Although therapeutic targets have been developed for colorectal cancer (CRC) therapy, the therapeutic effects are not ideal and the survival rate for CRC patients remains poor. Therefore, it is crucial to recognize a specific target and develop an efficacious delivery system for CRC therapy. Herein, we demonstrate that reduced ALKBH5 mediates aberrant m6A modification and tumor progression in CRC. Mechanically, histone deacetylase 2-mediated H3K27 deacetylation inhibits ALKBH5 transcription in CRC, whereas ectopic ALKBH5 expression decreases tumorigenesis of CRC cells and protects mice from colitis-associated tumor development. Further, METTL14/ALKBH5/IGF2BPs combine to modulate JMJD8 stability in an m6A-dependent manner, which increases glycolysis and accelerates the development of CRC by enhancing the enzymatic activity of PKM2. Moreover, ALKBH5 mRNA-loaded folic acid-modified exosome-liposome hybrid nanoparticles were synthesized and significantly inhibit the progression of CRC in preclinical tumor models by modulating the ALKBH5/JMJD8/PKM2 axis and inhibiting glycolysis. Overall, our research confirms the crucial function of ALKBH5 in regulating the m6A status in CRC and provides a direct preclinical approach for using ALKBH5 mRNA nanotherapeutics for CRC.

Ambient fine particulate matter (PM2.5) is linked to an increased risk of chronic obstructive pulmonary disease (COPD) exacerbations, which significantly increase the risk of mortality in COPD patients. Identifying the subtype of COPD patients who are sensitive to environmental aggressions is necessary. Using in vitro and in vivo PM2.5 exposure models, we demonstrate that exosomal hsa_circ_0005045 is upregulated by PM2.5 and binds to the protein cargo peroxiredoxin2, which functionally aggravates hallmarks of COPD by recruiting neutrophil elastase and triggering in situ release of tumor necrosis factor (TNF)-α by inflammatory cells. The biological function of hsa_circ_0005045 associated with aggravation of COPD is validated using exosome-transplantation and conditional circRNA-knockdown murine models. By sorting the major components of PM2.5, we find that PM2.5-bound heavy metals, which are distinguishable from the components of cigarette smoke, trigger the elevation of exosomal hsa_circ_0005045. Finally, using machine learning models in a cohort with 327 COPD patients, the PM2.5 exposure-sensitive COPD patients are characterized by relatively high hsa_circ_0005045 expression, non-smoking, and group C (mMRC 0–1 (or CAT < 10) and ≥ 2 exacerbations (or ≥ 1 exacerbation leading to hospital admission) in the past year). Thus, our results suggest that environmental reduction in PM2.5 emission provides a targeted approach to protecting non-smoking COPD patients against air pollution-related disease exacerbation.

Exposure to fine particulate matter (PM2.5) in outdoor air is carcinogenic and associated with the development of lung cancer; however, the underlying mechanism remains unclear. In the present study, the profiles of lncRNA, microRNA and mRNA expression profiles in human bronchial epithelia (HBE) following exposure to PM2.5, diesel exhaust particles (DEPs), or aluminum oxide nanoparticles (Al2O3 NPs) were explored by microarray to reveal the lncRNA-microRNA-mRNA network participating in the malignant transformation of HBE cells following long-term PM2.5 exposure. The results showed that lncRNA SOX2 overlapping transcript (SOX2-OT) was significantly induced in HBE cells exposed to PM2.5, DEPs, or Al2O3 NPs, acting as a sponge to microRNA-345-5p, which subsequently increased the expression levels of epidermal growth factor receptor (EGFR). EGFR is a therapeutic target in non-small cell lung cancer. Here, we found that SOX2-OT is an upstream trigger of EGFR in HBE cells during long-term PM2.5 exposure. Importantly, SOX2-OT knockdown effectively reduced the colony formation and migration capacities of HBE cells, compared to the wild type control. Collectively, SOX2-OT/microRNA-345-5p/EGFR is a ceRNA mechanism underlying the malignant transformation of bronchial epithelia exposed to PM2.5, which improves our understanding of the association between ambient PM2.5 exposure and the development of lung cancer.

Chimeric antigen receptor (CAR) - T cell therapy is a new class of cellular immunotherapies, which has made great achievements in the treatment of malignant tumors. Despite improvements in colorectal cancer (CRC) therapy, treatment of many patients fails because of metastasis and recurrence. The human epidermal growth factor receptor 2 (HER2) is a substantiated target for CAR-T therapy, and has been reported recently to be over-expressed in CRC, which may provide a potential therapeutic target for CRC treatment. Herein, HER2 was a promising target of metastatic colorectal cancer (mCRC) in CAR-T therapy as assessed by flow cytometry and tissue microarray (TMA) with 9-year survival follow-up data. Furthermore, HER2-specific CAR-T cells exhibited strong cytotoxicity and cytokine-secreting ability against CRC cells in vitro. Moreover, through the tumor-bearing model of the NOD-Prkdcem26cd52Il2rgem26Cd22/Nju (NCG) mice, HER2 CAR-T cells showed signs of effectively preventing CRC progression in three different xenograft models. Notably, HER2 CAR-T cells displayed greater aggressiveness in HER2+ CRC in the patient-derived tumor xenograft (PDX) models and had potent immunotherapeutic capacity for mCRC in the metastatic xenograft mouse models. In conclusion, our studies provide scientific evidence that HER2 CAR-T cells represent an emerging immunotherapy for the treatment of mCRC.

Exposure to atmospheric particulate matter (PM) has been related to the increasing incidence and mortality of pulmonary diseases, where microRNAs (miRNAs) play significant roles in these biological and pathological processes. In the present study, we found that miR-382-5p played an anti-inflammatory role in pulmonary inflammation induced by fine particulate matter (PM2.5) or diesel exhaust particles (DEPs) in vitro and in vivo. The expression level of miR-382-5p was downregulated, while its target gene, namely CXCL12, was elevated in HBE cells after exposure to PM2.5 or DEPs. Mechanistically, PM2.5 or DEPs exposure increased CXCL12/MMP9 expression via miR-382-5p inhibition, subsequently triggered pulmonary inflammation. Furthermore, antagonizing the function of CXCL12 significantly reduced the expression of MMP9 and local inflammation induced by PM2.5 or DEPs. PM2.5 or DEPs caused apoptosis and G1 phase arrest could be partially restored by overexpression of miR-382-5p and antagonism of CXCL12. In a murine model, enhanced miR-382-5p expression effectively reduced expression levels of CXCL12, MMP9 and inflammatory cytokines, hereby protected lung tissues against PM2.5 or DEPs-induced lesions. Collectively, the miR-382-5p/CXCL12/MMP9 pathway may provide a mechanism, which mediates inflammatory response to PM2.5 or DEPs exposure.

Abstract Diesel exhaust particles (DEPs) are common airborne ultrafine particles (UFPs); however, few studies have examined their effects on the gastrointestinal tract. To investigate the interaction of gut microbiota and DEPs‐induced colonic injury, adult C57BL/6 mice are kept in whole‐body inhalation chambers and exposed to filtered room air (FRA) or DEPs (300 µg m−3) 1 h per day for 28 consecutive days. DEPs exposure results in colon epithelial injury with inflammatory cell infiltration and mucus depletion. Abundance of Lactobacillus in murine feces is transiently increased following 7‐day DEPs exposure and then decreased until the end of 28‐day exposure. A reduction of the colonic mucus layer thickness is observed in mice receiving gut microbiota from DEPs‐exposed mice. Mechanistically, RNA‐sequencing suggests disruption of the nitrogen metabolism pathway in DEPs‐exposed NCM460 cells. Upregulation of carbonic anhydrase 9 (CA9) expression levels is observed in epithelia following DEPs exposure both in vivo and in vitro. Oral administration of probiotics protects the mice against DEPS‐induced colon epithelial injury. The results strongly suggest the involvement of gut microbiota in response to DEPs exposure and subsequently epithelial injury in vivo. Supplementation with probiotic may be a potential way to protect against UFPs‐induced colon epithelial injury.

Exposure to Aluminum oxide nanoparticles (Al2O3 NPs) has been associated with pulmonary inflammation in recent years; however, the underlying mechanism that causes adverse effects remains unclear. In the present study, we characterized microRNA (miRNA) expression profiling in human bronchial epithelial (HBE) cells exposed to Al2O3 NPs by miRNA microarray. Among the differentially expressed miRNAs, miR-297, a homologous miRNA in Homo sapiens and Mus musculus, was significantly up-regulated following exposure to Al2O3 NPs, compared with that in control. On combined bioinformatic analysis, proteomics analysis, and mRNA microarray, NF-κB-activating protein (NKAP) was found to be a target gene of miR-297 and it was significantly down-regulated in Al2O3 NPs-exposed HBE cells and murine lungs, compared with that in control. Meanwhile, inflammatory cytokines, including IL-1β and TNF-α, were significantly increased in bronchoalveolar lavage fluid (BALF) from mice exposed to Al2O3 NPs. Then we set up a mouse model with intranasal instillation of antagomiR-297 to further confirm that inhibition of miR-297 expression can rescue pulmonary inflammation via Notch pathway suppression. Collectively, our findings suggested that up-regulation of miR-297 expression was an upstream driver of Notch pathway activation, which might be the underlying mechanism involved in lung inflammation induced by exposure to Al2O3 NPs.