Epidemiological and clinical studies have increasingly shown that fine particulate matter (PM2.5) is associated with a number of pathological respiratory diseases, such as bronchitis, asthma, and chronic obstructive pulmonary disease, which share the common feature of airway inflammation induced by particle exposure. Thus, understanding how PM2.5 triggers inflammatory responses in the respiratory system is crucial for the study of PM2.5 toxicity. In the current study, we found that exposing human bronchial epithelial cells (immortalized Beas-2B cells and primary cells) to PM2.5 collected in the winter in Wuhan, a city in southern China, induced a significant upregulation of VEGFA (vascular endothelial growth factor A) production, a signaling event that typically functions to control chronic airway inflammation and vascular remodeling. Further investigations showed that macroautophagy/autophagy was induced upon PM2.5 exposure and then mediated VEGFA upregulation by activating the SRC (SRC proto-oncogene, non-receptor tyrosine kinase)-STAT3 (signal transducer and activator of transcription 3) pathway in bronchial epithelial cells. By exploring the upstream signaling events responsible for autophagy induction, we revealed a requirement for TP53 (tumor protein p53) activation and the expression of its downstream target DRAM1 (DNA damage regulated autophagy modulator 1) for the induction of autophagy. These results thus extend the role of TP53-DRAM1-dependent autophagy beyond cell fate determination under genotoxic stress and to the control of proinflammatory cytokine production. Moreover, PM2.5 exposure strongly induced the activation of the ATR (ATR serine/threonine kinase)-CHEK1/CHK1 (checkpoint kinase 1) axis, which subsequently triggered TP53-dependent autophagy and VEGFA production in Beas-2B cells. Therefore, these findings suggest a novel link between processes regulating genomic integrity and airway inflammation via autophagy induction in bronchial epithelial cells under PM2.5 exposure.
BackgroundReduced expression of retinoic acid-induced 2 (RAI2) was found in breast cancer. The regulation and function of RAI2 in human colorectal cancer (CRC) remain unclear.MethodsEight CRC cell lines and 237 cases of primary CRC were analyzed. Methylation-specific PCR (MSP), flow cytometry, xenograft mouse model, and shRNA technique were employed.ResultsRAI2 was completely methylated in RKO, LOVO, and HCT116 cells; partially methylated in HT29 cells; and unmethylated in SW480, SW620, DLD1, and DKO cells. RAI2 was methylated in 53.6% (127/237) of primary colorectal cancer. Methylation of RAI2 was significantly associated with gender (P < 0.001), TNM stage (P < 0.001), and lymph node metastasis (P < 0.001). Analyzing by the Kaplan-Meier method, methylation of RAI2 was significantly associated with poor 5-year overall survival (OS) (P = 0.0035) and 5-year relapse-free survival (RFS) (P = 0.0062). According to Cox proportional hazards model analysis, RAI2 methylation was an independent poor prognostic marker for 5-year OS (P = 0.002) and poor 5-year RFS (P = 0.022). RAI2 suppressed cell proliferation, migration, and invasion and induced cell apoptosis in CRC. In addition, RAI2 inhibited AKT signaling in CRC cells and suppressed human CRC cell xenograft growth in mice.ConclusionRAI2 is frequently methylated in human CRC, and the expression of RAI2 is regulated by promoter region methylation. Methylation of RAI2 is an independent poor prognostic marker of CRC. RAI2 suppresses CRC cell growth both in vitro and in vivo. RAI2 suppresses CRC by inhibiting AKT signaling.
Short- and long-term exposure to particulate matter (PM) 2.5 instigates adverse health effect upon the cardiovascular (CV) system. Disclosing the molecular events by which PM2.5 evokes CV injuries is essential in developing effective risk-reduction strategy. Here we found that rats after intratracheally instillation with PM2.5 displayed increased circulating level of ANGII, the major bioactive peptide in renin-angiotensin-system (RAS), which resulted from the elevation of ANGII production in the vascular endothelium. Further investigations demonstrated that activation of IRE1α/XBP1s branch of unfolded protein response (UPR) was essential for augmented vascular ANGII signaling in response to PM2.5 exposure, whose effects strictly depends on the assembly of XBP1s/HIF1α transcriptional complex. Moreover, ablation of IRE1/XBP1/HIFα-dependent ACE/ANGII/AT1R axis activation inhibited oxidative stress and proinflammatory response in the vascular endothelial cells induced by PM2.5. Therefore, we conclude that PM2.5 exposure instigates endoplasmic reticulum instability, leading to the induction of IRE1α/XBP1s branch of UPR and links HIF1α transactivation to mediate ANGII-dependent endothelial dysfunction. Identifying novel therapeutic targets to alleviate ER stress and restore local RAS homeostasis in the endothelium may be helpful for the management of PM2.5-induced CV burden.
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