain tumors 1, ERBB receptor feedback inhibitor 1 and gap junction protein β2. Another study observed gene methylation in healthy mice exposed to traffic-associated air pollution, including upregulation of p16 and adenomatous polyposis coli methylation, and downregulation of long interspersed nuclear element-1 and nitric oxide synthase 2 methylation (48). It has been demonstrated that following exposure to PM2.5, DNA methylation of tandem repeats increases (49). A tandem repeat (NBL2) methylation has been identified to be associated with PM2.5 silicon in truck drivers, and another tandem repeat (SATα) methylation has been associated with sulfur exposure in office workers (50), which may lead to an increase in the risk of lung cancer. These studies provide a basis for further investigation of the association between PM2.5-induced tumor suppressor gene methylation and lung cancer.

The tumor microenvironment is of importance to tumor behavior, particularly in lung cancer (51). The production of cytokines, inflammatory cells and angiogenesis has been identified to be associated with tumor metastasis and tumor cell proliferation (52). Numerous inflammatory cytokines and transcription factors function in the lung cancer tumor microenvironment, including interleukin (IL)-1β and −6, tumor necrosis factor α (TNF-α), NF-κB and STAT-3 (53). PM2.5 exposure is able to increase the mobility and proliferation of A549 and H1299 cells, and IL-1β and MMP-1 may be responsible for the effects of PM2.5 (54). It has also been suggested that alveolar macrophage polarization may serve a function in angiogenesis and tumor growth via secretion of IL-8 and VEGF (55). Previous studies have demonstrated that PM2.5 is able to induce HBE cells and macrophages to release various pro-inflammatory cytokines, including IL-6, TNF-α and granulocyte-macrophage colony stimulating factor (GM-CSF), resulting in airway inflammation (41,56,57). Therefore, by triggering angiogenesis and inflammatory reactions, PM2.5-induced tumor microenvironment alteration may promote tumor growth and metastasis.

Autophagy refers to the encapsulation of damaged proteins or organelles of eukaryotic cells by autophagic vesicles, followed by lysosomal degradation and recycling (58). Autophagy serves an important function in emergent cell processes, including starvation and infection (59). As a self-destructive activity, apoptosis serves an essential function in tissue homeostasis, embryonic development and organogenesis (60). Crosstalk between autophagic and apoptotic pathways have been characterized in cell fate decision making (61,62). Caspases, a group of cysteine proteases, are best known as apoptosis modulators, and function in the crosstalk between autophagy and apoptosis (63). Crucial autophagy proteins, including Beclin-1 and autophagy-related 5 may be degraded by activated caspases to attenuate the autophagic response (64,65). Furthermore, autophagy is able to regulate apoptosis by altering the level and activity of caspase proteins (66). PM2.5 exposure may induce macrophage autophagy and mediate the Src/STAT-3 signaling pathway to increase the expression of VEGF-A, an important pro-angiogenic factor (67). It has also been suggested that the phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin kinase signaling pathway may serve an important function in the autophagy of BEAS-2B cells exposed to PM2.5 (68). PM2.5 is able to induce autophagy of A549 cells by activating the AMPK signaling pathway (69). Autophagy serves as a protective mechanism, thus preventing further damage by PM2.5 (70).

PM2.5 induces inflammatory cell infiltration and alveolar cell autophagy, and also alters the cell cycle of alveolar epithelial cells and induces cell apoptosis. A number of studies have demonstrated that PM2.5 is able to induce mitotic arrest by breaking DNA double strands and activating the p53/retinoblastoma signaling pathway (71–73). PM2.5 has also been demonstrated to activate the TNF-α signaling pathway and manipulate the transcription of p53, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein, resulting in apoptosis of alveolar epithelial cells (74,75).

The most common chronic airway inflammatory diseases are asthma and COPD (76). Asthma is characterized by chronic pulmonary inflammation and airway hyper-responsiveness (77). It has been demonstrated that asthma is associated with numerous environmental and genetic factors (78). Epidemiological evidence suggests that air pollution, including ambient PM2.5, may increase the morbidity and hospitalization rate of patients with asthma (79–81). Furthermore, air pollution has become an independent risk factor of asthma (82). Increased PM10 exposure has been identified to be associated with poor control of asthma and poor health-associated quality of life (83). The airway inflammation and immune response in the pathogenesis of asthma have been identified to be associated with the chemical composition and size distribution of PM2.5 (84). It has been identified that with increased levels of the heavy metal lead in PM2.5 in e-waste recycling areas, the level of lead in pediatric blood samples also increased (85). This is a cause for concern since asthma may be induced when blood lead content >5 µg/dl (85).

COPD is a type of obstructive lung disease characterized by long-term poor airflow, which typically worsens over time (86). Numerous studies have demonstrated that AECOPD is associated with air pollution, particularly PM2.5 (87). Each additional 10 µg/m³ PM2.5 exposure has been demonstrated to increase the rate of coughing symptoms by 33% and expectoration symptoms by 23%, and to decrease the diurnal variation rate of peak expiratory flow in patients with COPD (88). Long-term exposure to PM2.5 has been demonstrated to decrease the population forced expiratory volume in 1 sec and the forced vital capacity, accelerating the decline in lung function in healthy adults in a population-based cohort (89). Therefore, preventive medication is required to avoid exacerbation of COPD following exposure to PM2.5 (90).

Oxidative stress is able to modulate critical signal transduction pathways, including NF-κB signaling, and histone modifications; alterations which are crucial in lung inflammation (91). PM2.5 has been demonstrated to increase the expression of inflammatory cytokine receptors, which are able to activate IL-1 receptor (IL-1R)- and IL-6R-mediated signaling pathways in cells of the lung (92). In a previous study, short-term exposure of PM2.5 to mice induced inflammatory cell infiltration and lung tissue congestion, increasing the expression of inflammatory mediators, including TNF-α, IL-6 and IL-1β, and oncogenes, including c-Fos and c-Jun, which dysregulated a variety of metabolic enzyme activities, including superoxide dismutase and nitric oxide synthase (93). It has been reported that lung oxidative stress and inflammation may be induced by a low dose of PM2.5 in healthy mice (94).

PM2.5 has been demonstrated to increase the level of NF-E2-related factor 2 (Nrf2) expression in mice with COPD, and Nrf2 was associated with oxidative stress (95). PM2.5 exposure was observed to increase the expression of IL-8 in vitro, which was mediated by oxidative stress and endocytosis (96). The enhanced expression of TNF-α and IL-6 has also been detected in sub-chronic (PM2.5 tracheal instillation once a week for 1, 3 or 6 months) PM2.5-exposed mice with COPD, and it is known that cytokine overexpression is able to aggravate immune system damage (97).

Sub-chronic exposure to PM2.5 has also been indicated to induce inflammatory injury in rats and impair the phagocytic function of AM (alveolar macrophage) (98). Furthermore, PM2.5 has been demonstrated to increase the phagocytic ability of macrophages in mice with COPD, thus increasing oxidative stress (99). PM2.5 also impairs the immune balance of mice with COPD by blocking the Notch signaling pathway (99). Exposing nasal mucosa epithelial cells to PM2.5 indicated that PM2.5 was able to increase ROS and Nrf2 levels, which have an association with oxidative stress (100). This study also revealed that PM2.5 increased the release of GM-CSF, TNF-α and IL-13, accelerating the inflammatory reaction. Previous research has revealed that the process of inflammation and oxidative stress occur via different pathways (101), and different PM sources may result in different ROS viabilities (102). In order to explore the function of PM2.5 in the pathogenesis of asthma, one research group exposed asthmatic mice to PM2.5, revealing that the content of IL-4 and IL-10, mediated by TNF-α and T helper 2 cells, increased, coupled with the decreased content of INF-γ mediated by T helper 1 cells. Inflammatory infiltration and goblet cell metaplasia were also demonstrated to be accelerated following PM2.5 exposure (103). The acute inflammatory response following PM2.5 exposure has been revealed to involve TLR2 and TLR4, and a T helper 2 cell-mediated immune response was also detected (104). Furthermore, PM was demonstrated to induce T helper 1/2 cell inflammatory responses in healthy mice and may contribute to the initial onset of asthma (105).