Sulfate Aerosols Promote Lung Cancer Metastasis by Epigenetically Regulating the Epithelial-to-Mesenchymal Transition (EMT)

Abstract

Secondary inorganic aerosols (SIA), particularly sulfate aerosols, are central particulate matter (PM) constituents of severe haze formation in China and exert profound impacts on human health; however, our understanding of the mechanisms by which sulfate aerosols cause malignancy in lung carcinogenesis remains incomplete. Here, we show that exposure to secondary inorganic aerosols induced the invasion and migration of lung epithelial cells, and that (NH)SO exerted the most serious effects in vitro and promoted lung tumor metastasis in vivo. This action was associated with alterations of phenotype markers in the epithelial-to-mesenchymal transition (EMT), such as the up-regulation of fibronectin (Fn1) and the down-regulation of E-cadherin (E-cad). Hypoxia-inducible factor 1α (HIF-1α)-Snail signaling, regulated by the generation of reactive oxygen species (ROS), was involved in the (NH)SO-induced EMT, and the potent antioxidant N-acetylcysteine (NAC) inhibited the activation of HIF-1α-Snail and blocked the EMT, cell invasion, and migration in response to (NH)SO. Additionally, CpG hypermethylation in the E-cad promoter regions partly contributed to the (NH)SO-regulated E-cad repression, and the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-Aza) restored the (NH)SO-induced down-regulation of E-cad. Our findings reveal a potential mechanistic basis for exploring the association between sulfate aerosol exposure and increased malignancy during lung carcinogenesis, and suggest new approaches for the treatment, improvement, and prevention of lung cancer resulting from sulfate aerosol exposure in severe haze-fog.

Ang-2 promotes lung cancer metastasis by increasing epithelial-mesenchymal transition

“…EMT is a process that increases the metastasis and invasive potential of tumor cells, with losing epithelial cell characteristics and acquiring a mesenchymal pheno-type, including decreasing epithelial markers (cytokeratin or E-cadherin) and up-regulating mesenchymal indicators (VIM or N-cadherin) or transcription factors (Twist, Snail) [ 35 – 37 ]. Usually, inhibiting E-cadherin can induce invasiveness-related N-cadherin expression [ 38 , 39 ]. VIM may enhance migration and invasiveness and related to reduce E-cadherin and upregulating N-cadherin, while increased VIM is correlated with poor prognosis [ 20 , 40 ].…”

Ionizing radiation induces epithelial–mesenchymal transition in human bronchial epithelial cells

“…FN1, a member of the glycoprotein family, is involved in cell migration and adhesion [30]. Many studies have reported that FN1 has an indispensable role in EMT [31][32][33][34]. FN1, together with E-cad and VIM, serves as a marker for EMT in non-small cell lung cancer.…”

The Role of Particulate Matter Air Pollution in Cancer Pathogenesis

“…Кроме того, в воздухе происходит формирование вторичных частиц в результате химических реакций c газообразными загрязняющими веществами, которые, в свою очередь, являются продуктом происходящей в атмосфере трансформации окислов азота и серы либо выбрасываются автотранспортом и промышленностью. Вторичные частицы в основном содержатся в мелкодисперсных РМ [12,13].…”