Long-isoform NFE2L1 silencing inhibits acquisition of malignant phenotypes induced by arsenite in human bronchial epithelial cells.

Chronic arsenic exposure is associated with the increased risk of several types of cancer, among which, lung cancer is the most deadly one. Nuclear factor erythroid 2 like 1 (NFE2L1), a transcription factor belonging to CNC-bZIP family, regulates multiple important cellular functions in response to acute arsenite exposure. However, the role of NFE2L1 in lung cancer induced by chronic arsenite exposure is unknown. In this study, we firstly showed that chronic arsenite exposure (36 weeks) led to epithelial-mesenchymal transition (EMT) and malignant transformation in human bronchial epithelial cells (BEAS-2B). During the process of malignant transformation, the expression of long isoforms of NFE2L1 (NFE2L1-L) was elevated. Thereafter, BEAS-2B cells with NFE2L1-L stable knockdown (NFE2L1-L-KD) was chronically exposed to arsenite. As expected, silencing of NFE2L1-L gene strikingly inhibited the arsenite-induced EMT and the subsequent malignant transformation. Additionally, NFE2L1-L silencing suppressed the transcription of EMT-inducer SNAIL1 and increased the expression of E-cadherin. Conversely, NFE2L1-L overexpression increased SNAIL1 transcription but decreased E-cadherin expression. Collectively, our data suggest that NFE2L1-L promotes EMT by positively regulating SNAIL1 transcription, and is involved in malignant transformation induced by arsenite.

Metabolic reprogramming in the arsenic carcinogenesis.

Chronic exposure to arsenic has been associated with a variety of cancers with the mechanisms undefined. Arsenic exposure causes alterations in metabolites in bio-samples. Recent research progress on cancer biology suggests that metabolic reprogramming contributes to tumorigenesis. Therefore, metabolic reprogramming provides a new clue for the mechanisms of arsenic carcinogenesis. In the present manuscript, we review the latest findings in reprogramming of glucose, lipids, and amino acids in response to arsenic exposure. Most studies focused on glucose reprogramming and found that arsenic exposure enhanced glycolysis. However, in vivo studies observed "reverse Warburg effect" in some cases due to the complexity of the disease evolution and microenvironment. Arsenic exposure has been reported to disturb lipid deposition by inhibiting lipolysis, and induce serine-glycine one-carbon pathway. As a dominant mechanism for arsenic toxicity, oxidative stress is considered to link with metabolism reprogramming. Few studies analyzed the causal relationship between metabolic reprogramming and arsenic-induced cancers. Metabolic alterations may vary with exposure doses and periods. Identifying metabolic alterations common among humans and experiment models with human-relevant exposure characteristics may guide future investigations.

Acute lung inflammation induced by zinc oxide nanoparticles: Evolution and intervention via NRF2 activator.

Zinc oxide nanoparticles (ZnONPs) are widely used worldwide. Human inhalation exposure to ZnONPs induces acute lung inflammation (ALI); however, the characteristics and therapeutic targets of ALI are unclear. In this study, female C57BL/6J mice were subjected to a single intratracheal instillation of 20 µg of ZnONPs. Increased lung malondialdehyde levels and decreased total antioxidant capacity at 6 h, as well as increased lactate dehydrogenase levels in bronchoalveolar lavage fluid (BALF) at 1 day (d) post treatment were observed. A significant inflammatory response was observed at 3 d and 7 d, as evidenced by increased leukocyte numbers and total protein concentration in BALF, and histological abnormalities. Pulmonary NRF2 signaling was significantly activated at 3 d post treatment. To investigate a protective role of NRF2 activator against ZnONP-induced ALI, the mice were intraperitoneally injected with 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) (2 mg/kg) 1 d before and 1 d after ZnONPs treatment. CDDO-Im significantly decreased leukocyte numbers and total protein concentration in BALF and pulmonary inflammatory gene expression, and ameliorated histopathological abnormalities induced by ZnONPs. Collectively, the present study indicates that ZnONPs exposure leads to oxidative stress, cell injury and inflammation in the lung successively. Moreover, the NRF2 activator protects against ZnONPs-induced ALI.