As a novel class of noncoding RNAs, circRNAs have been recently identified to regulate tumorigenesis and aggressiveness. However, the function of circRNAs in colorectal cancer (CRC) metastasis ...remains unclear. We aimed to identify circRNAs that are upregulated in CRC tissues from patients and study their function in CRC metastasis.
We compared six pairs of CRC tissues and their matched adjacent non-tumor tissues by using circRNA microarray. We first evaluated the expression of circPTK2 (hsa_circ_0005273) in fresh tissues from CRC tumors and corresponding adjacent tissues by qPCR analysis. CircPTK2 expression levels in the tissue microarray with 5 years of survival information were determined by RNA-ISH analysis. Meanwhile, the expression levels of circulating circPTK2 were further analyzed according to the patients' clinical features. We analyzed cell apoptosis, colony formation, migration, and invasion in CRC cells. To further elucidate the effect of circPTK2 in CRC metastasis, we also conducted a colon cancer hepatic and pulmonary metastasis experiment. We used RNA biotin-labeled pull down and mass spectrometry to identify the target of circPTK2. We established a PDTX model to evaluate the effect of shRNA specifically targeting circPTK2 on tumor metastasis.
We identified a novel circRNA, circPTK2, which is back-spliced of three exons (exons 27, 28 and 29) of PTK2 by using circRNA microarray, bioinformatics and functional studies. CircPTK2 was elevated in CRC tissues and positively associated with tumor growth and metastasis. CRC patients with increased circPTK2 expression were positively correlated with poorer survival rates. Furthermore, our studies showed that circPTK2 could promote EMT of CRC cells in vitro and in vivo by binding to vimentin protein on sites Ser38, Ser55 and Ser82. We further demonstrated the interaction of circPTK2 and vimentin mediated the regulation of CRC by knockdown or overexpression of vimentin. In addition, we revealed that tail vein injection of shRNA specifically targeting circPTK2 blunt tumor metastasis in a patient-derived CRC xenograft model.
Collectively, these results demonstrate that circPTK2 exerts critical roles in CRC growth and metastasis and may serve as a potential therapeutic target for CRC metastasis, and also a promising biomarker for early diagnosis of metastasis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A proposed model illustrating the therapeutic effect of QCT on AKI. QCT inhibits the expression of ATF3. While ATF3 blocks the system Xc-, and then suppresses GPX4, inducing ferroptosis. In another ...side, ferroptotic cells secrete chemokines like CCL2, CCL7, induce the recruitment of macrophages, and then cause the inflammation in AKI. In summary, QCT ameliorates AKI through the inhibition on ferroptosis and the following inflammation.
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•Quercetin (QCT) inhibits ferroptosis but not apoptosis, necrosis or autophagy of renal proximal tubular epithelial cells, and ameliorates AKI induced by ischemia–reperfusion (I/R) or folic acid (FA).•Activation transcription factor 3 (ATF3) plays an important role in cell ferroptosis, while QCT significantly inhibits the expression of ATF3 and further blocks the downstream signaling pathway of ferroptosis.•Ferroptotic cells induce the recruitment and chemotaxis of macrophages through CCL2, triggering inflammation and enhancing tissue injury.
Ferroptosis is an iron-dependent regulated necrosis and has been proven to contribute to the progress of acute kidney injury (AKI). Quercetin (QCT), a natural flavonoid which is commonly found in numerous fruits and vegetables, has extensive pharmacological effects, such as anti-oxidant, anti-inflammatory and anti-senescence effects.
This study aims to explain whether ferroptosis is a therapeutic strategy to AKI, and to explore the effect of QCT on AKI ferroptosis.
NRK-52E cells and HK-2 cells were used for in vitro ferroptosis studies. Morphology of cells was detected by transmission electron microscopy. Lipid ROS was assayed using flow cytometry. In vivo, AKI was induced by ischemia–reperfusion (I/R) or folic acid (FA). To explore the molecular mechanisms, RNA-sequence analysis was performed. Transwell was used to detect macrophage migration.
We discovered that quercetin (QCT), a natural flavonoid, inhibited ferroptosis in renal proximal tubular epithelial cells. QCT blocked the typical morphologic changes of ferroptotic cells by reducing the levels of malondialdehyde (MDA) and lipid ROS and increasing the levels of glutathione (GSH). Moreover, QCT ameliorated AKI induced by I/R or FA. RNA-sequence analysis highlighted activation transcription factor 3 (ATF3), as it was the dominant one among all the 299 down-regulated genes by QCT. Knockdown of ATF3 could significantly increase the levels of SLC7A11, GPX4 and increased the cell viability. In addition, ferroptotic cells were found to be extremely pro-inflammatory by recruiting macrophages through CCL2, while QCT inhibited the chemotaxis of macrophages induced by ferroptosis in AKI.
Collectively, these results identify QCT as a ferroptosis inhibitor and provide new therapeutic strategies for diseases related to ferroptosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chronic stress is known to promote inflammatory bowel disease (IBD), but the underlying mechanism remains largely unresolved. Here, we found chronic stress to sensitize mice to dextran sulfate sodium ...(DSS)-induced colitis; to increase the infiltration of B cells, neutrophils, and proinflammatory ly6Chi macrophages in colonic lamina propria; and to present with decreased thymus and mesenteric lymph node (MLN) coefficients. Circulating total white blood cells were significantly increased after stress, and the proportion of MLN-associated immune cells were largely changed. Results showed a marked activation of IL-6/STAT3 signaling by stress. The detrimental action of stress was not terminated in IL-6−/− mice. Interestingly, the composition of gut microbiota was dramatically changed after stress, with expansion of inflammation-promoting bacteria. Furthermore, results showed stress-induced deficient expression of mucin-2 and lysozyme, which may contribute to the disorder of gut microbiota. Of note is that, in the case of cohousing, the stress-induced immune reaction and decreased body weight were abrogated, and transferred gut microbiota from stressed mice to control mice was sufficient to facilitate DSS-induced colitis. The important role of gut microbiota was further reinforced by broad-spectrum antibiotic treatment. Taken together, our results reveal that chronic stress disturbs gut microbiota, triggering immune system response and facilitating DSS-induced colitis.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Chronic obstructive pulmonary disease (COPD) has been linked to particulate matter (PM) exposure. Using transcriptomic analysis, we demonstrate that diesel exhaust particles, one of the major sources ...of particulate emission, down-regulated genes located in mitochondrial complexes I and V and induced experimental COPD in a mouse model. 1-Nitropyrene was identified as a major toxic component of PM-induced COPD. In the panel study, COPD patients were found to be more susceptible to PM than individuals with normal lung function due to an increased inflammatory response. Mechanistically, exposure to PM in human bronchial epithelial cells led to a decline in CCAAT/enhancer-binding protein alpha (C/EBPα), which triggered aberrant expression of NADH dehydrogenase genes and ultimately led to enhanced autophagy. ATG7-deficient mice, which have lower autophagy rates, were protected from PM-induced experimental COPD. Using metabolomics analysis, we further established that treatment with taurine and 3-methyladenine completely restored mitochondrial gene expression levels, thereby ameliorating the PM-induced emphysema. Our studies suggest a potential therapeutic intervention for the C/EBPα/mitochondria/autophagy axis in PM-induced COPD.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
•DEPs-induced neural disorders are triggered by sustained activation of microglia.•Inhibition of NLRP3 inflammasome activation ameliorates the neural disorders.•Taurine protects mice from ...DEPs-induced neural disorders.
The major components of traffic pollution particulate matter, diesel exhaust particles (DEPs), are airborne ultrafine particles (UFPs). DEPs can enter the central nervous system (CNS), where they may cause neurotoxicity.
We established murine models with intranasal DEPs instillation in male C57BL/6 and Nlrp3 knock-out (Nlrp3−/−) mice to investigate the effects of DEPs exposure on murine neurobehaviors and related mechanisms. Morris water maze (MWM) tests were performed to evaluate the learning and memory behaviors of mice following DEPs instillation. Metabolomics were assessed using an gas chromatography system coupled to a mass spectrometer. Real-time PCR and immunohistochemistry assays were used to analyze the mRNA and protein expression levels of target genes. Murine microglia, BV2 cells were employed to assay the effects of DEPs exposure in vitro.
Intranasal administration of DEPs in mice led to impairment in hippocampal-dependent learning and memory. Moreover, this phenotype was linked to increased number of Iba-1+ microglia and NLRP3 inflammasome, as well as suppression of mitochondrial gene expression in the hippocampus of mice exposed to DEPs. Nlrp3−/− mice were resistant to DEPs-induced learning and memory impairment, concomitant with protection against the suppression of mitochondrial gene expression. Murine microglia cells (BV2) were exposed to DEPs in vitro and taurine was identified as one of the significantly suppressed metabolites in DEPs-treated microglia by metabolomics analysis. Supplementation with taurine efficiently rescued learning, memory and mitochondrial gene expression levels in the hippocampus of DEPs-exposed mice.
Mechanistically, our study revealed that microglia-mediated NLRP3 inflammasome activation plays a deleterious role in DEPs-induced neurotoxicity by inhibiting mitochondrial gene expression. These results shed novel light on the potential value of nutritional supplementation against DEPs-induced neurotoxicity in individuals exposed to severe airborne traffic-related air pollutions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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-Prkdc
Il2rg
/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.
Growing evidences suggest that long non-coding RNAs (lncRNAs) are closely correlated to the development of human cancer, such as colorectal cancer (CRC). A previous report suggested that DLEU1 ...accelerated CRC development. However, DLEU1’s underlying mechanism in CRC remains unclear. In our study, the level of DLEU1 in CRC tissues is investigated by qRT-PCR. Our data exhibited that DLEU1 level was observably increased in CRC tissues and CRC cell lines and was closely associated with bad prognosis of CRC patients. CRC cell proliferation was repressed by sh-LncRNA DLEU1, whereas cell apoptosis was markedly stimulated. Moreover, knockdown of DLEU1 inhibited cell migration and invasion. Mechanistically, through interacting with miR-320b in CRC, DLEU1 promoted the level of PRPS1 which was a target of miR-320b. The rescue experiment confirmed that knockdown of DLEU1 repressed cell proliferation, migration and invasion while stimulated cell apoptosis via miR-320b/phosphoribosyl pyrophosphate synthetase 1 (PRPS1) axis. Meanwhile, the data of xenograft model exhibited that inhibition of DLEU1 suppressed tumor growth
in vivo
. In summary, DLEU1 knockdown may repress PRPS1 expression via miR-320b, and then repress cell proliferation, migration and invasion while stimulate cell apoptosis. Our research may provide a novel target for the treatment of CRC.
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.
Diesel exhaust particles (DEPs) exemplify airborne ultrafine particulate, with an aerodynamic diameter less than 100 nm. They have unique distribution characteristics in circulation and biological effects on tissues. This study demonstrates that gut microbiota mediate the toxicity of DEPs to colonic epithelia and also promote the consumption of probiotics as a safe nutritional strategy to alleviate DEPS‐induced colon epithelial injury.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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