Hsa-circ-0052001 promotes gastric cancer cell proliferation and invasion via the MAPK pathway.

BACKGROUND: Gastric cancer (GC) ranks fourth among the causes of death from malignant tumors in the world. Studies have implicated the dysregulation of circRNAs with GC. However, the relationship between hsa-circ-0052001 and GC is unclear. METHODS: In our current study, we assessed the expression levels of hsa-circ-0052001 in GC cells and tissues using quantitative real-time PCR (qPCR). The role of hsa-circ-0052001 expression on the proliferation and invasion of GC cells was assessed using in vitro experiments. The role of hsa-circ-0052001 on the proliferation of GC cells was also analyzed using in vivo models. The pathways downstream of hsa-circ-0052001 were identified using bioinformatics analyses, western blot (WB) assays, and qRT-PCR. RESULTS: We found that compared with normal gastric mucosa epithelial cells and adjacent paracancer tissues, hsa-circ-0052001 was overexpressed in GC cells and tissues. Also, the hsa-circ-0052001 level was linked to patient clinicopathological characteristics of GC. Cell proliferation and metastatic ability were inhibited in gastric cancer cells when hsa-circ-0052001 was knocked down in vitro and cancer growth in vivo. Mechanistically, hsa-circ-0052001 promoted the carcinogenesis of GC cells via the MAPK signal pathway. CONCLUSION: Hsa-circ-0052001 functions as a tumor gene in promoting the progression of GC through MAPK pathway, which has provided a promising target for patients with GC.

TYRO3 promotes tumorigenesis and drug resistance in colorectal cancer by enhancing the epithelial-mesenchymal transition process.

Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. Although considerable advances in CRC treatment have been achieved, effective treatment improvement has hit a bottleneck. This study demonstrated that TYRO3 expression was aberrantly increased in CRC tissues with prognosis association. The prediction model of prognosis for CRC patients was constructed based on TYRO3 expression. The model suggested that the TYRO3 level is crucial to the final prediction results. We observed that knockdown TYRO3 expression could inhibit the proliferation and migration ability and reverse the drug resistance by constructing drug-resistant CRC cell lines. In vivo experiments also confirmed this conclusion. Thus, targeting TYRO3 combined with 5-Fu treatment could provide a better therapeutic effect. Additionally, TYRO3 could inhibit the EMT process by down-regulating ENO1, which may be achieved by interfering with energy metabolism in cancer cells. Therefore, the current study provides a theoretical basis for TYRO3 in drug-resistance of CRC cells and highlights a new strategy for CRC-targeted therapy.

High-fat diet promotes colitis-associated tumorigenesis by altering gut microbial butyrate metabolism.

Background: Dietary fat intake is associated with an increased risk of colitis associated cancer (CAC). A high-fat diet (HFD) leads to systemic low-grade inflammation. The colon is believed to be the first organ suffering from inflammation caused by the infiltration of pro-inflammatory macrophages, and promotes CAC progression. We explored the role of HFD in driving CAC by altering gut microbial butyrate metabolism. Methods: Changes in the gut microbiota caused by HFD were investigated via HFD treatment or fecal microbiota transplantation (FMT). The underlying mechanisms were further explored by analyzing the role of gut microbiota, microbial butyrate metabolism, and NLRP3 inflammasome in colon tissues in a CAC mouse model. Results: HFD accelerated CAC progression in mice, and it could be reversed by broad-spectrum antibiotics (ABX). 16S-rRNA sequencing revealed that HFD inhibited the abundance of butyrate-producing bacteria in the gut. The level of short-chain fatty acids (SCFAs), especially butyrate, in the gut of mice treated with HFD was significantly reduced. In addition, treatment with exogenous butyrate reversed the M1 polarization of proinflammatory macrophages, aggravation of intestinal inflammation, and accelerated tumor growth induced by HFD; the NLRP3/Caspase-1 pathway activated by HFD in the colon was also significantly inhibited. In vitro, macrophages were treated with lipopolysaccharide combined with butyrate to detect the M1 polarization level and NLRP3/Caspase-1 pathway expression, and the results were consistent with those of the in vivo experiments. Conclusion: HFD drives colitis-associated tumorigenesis by inducing gut microbial dysbiosis and inhibiting butyrate metabolism to skew macrophage polarization. Exogenous butyrate is a feasible new treatment strategy for CAC, and has good prospect for clinical application.

Emergence of the resistance-nodulation-division efflux pump tmexCD3-toprJ3 gene confers resistance to tigecycline in Pseudomonas juntendi and Proteus terrae isolated from a pig farm in China.

BACKGROUND: Tigecycline is regarded as a last-resort antimicrobial agent against multidrug resistance (MDR). However, resistance-nodulation-division efflux pump resistance genes, such as tmexCD3-toprJ3, that confer resistance to tigecycline have emerged. OBJECTIVES: This study aimed to characterise the tmexCD3-toprJ3 gene cluster in Pseudomonas juntendi and Proteus terrae isolated from a pig farm. METHODS: Samples were obtained from a Chinese piggery and included 92 pig faecal samples, 56 wastewater samples, 23 drinking water samples, 28 sow vagina samples and nine sow uterus swabs. The presence of tmexCD3-toprJ3 was detected using a polymerase chain reaction assay, and the antimicrobial susceptibility profile of the tmexCD3-toprJ3-positive isolates was determined using the broth dilution method. Genomic locations were identified using whole-genome sequencing and bioinformatics. RESULTS: We identified two tmexCD3-toprJ3-positive isolates, and both isolates were highly resistant to antibiotics such as tigecycline. In addition, we identified several mobile elements (ISPa7, ISCfr1, ISVsa3) and insertion sequences (TnAs2, TnAs3) in tmexCD3-toprJ3-positive isolates that could increase the potential for the spread of MDR. CONCLUSIONS: To the best of our knowledge, this study is the first to report the detection of tmexCD3-toprJ3 in P. juntendi and P. terrae isolated from a pig farm.

Prevalence and antimicrobial susceptibility of CTX-M-type-producing Escherichia coli from a wildlife zoo in China.

BACKGROUND: Wildlife zoos provide the opportunity for children and adults to interact with animals, However, it's unknown that the risk of contact with animals, which carried zoonotic pathogens and antimicrobial resistant bacteria. OBJECTIVES: This study aimed to investigate the prevalence and antimicrobial susceptibility of extended-spectrum ß-lactamases Escherichia coli (ESBLs-EC) from a wildlife zoo in China. METHODS: A total of 93 wildlife faecal samples were collected from a wildlife zoo. Agar dilution method was used to determine the resistant phenotype. Whole genomes sequencing and bioinformatic analysis were employed to evaluate the molecular typing and genetic relationships of ESBLs-EC. RESULTS: A total of 23 CTX-M-positive ESBLs-EC were isolated from swan (n = 14), squirrel monkey (n = 5), black hat hanging monkey (n = 2), gibbon monkey (n = 1) and phoenicopteridae (n = 1) respectively. All ESBLs-EC strains were resistant to cefotaxime, tetracycline, ciprofloxacin and trimethoprim-sulfamethoxazole, but susceptible to colistin, tigecycline, meropenem and amikacin. By screening whole genome sequences, ESBLs-EC strains main carried blaCTX-M-55 (34.8%, 8/23) and blaCTX-M-14 (26.0%, 6/23), following by blaCTX-M-27 (21.7%, 5/23), blaCTX-M-15 (13.0%, 3/23) and blaCTX-M-121 (4.3%, 1/23). ESBLs-EC strains mainly belonged to phylogroup A (60.9%, 14/23), and ST48, ST746 and ST616 (3 strains respectively, 13.0%) were major ST types. Core genome-based single nucleotide polymorphism (SNP) analysis suggested that strains from the swan, over the phylogenetic tree, have a closer genetic relationship with strains from other animals (black hat hanging monkey, gibbon monkey, phoenicopteridae and squirrel monkey). CONCLUSIONS: CTX-M type ESBLs-EC can transmit between animals in wildlife zoos, which may be a risk of spread to animal keepers, veterinarians and visitors when contact with animals. Our study provides that the importance of hygiene measures to minimise the risk of transmission of ESBLs-EC to visitors in wildlife zoos.

Roux-en-Y reconstruction alleviates radical gastrectomy-induced colitis via down-regulation of the butyrate/NLRP3 signaling pathway.

BACKGROUND: Different methods for digestive tract reconstruction have a complex impact on the nutritional status of gastric cancer (GC) patients after radical gastrectomy. Previous studies reported that Roux-en-Y (R-Y) reconstruction resulted in obvious weight reduction and improvement in type 2 diabetes in obese patients. We investigated the relationship between R-Y reconstruction, gut microbiota, and the NLRP3 inflammasome in GC patients with poor basic nutrition. METHODS: Changes in the gut microbiota after radical gastrectomy accomplished by different methods of digestive tract reconstruction were investigated via fecal microbiota transplantation. The underlying mechanisms were also explored by analyzing the role of the microbiota, butyrate, and the NLRP3 inflammasome in the colon tissues of colitis model mice and GC patients after radical gastrectomy. FINDINGS: R-Y reconstruction effectively relieved intestinal inflammation and facilitated nutrient absorption. 16S rRNA analysis revealed that gavage transplantation with the fecal microbiota of R-Y reconstruction patients could reverse dysbacteriosis triggered by radical gastrectomy and elevate the relative abundance of some short-chain fatty acid (SCFA)-producing bacteria. Subsequently, butyrate negatively regulated the NLRP3-mediated inflammatory signaling pathway to inhibit the activation of macrophages and the secretion of pro-inflammatory mediators such as caspase-1 and interleukin (IL)-1ß, decreasing the level of intestinal inflammation and promoting nutrient absorption. INTERPRETATION: R-Y reconstruction induced colonization with SCFA-producing bacteria to alleviate radical gastrectomy-induced colitis by down-regulating the NLRP3 signaling pathway. This can be a new strategy and theoretical basis for the management of the postoperative nutritional status of GC patients. FUNDING: This work was supported by the National Nature Science Foundation of China (81974375), the BoXi cultivation program (BXQN202130), and the Project of Youth Foundation in Science and Education of the Department of Public Health of Suzhou (KJXW2018001).

ENO1 contributes to 5-fluorouracil resistance in colorectal cancer cells via EMT pathway.

Introduction: Chemoresistance is a major barrier in the treatment of colorectal cancer (CRC) and many other cancers. ENO1 has been associated with various biological characteristics of CRC. This study aimed to investigate the function of ENO1 in regulating 5-Fluorouracil (5-FU) resistance in CRC. Methods: ENO1 level in 120 pairs of tumor tissues and adjacent normal tissues was examined by immunohistochemistry, and the correlation between ENO1 expression and prognosis was explored by survival analysis. Its role and potential mechanisms in regulating 5-FU resistance in CRC were studied by Western blotting, MTT assay, colony formation assay and transwell invasion assay. Murine xenograft assay was implied to verify the results in vivo. Results: Our study indicated that ENO1 was elevated in CRC tissues and was associated with poor patient prognosis. High levels of ENO1 expression were detected as a significant influencing factor for overall survival. Furthermore, ENO1 expression was found to have increased in drug-resistant cells (HCT116/5-FU and SW620/5-FU) constructed by increasing concentrations of 5-FU. Knockdown of ENO1 markedly increased the drug susceptibility and inhibited the proliferation and migration ability of HCT116/5-FU and SW620/5-FU cells. It was found that down-regulation of ENO1 inhibited the epithelial-mesenchymal transformation (EMT) signaling process. Finally, a murine xenograft assay verified that the depletion of ENO1 alleviated 5-FU resistance. Conclusion: This study identified that ENO1 regulated 5-FU resistance via the EMT pathway and may be a novel target in the prevention and treatment of 5-FUresistant CRC.