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1.
Cell Death Dis ; 12(12): 1109, 2021 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-34839348

RESUMO

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.

2.
J Hazard Mater ; 424(Pt B): 127354, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34634699

RESUMO

Due to its wide applications in tire and rubber products, carbon black (CB) implicates concerns on its safety during production, collection, and handling. Here we report that exposure CB, increases coagulation-thrombosis potential in a splenic extramedullary hemopoiesis (EMH)-dependent manner. Adult C57BL/6 mice are kept in whole-body inhalation chambers, and exposed to filtered room air (FRA) or CB for 28 consecutive days. CB exposure resulted in splenic EMH characterized with platelet precursor cells, megakaryocytes (MKs), hyperplasia and enhanced in vivo blood coagulation ability. Metabolomics analysis suggests significant enhance in PGE2 production but reduction in folic acid (FA) levels in murine serum following CB exposure. Mechanistically, activation of COX-dependent PGE2 production promotes IL-6 expression in splenic macrophages, which subsequently results in splenic EMH and increased platelet counts in circulation. Administration of FA protects the mice against CB-induced splenic EMH through inhibiting prostaglandin-endoperoxide synthase 2 (Ptgs2 or Cox2) and prostaglandin E synthase (Ptges) expression in splenic macrophages, eventually recover the coagulation capacity to normal level. The results strongly suggest the involvement of splenic EMH in response to CB exposure and subsequently increased coagulation-thrombosis potential. Supplementation with FA may be a candidate to prevent thrombosis potential attributable to CB exposure.

3.
Hepatology ; 74(5): 2633-2651, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34110633

RESUMO

BACKGROUND AND AIMS: Liver metastasis is a frequent occurrence in patients with colorectal cancer (CRC), with 15%-25% of CRC patients having liver metastases at the time of initial diagnosis. Specifically, some regional-stage patients with mild symptoms (stage 1 or 2) will also advance to liver metastases rapidly, even if the CRC lesion in situ is resected in time. Nevertheless, the precise mechanism of liver metastasis is still unclear. APPROACH AND RESULTS: Fresh tumor tissues from patients with CRC, adjacent noncancerous tissues, and colorectal adenoma tissues were subjected to microarray analysis to identify differentially expressed microRNA. Exosomes from human serum and cell culture medium were separated, quantitated, and verified by transmission electronic microscopy and Zetasizer Nano. Luciferase reporter assay, real-time quantitative PCR, western blot, immunoprecipitation, chromatin and re-chromatin immunoprecipitation, migration and invasion assay, PDX mouse model, flow cytometry, immunohistochemistry, and immunofluorescence staining were employed to explore the regulation among CRC liver metastases, immunosuppression, and cell adhesion. In this study, we demonstrated that the hypoxic microenvironment in primary CRC lesions boosted exosome release, selectively initiated favorable premetastatic niche formation in the liver but not in other organs. Mechanistically, Kupffer cells (KCs) can phagocytose exosomes containing highly expressed miR-135a-5p from the blood circulation into the liver. Exosomal miR-135a-5p initiated the large tumor suppressor kinase 2-yes-associated protein-matrix metalloproteinase 7 axis to promote the occurrence of CRC liver metastasis, and cluster of differentiation 30-TNF receptor-associated factor 2-p65-mediated immunosuppression signaling also contributed to this process. CONCLUSIONS: Hypoxia-induced exosomal miR-135a-5p correlates with the development, clinical severity, and prognosis of CRC liver metastases through the premetastatic niche; and our findings revealed that miR-135a-5p might be a promising target in halting CRC liver metastases.

4.
Orthop Surg ; 13(1): 161-167, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33403818

RESUMO

OBJECTIVE: To assess the efficacy and safety of ultrasonic bone curette-assisted dome-like laminoplasty in the treatment of ossification of longitudinal ligament (OPLL) involving C2 . METHODS: A total of 64 patients with OPLL involving C2 level were enrolled. Thirty-eight patients who underwent ultrasonic bone curette-assisted dome-like laminoplasty were defined as ultrasonic bone curette group (UBC), and 28 patients who underwent traditional high-speed drill-assisted dome-like laminoplasty were defined as high-speed drill group (HSD). Patient characteristics such as age, sex, body mass index (BMI), symptomatic duration, and other information like the type of OPLL, the time of surgery, blood loss, C2 -C7 Cobb angle change and complications were all recorded and compared. The Japanese Orthopaedic Association (JOA) score, the nerve root functional improvement rate (IR), and the visual analogue scale (VAS) were used to assess neurological recovery and pain relief. The change of the distance between the apex of ossification and a continuous line connecting the anterior edges of the lamina was measured to assess the spinal expansion extent. The measured data were statistically processed and analyzed using SPSS 21.0 software, and the measurement data were expressed as mean ± SD. RESULTS: In ultrasonic bone curette (UBC) group and high-speed drill group (HSD) group, the average time for laminoplasty was 52.3 ± 18.2 min and 76.0 ± 21.8 min and the mean bleeding loss volume was 155.5 ± 41.3 mL and 177.4 ± 54.7 mL, respectively, with a statistically significant difference between the groups. Both groups demonstrated a significant improvement in neurological function. However, the VAS score in UBC group was lower than in HSD group at the 6-month follow-up (P < 0.05), but there was no significant difference at 1-year follow-up. We found that the loss of lordosis was 1.5° ± 1.0° in UBC group, which is significantly lower than that of HSD group at 1-year follow-up (3.8° ± 1.2°, P < 0.05). According to the change of canal dimension, we found that the expansion extent of the spinal canal in UBC group was similar to that of HSD group (P > 0.05). Only one patient in the UBC group and five patients in the HSD group displayed cerebrospinal fluid (CSF) leakag. CONCLUSIONS: With the use of ultrasonic bone curette in OPLL dome-like decompression, the decompression surgery could be completed relatively safely and quickly. It effectively reduced the amount of intraoperative blood loss and complications, and had better initial recovery of neck pain.


Assuntos
Vértebras Cervicais/cirurgia , Curetagem/métodos , Laminoplastia/métodos , Ossificação do Ligamento Longitudinal Posterior/cirurgia , Terapia por Ultrassom/métodos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Inquéritos e Questionários
5.
Plant Biotechnol J ; 19(6): 1195-1205, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33386670

RESUMO

Low grain moisture at harvest is crucial for safe production, transport and storage, but the genetic architecture of this trait in maize (Zea mays) remains elusive. Here, we measured the dynamic changes in grain moisture content in an association-mapping panel of 513 diverse maize inbred lines at five successive stages across five geographical environments. Genome-wide association study (GWAS) revealed 71 quantitative trait loci (QTLs) that influence grain moisture in maize. Epistatic effects play vital roles in the variability in moisture levels, even outperforming main-effect QTLs during the early dry-down stages. Distinct QTL-environment interactions influence the spatio-temporal variability of maize grain moisture, which is primarily triggered at specific times. By combining genetic population analysis, transcriptomic profiling and gene editing, we identified GRMZM5G805627 and GRMZM2G137211 as candidate genes underlying major QTLs for grain moisture in maize. Our results provide insights into the genetic architecture of dynamic changes in grain moisture, which should facilitate maize breeding.


Assuntos
Estudo de Associação Genômica Ampla , Zea mays , Mapeamento Cromossômico , Grão Comestível/genética , Fenótipo , Melhoramento Vegetal , Sementes/genética , Zea mays/genética
6.
iScience ; 23(6): 101241, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32629608

RESUMO

As one of the most extensively cultivated crops, maize (Zea mays L.) has been extensively studied by researchers and breeders for over a century. With advances in high-throughput detection of various omics data, a wealth of multi-dimensional and multi-omics information has been accumulated for maize and its wild relative, teosinte. Integration of this information has the potential to accelerate genetic research and generate improvements in maize agronomic traits. To this end, we constructed ZEAMAP, a comprehensive database incorporating multiple reference genomes, annotations, comparative genomics, transcriptomes, open chromatin regions, chromatin interactions, high-quality genetic variants, phenotypes, metabolomics, genetic maps, genetic mapping loci, population structures, and populational DNA methylation signals within maize inbred lines. ZEAMAP is user friendly, with the ability to interactively integrate, visualize, and cross-reference multiple different omics datasets.

7.
J Clin Lab Anal ; 34(10): e23431, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32533587

RESUMO

BACKGROUND: It has been indicated that the single nuclear polymorphisms (SNPs) in the long noncoding RNA (lncRNA) have association with colorectal cancer (CRC) susceptibility. METHODS: We enrolled 1078 cases with CRC and 1175 age- and gender-matched cancer-free controls to explore whether the polymorphisms in MAGI2-AS3 have associations with CRC risk. qRT-PCR, expression quantitative trait loci (eQTL) analyses, dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), flow cytometry, and transwell assays were performed to explore the specific mechanisms in which MAGI2-AS3 rs7783388 variation influenced the tumorigenesis of CRC. RESULTS: Subjects carrying rs7783388 GG genotype presented a higher risk of CRC compared with the AG/AA genotypes. Mechanistically, we found that the functional genetic variant of rs7783388 A > G decreased binding affinity of transcription factor glucocorticoid receptor (GR) to the MAGI2-AS3 promoter, resulting in decreased transcriptional activity that subsequently downregulated MAGI2-AS3 expression. Furthermore, functional experiments elucidated that MAGI2-AS3 overexpression suppressed CRC cell proliferation, migration, and invasion capacities, arrested cell cycle at G0/G1 phase, and promoted cell apoptosis. CONCLUSION: Taken together, our study demonstrated that the potential function of MAGI2-AS3 as a tumor suppressor for CRC, and the MAGI2-AS3 rs7783388 polymorphism is associated with the increased susceptibility to CRC by altering the binding ability of GR to the MAGI2-AS3 promoter.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas , RNA Longo não Codificante/metabolismo , Receptores de Glucocorticoides/metabolismo , Apoptose/genética , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Ligação Proteica/genética , RNA Longo não Codificante/genética , Fatores de Risco
8.
Environ Pollut ; 262: 114278, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32146367

RESUMO

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.


Assuntos
MicroRNAs , Pneumonia , Animais , Inflamação , Pulmão , Camundongos , Material Particulado
9.
Environ Pollut ; 259: 113839, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31918133

RESUMO

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-1ß 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.


Assuntos
Óxido de Alumínio , Células Epiteliais , Inflamação , Nanopartículas , Regulação para Cima , Óxido de Alumínio/toxicidade , Animais , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Inflamação/induzido quimicamente , Pulmão/efeitos dos fármacos , Camundongos , MicroRNAs , Nanopartículas/toxicidade , Pneumonia , Receptores Notch/genética , Ativação Transcricional/efeitos dos fármacos
10.
Mol Cancer ; 19(1): 13, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31973707

RESUMO

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/patologia , Quinase 1 de Adesão Focal/genética , Neoplasias Pulmonares/secundário , Animais , Apoptose , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , RNA Circular/genética , RNA Circular/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Environ Int ; 136: 105487, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31999974

RESUMO

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Transtornos da Memória , Microglia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Emissões de Veículos , Animais , Aprendizagem , Masculino , Memória , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Emissões de Veículos/toxicidade
12.
J Clin Lab Anal ; 33(8): e22956, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31568607

RESUMO

BACKGROUND: The nucleotide excision repair system removes a wide variety of DNA lesions from the human genome, and plays an important role in maintaining genomic stability. Single nucleotide polymorphisms (SNPs) in nucleotide excision repair are associated with the various forms of tumor susceptibility. However, the relationship between NER polymorphism and colorectal cancer is not clear. METHODS: In this study, three candidate SNPs including ERCC4 (rs6498486), ERCC1 (rs3212986), and ERCC5 (rs17655) were analyzed in 1101colorectal cancer patients and 1175 healthy control patients from Jiangsu province (China). Then, we performed Immunohistochemistry, qPCR, and luciferase assay to determine the potential mechanisms. RESULTS: The ERCC4 rs6498486 AC/CC genotypes show lower susceptibility to CRC than those carrying rs6498486 AA (Adjusted OR = 0.82, 95% CI = 0.69-0.97). However, we did not observe any association between the colorectal cancer risk and the rs3212986(ERCC1) and rs17655(ERCC5) polymorphisms. Immunohistochemistry, qPCR, and luciferase assay revealed that rs6498486 A > C polymorphism in the ERCC4 promoter region could lessen the expression level of ERCC4 by impacting the binding ability of the transcription factor NF-kB, thereby affecting the transcription activity of the ERCC4 gene and decreased ERCC4 gene expression. CONCLUSION: In brief, our finding demonstrated that ERCC4 rs6498486 serves as a potential biomarker of CRC susceptibility for the development of colorectal cancer.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/etiologia , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Estudos de Casos e Controles , China , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Fatores de Risco
13.
Adv Sci (Weinh) ; 6(18): 1900972, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31559135

RESUMO

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.

15.
Cancer Res ; 79(19): 4882-4895, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31409641

RESUMO

Immune dysregulation plays a vital role in colorectal cancer initiation and progression. Long noncoding RNAs (lncRNA) exhibit multiple functions including regulation of gene expression. Here, we identified an immune-related lncRNA, MIR17HG, whose expression was gradually upregulated in adjacent, adenoma, and colorectal cancer tissue. MIR17HG promoted tumorigenesis and metastasis in colorectal cancer cells both in vitro and in vivo. Mechanistically, MIR17HG increased the expression of NF-κB/RELA by competitively sponging the microRNA miR-375. In addition, RELA transcriptionally activated MIR17HG in a positive feedback loop by directly binding to its promoter region. Moreover, miR-17-5p, one of the transcribed miRNAs from MIR17HG, reduced the expression of the tumor suppressor B-cell linker (BLNK), resulting in increased migration and invasion of colorectal cancer cells. MIR17HG also upregulated PD-L1, indicating its potential role in immunotherapy. Overall, these findings demonstrate that MIR17HG plays an oncogenic role in colorectal cancer and may serve as a promising therapeutic target. SIGNIFICANCE: These findings provide mechanistic insight into the role of the lncRNA MIR17HG and its miRNA members in regulating colorectal cancer carcinogenesis and progression.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica/fisiologia , MicroRNAs/metabolismo , Adenocarcinoma/patologia , Adenoma/patologia , Animais , Carcinogênese/genética , Progressão da Doença , Humanos , Camundongos , MicroRNAs/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia
16.
Arch Med Res ; 50(2): 55-62, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31349954

RESUMO

BACKGROUND: Colorectal cancer (CRC) is a major cause of cancer-related deaths worldwide. miR-34 induces changes of its downstream genes and plays a key role in altering the apoptotic cycle and pathways of downstream cells and therefore influences carcinogenesis. OBJECTIVE: The present study investigated whether the single nucleotide polymorphism rs4938723T > C in the promoter of region of miR-34b/c may increase the risk of CRC and influence outcome in patients with CRC. METHODS: We enrolled 1078 CRC patients and 1175 cancer-free controls subjects from the Chinese population. miR-34b/c rs4938723T > C polymorphisms were genotyped using a TaqMan PCR method. RESULTS: We found that subjects carrying rs4938723CT/CC genotypes have significantly decreased risk of CRC (adjusted odds ratios (AOR) = 0.75, 95% CI (0.63-0.90) for CT vs.TT; AOR = 0.61, 95% CI (0.46-0.83) for CC vs. TT and AOR = 0.73,95% CI (0.61-0.86) for CT/CC vs. TT) and a significant increased median survival time (MST) compared with those with TT genotypes (MST = 96.500; 75.883 and 71.370 months for CT, CC and CT/CC respectively vs. MST = 54.300 months for TT, p <0.0001). Stratified analysis by both life style and clinicopathological risks revealed that subjects carrying rs4938723CT/CC genotypes were remained significantly associated with increased survival and low risk of CRC compared with those with TT genotypes in all subgroup (all p <0.05). Similar observation was also reported for the prognostic value of rs4938723TC/CC genotypes across all subgroups. CONCLUSION: These findings indicate that the miR-34b/c rs4938723T > C polymorphism is an independent variable and associated with a decreased risk of CRC in Chinese population. This study provides evidence of the protective effects of rs4938723CT/CC genotypes in the development of CRC.


Assuntos
Neoplasias do Colo/genética , Neoplasias do Colo/terapia , Predisposição Genética para Doença/genética , MicroRNAs/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Regiões Promotoras Genéticas/genética , Risco
17.
Cancer Res ; 79(20): 5432-5441, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31311811

RESUMO

Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) is an evolutionarily highly conserved lncRNA that contributes to colorectal cancer development. However, the exact molecular mechanisms connecting MALAT1 to colorectal cancer have not been fully elucidated. Here, we performed a case-control study in 1,078 patients with colorectal cancer and 1,175 healthy controls to evaluate the association between potentially functional genetic variants of MALAT1 and survival outcomes in patients with colorectal cancer. MALAT1 rs664589 CG/GG genotypes significantly increased the associated risk and decreased overall survival of patients with colorectal cancer compared with the CC genotype. In vitro and in vivo experiments showed that the rs664589 C to G mutation facilitated carcinogenesis and metastasis of colorectal cancer. Mechanistically, the miRNA miR-194-5p targeted MALAT1 for degradation in the nucleus in an Ago2-dependent manner; the rs664589 G allele altered the binding of MALAT1 to miR-194-5p, resulting in increased expression of MALAT1. Colorectal cancer cells and human tissues with the rs664589 CG/GG genotype expressed significantly higher MALAT1 than those with the rs664589 CC genotype. Multivariate Cox regression analysis showed that MALAT1 was a poor prognostic factor of colorectal cancer. In summary, MALAT1 with the rs664589 G allele demonstrates altered binding to miR-194-5p in the nucleus, leading to increased MALAT1 expression and enhanced colorectal cancer development. SIGNIFICANCE: These findings highlight the functional role of MALAT1 polymorphism in colorectal cancer metastasis and survival as well as the underlying mechanism.


Assuntos
Neoplasias Colorretais/genética , MicroRNAs/metabolismo , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/metabolismo , RNA Neoplásico/metabolismo , Alelos , Animais , Proteínas Argonauta/metabolismo , Carcinogênese , Estudos de Casos e Controles , Movimento Celular , Núcleo Celular/metabolismo , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Genótipo , Xenoenxertos , Humanos , Estimativa de Kaplan-Meier , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Metástase Neoplásica , Transplante de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Método Simples-Cego , Células Tumorais Cultivadas , Ensaio Tumoral de Célula-Tronco
18.
Adv Sci (Weinh) ; 6(11): 1900180, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31179224

RESUMO

Particulate matter (PM) exposure has been associated with intestinal disorders. Therefore, there is an urgent need to understand the precise molecular mechanism involved and explore potential prevention strategies. In this study, inhaled PM is shown to activate inflammatory pathways in murine colon. In a panel study, it is found that ambient PM levels are significantly associated with elevated number of fecal white blood cells in healthy subjects. Acting as a promoter, PM exposure accelerates chemical carcinogenesis-induced colonic tumor formation in a murine model. Mechanistically, RNA-seq assays suggest activation of phosphoinositide 3-kinase (PI3K)/AKT cascades in chronically PM-exposed human colon mucosal epithelial cells. Ablation of up-stream driver fibroblast growth factor receptor 4 (FGFR4) effectively inhibits inflammation and neoplasia in PM-exposed murine colons. Notably, dietary curcumin supplement is shown to protect against PM-induced colonic injuries in mice. Collectively, these findings identify that PM exposure accelerates colonic tumorigenesis in a PI3K/AKT-dependent manner and suggests potential nutrient supplement for prevention.

19.
Biosci Rep ; 39(4)2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30902880

RESUMO

The growth arrest special 5 (GAS5), as a research hotspot of long noncoding RNAs (lncRNAs), has been reported to be associated with colorectal cancer (CRC). However, the association between polymorphisms in GAS5 and the risk of CRC was not clear. In the present study, a case-control study in 1078 CRC patients and 1175 matched healthy controls was performed to evaluate the association between the potential functional genetic variants in GAS5 and the risk of CRC. PCR-TaqMan, qPCR, dual-luciferase assay, electrophoretic mobility shift assay (EMSA), flow cytometry, migration and invasion assays were performed to evaluate the function of polymorphism. Results showed that subjects carrying the rs55829688 CT/TT genotypes had a significantly higher risk of CRC when compared with the CC genotype. Further qPCR assay confirmed that the CRC tissues with rs55829688 CT/TT genotypes had a higher GAS5 mRNA expression level. The dual-luciferase assay, qPCR and EMSA assay revealed that rs55829688 T>C polymorphism could decrease the expression level of GAS5 by impacting the binding ability of the transcription factor Yin Yang-1 (YY1) to the GAS5 promoter region. The expression of apoptosis-related proteins were detected by Western blot. Further, flow cytometry, migration, and invasion experiments showed that GAS5 repressed apoptosis and increased invasion and migration capability of CRC cells. Taken together, our findings provided evidence that the rs55829688 variant in the GAS5 promoter was associated with the risk of CRC and decreased expression of GAS5 by affecting the binding affinity of the transcription factors YY1 to GAS5.


Assuntos
Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Estudos de Casos e Controles , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/patologia , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Regiões Promotoras Genéticas
20.
Ecotoxicol Environ Saf ; 167: 309-316, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30343145

RESUMO

Epidemiological studies have associated ambient fine particulate matter (PM2.5) exposure with lung cancer, in which epithelial-mesenchymal transition (EMT) is an initial process. Thus, it is important to identify the key molecule or pathway involved in the PM2.5 induced EMT. Human bronchial epithelial (HBE) cells were exposed to PM2.5 (100 or 500 µg/ml) for 30 passages and analyzed by metabolomics to identify the alteration of metabolites related to PM2.5 exposure. The expression levels of EMT markers were evaluated by qRT-PCR and Western blot assays in HBE cells and murine lung tissues. Reduced epithelial markers, increased mesenchymal markers expression levels and increased capacity of metastasis were observed in PM2.5-exposed HBE cells. Metabolomics analysis suggested upregulation of citrate acid with fold change (FC) of 2.89 or 4.18 in 100 or 500 µg/ml PM2.5 treated HBE cells. For both of the in vitro and in vivo study, the up-regulation of ATP citrate lyase (ACLY) was confirmed following PM2.5 exposure. Importantly, ACLY knockdown in HBE cells reversed EMT, migration and invasion capacities in HBE cells induced by PM2.5. Taken together, our data suggest that inhibition of ACLY demonstrates a protection against PM2.5-induced EMT, providing a concern on the molecular mechanisms of PM2.5-associated pulmonary disorders.


Assuntos
ATP Citrato (pro-S)-Liase/genética , Células Epiteliais/efeitos dos fármacos , Transição Epitelial-Mesenquimal , Epitélio/efeitos dos fármacos , Material Particulado/toxicidade , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , ATP Citrato (pro-S)-Liase/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Epitélio/metabolismo , Humanos , Pulmão/citologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Substâncias Protetoras/metabolismo
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