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BACKGROUND: Large fragment deletion (LFD) of EGFR was associated with carcinogenesis in many types of cancers. However, the molecular features of EGFR-LFD have not been studied in the Asian cancer population. METHOD: Here we retrospectively analyzed the targeted sequencing data from a large cancer database. RESULTS: EGFR-LFD was detected at a frequency of 0.03% with EGFRvIII being the most frequently observed LFD. TERTp variants were identified in 60% of the cases. TP53 alterations (33%) were mutually exclusive with TERTp variants and coexisted with EGFR-LFD in lung cancer and colorectal cancer. EGFR amplification (67%) and chromosome 10p deletion (53%) were the most focal-level and arm-level CNV in this cohort. EGFR exon2-17 skipping was found in the tumor tissue of one patient after progressing on osimertinib. CONCLUSION: Our study provided valuable insights into the distribution and molecular characteristics of EGFR-LFD, hoping to shed light on the treatment management for EGFR-LFD carriers.
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Neoplasias Encefálicas , Glioblastoma , Neoplasias Pulmonares , Humanos , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Estudos Retrospectivos , Receptores ErbB/genética , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , MutaçãoRESUMO
BACKGROUND: Nasopharyngeal carcinoma (NPC) is a usual head and neck malignancy. Guggulsterone (GS) has potential in cancer chemoprophylaxis and treatment, but its therapeutic effect on NPC is unknown. We aimed to explore whether GS could promote the secretion of exosomal circFIP1L1 from NPC cells and its regulatory mechanism. METHODS: NPC tissues and adjacent tissues were collected from NPC patients. Human nasopharyngeal epithelial cell lines (NP69) and NPC lines (5-8F, CNE1, and HNE1) were used for in vitro experiments. HNE1 cells were treated with GS (20, 40, 60 µmol/L). The expressions of miR-125a-5p and circFIP1L1 were evaluated by qRT-PCR. Cell proliferation and apoptosis abilities were measured by CCK-8 and flow cytometry. HNE1 cell exosomes were extracted and identified, and the levels of VEGFA and VEGFR2 were detected by ELISA. Then miR-125a-5p was knocked down and overexpressed. HUVECs angiogenesis was determined by the tube formation assay. qRT-PCR and Western blot were utilized to evaluate the expressions of VEGFA, MMP-2, MMP-9, and ICAM-1 in HUVECs. RESULTS: miR-125a-5p was highly expressed in NPC tissues and cells. GS promoted the secretion of exosomal circFIP1L1 from HNE1 cells to affect HUVECs proliferation and angiogenesis. Overexpression of miR-125a-5p accelerated HUVECs proliferation and angiogenesis. Knocking down miR-125a- 5p inhibited VEGFA expression. In addition, exosomal circFIP1L1 sponged miR-125a-5p, inhibiting the VEGFA pathway to repress HUVECs angiogenesis. CONCLUSIONS: GS promoted exosomal circFIP1L1 in NPC cells to mediate miR-125a-5p/VEGFA axis affecting tumor angiogenesis.
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Exossomos , MicroRNAs , Neoplasias Nasofaríngeas , Humanos , Linhagem Celular Tumoral , Proliferação de Células , MicroRNAs/genética , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Fator A de Crescimento do Endotélio Vascular/genética , RNA Circular/efeitos dos fármacos , RNA Circular/genética , Exossomos/efeitos dos fármacos , Exossomos/genéticaRESUMO
Nasopharyngeal carcinoma (NPC) is one of the most frequent malignant tumors diagnosed in China. Cisplatin is one of the most commonly used anticancer drugs containing platinum in combined chemotherapy. The molecular mechanism of NPC is still largely unknown, and we aim to spare no effort to elucidate it. Normal human nasopharyngeal epithelial cells and NPC cell lines were cultured. The expression levels of miR-302c-5p and HSP90AA1 were detected with quantitative real-time PCR. Western blotting was used to analyze levels of the HSP90AA1, protein kinase B (AKT), p-AKT, CD44 and SOX2 proteins. The interaction between miR-302c-5p and HSP90AA1 was detected using a luciferase reporter assay. The bicinchoninic acid assay was used to observe cisplatin resistance in NPC cells. Our records confirmed that the expression of miR-302c-5p was substantially reduced and HSP90AA1 was increased in NPC cells. Additionally, miR-302c-5p inhibited cisplatin resistance and the traits of stem cells in NPC. A luciferase assay confirmed that miR-302c-5p is bound to HSP90AA1. Overexpression of HSP90AA1 may reverse the effects of overexpressed miR-302c-5p and inhibit cisplatin resistance and stem cell traits of NPC. This study investigated whether miR-302c-5p inhibited the AKT pathway by regulating HSP90AA1 expression and altered the resistance of NPC cells to cisplatin and the traits of tumor stem cells, which has not yet been reported.
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MicroRNAs , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Cisplatino/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Proliferação de Células , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP90/metabolismoRESUMO
Nasopharyngeal carcinoma (NPC) is a rare head and neck tumor that threatens people's health. Radiotherapy is a major treatment for NPC, however, radioresistance of the NPC cells may contribute to treatment failure. LncRNA SNHG16 was upregulated in NPC; however, the function of SNHG16 in radioresistant NPC cells remains unexplored. RT-qPCR was applied for detecting SNHG16, miR-31-5p and SFN levels. MTT assay and colony formation assay were applied to assess the cell viability and proliferation. Dual luciferase was applied for assessing the relation among SNHG16, miR-31-5p and SFN. SFN level in NPC cells was examined by Western blot. The level of SNHG16 and SFN in NPC cells was significantly upregulated by exposure to radiation. In addition, silencing of SNHG16 or miR-31-5p mimics notably attenuated radioresistance of NPC cells. SNHG16 could positively regulate the expression of SFN in NPC cells through binding with miR-31-5p. Furthermore, SNHG16 downregulation obviously attenuated the proliferation and radioresistance of NPC cells by regulation of miR-31-5p/SFN axis. Knockdown of lncRNA SNHG16 attenuates radioresistance of nasopharyngeal carcinoma cells by miR-31-5p/SFN axis. Thus, our research data show a novel method for improving the efficacy of radiotherapy for NPC.
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MicroRNAs , Neoplasias Nasofaríngeas , RNA Longo não Codificante , Humanos , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/patologia , RNA Longo não Codificante/genéticaRESUMO
BACKGROUND: Radiation is currently used to be a mainstay of salvage therapy for nasopharyngeal carcinoma (NPC), however, development of radioresistance largely limits the radiation efficacy. Circular RNAs (circRNAs) have been shown to affect NPC progression, but its role in radioresistance remain unclear. METHODS: The circular structure of circFIP1L1(circ_0069740) was verified by RNA-sequencing, RT-PCR based on gDNA or cDNA, RNase R treatment, and actinomycin D treatment. Cellular localization of circFIP1L1 and miR-1253 was detected by nucleoplasmic separation and/or fluorescence in situ hybridization. Expression of non-coding RNAs and mRNAs was detected by qRT-PCR, protein expression was detected by Western blot. Functionally, EdU, CCK-8, and colony formation experiments were employed to assess cell proliferation, flow cytometry was adopted to estimate cell cycle and apoptosis. Xenograft tumor growth was performed to detect the role of circFIP1L1 in vivo. Mechanistically, we examined the interplay between miR-1253 and circFIP1L1 or EIF4A3 through dual-luciferase reporter assay. The potential regulatory impacts of EIF4A3 on circFIP1L1 or PTEN was examined by RNA immunoprecipitation and RNA pull-down assays. RESULTS: CircFIP1L1 overexpression and miR-1253 knockdown repressed NPC cell proliferation, facilitated NPC cell apoptosis, and enhanced NPC radiosensitivity. Mechanistically, circFIP1L1 was revealed to repress miR-1253 by binding to it, and EIF4A3 is a target gene of miR-1253. CircFIP1L1 regulated NPC proliferation, apoptosis, and radiosensitivity through miR-1253/EIF4A3. Moreover, we found that EIF4A3 bound to FIP1L1 mRNA transcript and induced circFIP1L1 formation, and thus stabilizing PTEN mRNA. CONCLUSION: Our findings suggested that EIF4A3-induced circFIP1L1 repressed NPC cell proliferation, facilitated NPC cell apoptosis, and enhanced NPC radiosensitivity by miR-1253.
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MicroRNAs , Neoplasias Nasofaríngeas , Linhagem Celular Tumoral , Proliferação de Células/genética , RNA Helicases DEAD-box/genética , Fator de Iniciação 4A em Eucariotos/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , MicroRNAs/genética , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/radioterapia , RNA Mensageiro , Tolerância a Radiação/genéticaRESUMO
BACKGROUND: Nasopharyngeal carcinoma (NPC) is a rare malignancy with multiple risk factors (Epstein-Barr virus, etc.) that seriously threatens the health of people. CircRNAs are known to regulate the tumorigenesis of malignant tumours, including NPC. Moreover, circCRIM1 expression is reported to be upregulated in NPC. Nevertheless, the impact of circCRIM1 on NPC progression is not clear. METHODS: An MTT assay was performed to assess cell viability. In addition, cell invasion and migration were assessed by the transwell assay. Dual luciferase assays were performed to assess the association among circCRIM1, miR-34c-5p and FOSL1. Moreover, RT-qPCR was applied to assess mRNA levels, and protein levels were determined by Western blot. RESULTS: CircCRIM1 and FOSL1 were upregulated in NPC cells, while miR-34c-5p was downregulated. Knockdown of circCRIM1 significantly decreased the invasion, viability and migration of NPC cells. The miR-34c-5p inhibitor notably promoted the malignant behaviour of NPC cells, while miR-34c-5p mimics exerted the opposite effect. Moreover, circCRIM1 could bind with miR-34c-5p, and FOSL1 was identified to be downstream of miR-34c-5p. Furthermore, circCRIM1 downregulation notably inhibited the proliferation and invasion of NPC cells, while this phenomenon was significantly reversed by FOSL1 overexpression. CONCLUSION: Silencing circCRIM1 inhibited the tumorigenesis of NPC. Thus, circCRIM1 might be a novel target for NPC.
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Infecções por Vírus Epstein-Barr , MicroRNAs , Neoplasias Nasofaríngeas , RNA Circular/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Infecções por Vírus Epstein-Barr/genética , Regulação Neoplásica da Expressão Gênica , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologiaRESUMO
BACKGROUND: Dihydropyrimidinase like 2 (DPYSL2) has been linked to tumor metastasis. However, the function of DPSY2L in lung adenocarcinoma (LUAD) is yet to be explored. METHODS: Herein, we assessed DPYSL2 expression in various tumor types via online databases such as Oncomine and Tumor Immune Estimation Resource (TIMER). Further, we verified the low protein and mRNA expressions of DPYSL2 in LUAD via the ULCAN, The TCGA and GEPIA databases. We applied the ROC curve to examine the role of DPYSL2 in diagnosis. The prognostic significance of DPYSL2 was established through the Kaplan-Meier plotter and the Cox analyses (univariate and multivariate). TIMER was used to explore DPYSL2 expression and its connection to immune infiltrated cells. Through Gene Set Enrichment Analysis, the possible mechanism of DPYSL2 in LUAD was investigated. RESULTS: In this study, database analysis revealed lower DPYSL2 expression in LUAD than in normal tissues. The ROC curve suggested that expression of DPYSL2 had high diagnostic efficiency in LUAD. The DPYSL2 expression had an association with the survival time of LUAD patients in the Kaplan-Meier plotter and the Cox analyses. The results from TIMER depicted a markedly positive correlation of DPYSL2 expression with immune cells infiltrated in LUAD, such as macrophages, dendritic cells, CD4+ T cells, and neutrophils. Additionally, many gene markers for the immune system had similar positive correlations in the TIMER analysis. In Gene Set Enrichment Analysis, six immune-related signaling pathways were associated with DPYSL2. CONCLUSIONS: In summary, DPYSL2 is a novel biomarker with diagnostic and prognostic potential for LUAD as well as an immunotherapy target. HIGHLIGHTS: 1. Expression of DPYSL2 was considerably lower in LUAD than in normal tissues. 2. Investigation of multiple databases showed a high diagnostic value of DPYSL2 in LUAD. 3. DPYSL2 can independently predict the LUAD outcomes. 4. Immune-related mechanisms may be potential ways for DPYSL2 to play a role in LUAD.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Linfócitos do Interstício Tumoral , Prognóstico , Microambiente TumoralRESUMO
AIMS: Lung adenocarcinoma (LUAD) cells could escape from the monitoring of immune cells and metastasize rapidly through immune escape. Therefore, we aimed to develop a method to predict the prognosis of LUAD patients based on immune checkpoints and their associated genes, thus providing guidance for LUAD treatment. METHODS: Gene sequencing data were downloaded from the Cancer Genome Atlas (TCGA) and analyzed by R software and R Bioconductor software package. Based on immune checkpoint genes, kmdist clustering in ConsensusClusterPlus R software package was utilized to classify LUAD. CIBERSORT was used to quantify the abundance of immune cells in LUAD samples. LM22 signature was performed to distinguish 22 phenotypes of human infiltrating immune cells. Gene set variation analysis (GSVA) was performed on immune checkpoint cluster and immune checkpoint score using GSVA R software package. The risk score was calculated by LASSO regression coefficient. Gene Ontology (GO), Hallmark, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed. PROC was performed to generate the ROC curve and calculate the area under the curve (AUC). RESULTS: According to the immune checkpoint, LUAD was classified into clusters 1 and 2. Survival rate, immune infiltration patterns, TMB, and immune score were significantly different between the two clusters. Functional prediction showed that the functions of cluster 1 focused on apoptosis, JAK/STAT signaling pathway, TNF-α/NFκB signaling pathway, and STAT5 signaling pathway. The risk score model was constructed based on nine genes associated with immune checkpoints. Survival analysis and ROC analysis showed that patients with high-risk score had poor prognosis. The risk score was significantly correlated with cancer status (with tumor), male proportion, status, tobacco intake, and cancer stage. With the increase of the risk score, the enrichment of 22 biological functions increased, such as p53 signaling pathway. The signature was verified in IMvigor immunotherapy dataset with excellent diagnostic accuracy. CONCLUSION: We established a nine-gene signature based on immune checkpoints, which may contribute to the diagnosis, prognosis, and clinical treatment of LUAD.
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BACKGROUND: Gastric cancer (GC) is a malignant tumour originating from the gastric mucosa epithelium that seriously threatens human health. DCLK1, miR-15b and lncRNA SNHG1 play potential roles in the occurrence of GC, but the mechanism remains unclear. METHODS: Gene expression of DCLK1, miR-15b and lncRNA SNHG1 was investigated by qRT-PCR. Protein expression was detected by Western blotting. Migration and invasion of gastric cancer cells was tested by a Transwell assay and wound healing assay. Cell proliferation was measured by an MTT assay. Finally, the correctness of the prediction results was confirmed by a dual-luciferase reporter assay. RESULTS: The expression of DCLK1, Notch1, and SNHG1 was increased in GC tissues, while the expression of miR-15b was decreased. Overexpression of lncRNA SNHG1 promoted the expression of DCLK1 and Nothc1 in GC cells. Moreover, miR-15b targeted DCLK1 to regulate Notch1 expression and inhibited the EMT process in GC cells. SNHG1 enhanced the effects of DCLK1/Notch1 on the EMT process through regulating miR-15b expression. CONCLUSION: SNHG1 enhances the EMT process in GC cells through DCLK1-mediated Notch1 pathway, which can be a potential target for treating GC.
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Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs/genética , Proteínas Serina-Treonina Quinases/genética , RNA Longo não Codificante/genética , Receptor Notch1/genética , Neoplasias Gástricas/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Quinases Semelhantes a Duplacortina , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND: Increasing evidence indicates that the dysregulation of miRNAs plays a vital role in tumorigenesis and progression of nasopharyngeal carcinoma (NPC). Thus, it is necessary to further investigate the function and mechanism of miRNAs in NPC. METHODS: miR-100 expression was analyzed using publicly available databases and then tested using quantitative RT-PCR in NPC tissues and cell lines. MTT and colony formation assays and xenograft tumor model were used to test the NPC cell growth and proliferation abilities while modulating miR-100 expression. The target of miR-100 was predicted with TargetScan and validated with luciferase reporter assay, quantitative RT-PCR, and Western blot. RESULTS: The expression of miR-100 was significantly reduced in NPC tissues and cell lines. Overexpression of miR-100 obviously suppressed NPC cell growth and proliferation, whereas silencing miR-100 promoted NPC cell growth and proliferation in vitro. HOXA1 (homeobox A1) was validated as a direct target of miR-100, and restoring HOXA1 expression could reverse the inhibitive effect of miR-100 on NPC cell growth and proliferation. The mRNA and protein expression of HOXA1 was increased in NPC cell lines. Furthermore, ectopic expression of miR-100 inhibited xenograft tumor growth in vivo. CONCLUSION: Taken together, our findings suggest that miR-100 could suppress NPC growth and proliferation through targeting HOXA1, providing a novel target for the miRNA-mediated therapy for patients with NPC in the future.
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BACKGROUND: Recently research reported that miR-185-3p could serve as an independent prognosis factor in gastric cancer (GC). However, the functional role and underlying mechanism of miR-185-3p in GC and epithelial-mesenchymal transition (EMT) progression remains largely elusive. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to analyze the expression of miR-185-3p and cathepsin D in patient-derived GC samples and various GC cell lines. Scratch assay and Transwell assay were used to evaluate the migration ability. The influence of miR-185-3p on the cell cycle distribution and cell apoptosis was evaluated using flow cytometry. Western blotting assay was performed to detect the expression of EMT associated proteins and the activity of PI3K/Akt signaling pathway. Furthermore, the interaction between miR-185-3p and cathepsin D was explored by dual-luciferase reporter assay. RESULTS: Our data revealed that miR-185-3p was down-regulated, while cathepsin D was up-regulated in both patient-derived GC samples and GC cells. Apart from inducing apoptosis, overexpression of miR-185-3p also inhibited EMT process and migration of GC cells. Mechanically, we firstly verified that miR-185-3p directly targeted the cathepsin D. Furthermore, miR-185-3p exerted its function on EMT process and migration via inhibiting cathepsin D to mediated PI3K/Akt signaling pathway. CONCLUSIONS: Our findings suggested that miR-185-3p targeted cathepsin D inhibiting EMT process via PI3K/Akt signaling, which may serve as a potential prognosis factor and therapeutic target to reduce the malignancy of GCs.
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Bird predation during seed maturation causes great loss to agricultural production. In this study, through GWAS analysis of a large-scale sorghum germplasm diversity panel, we identified that Tannin1, which encodes a WD40 protein functioning in the WD40/MYB/bHLH complex, controls bird feeding behavior in sorghum. Metabolic profiling analysis showed that a group of sorghum accessions preferred by birds contain mutated tan1-a/b alleles and accumulate significantly lower levels of anthocyanins and condensed tannin compounds. In contrast, a variety of aromatic and fatty acid-derived volatiles accumulate at significantly higher levels in these bird-preference accessions. We subsequently conducted both sparrow feeding and sparrow volatile attractant assays, which confirmed, respectively, the antifeedant and attractant functions of these differentially accumulated metabolites. In addition, the connection between the biosynthesis pathway of anthocyanin and proanthocyanidin and the pathway of fatty acid-derived volatile biosynthesis was demonstrated by discovering that Tannin1 complex modulates fatty acid biosynthesis by regulating the expression of SbGL2 in sorghum, thus affecting the accumulation of fatty acid-derived volatiles. Taken together, our study identified Tannin1 as the gene underlying the major locus controlling bird feeding behavior in sorghum, illustrating an example of the identification of an ecologically impactful molecular mechanism from field observation and providing significant insights into the chemistry of bird-plant ecological interactions.
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Aves , Ácidos Graxos/química , Comportamento Alimentar , Proteínas de Plantas/metabolismo , Polifenóis/biossíntese , Sorghum/metabolismo , Compostos Orgânicos Voláteis/metabolismo , Animais , Comportamento Alimentar/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Comportamento Predatório/efeitos dos fármacos , Sorghum/genética , Compostos Orgânicos Voláteis/química , Compostos Orgânicos Voláteis/farmacologiaRESUMO
OBJECTIVE: To investigate the clinical efficacy of stereotactic radiation therapy combined with temozolomide on recurrent glioma.â© Methods: A total of 36 patients with recurrent glioma were retrospectively analyzed and divided into a control group (n=12), who received stereotactic radiation therapy, and an experimental group (n=24), who received stereotactic radiation therapy plus temozolomide. The clinical efficacy and adverse reactions for the 2 groups were compared.â© Results: Total effective rate and local control rate for clinical treatment were 66.67% and 93.94%, respectively. Late adverse reaction was not observed. The effective rate and local control rate in the experimental group were 77.27% and 95.45%, which were slight higher than those in the control group, with no statistical significance (P>0.05). The 0.5-, 1-, 2-, 3-year follow-up total survival rates were 90.91%, 63.64%, 42.42%, and 15.15%, respectively. The 0.5-, 1-, 2-, 3-year follow-up survival rates in the experimental group were 95.45%, 72.72%, 54.54% and 22.73%, respectively, while those in the control group were 81.82%, 45.45%, 18.18%, and 0%, respectively. Survival analysis showed the survival time for the experimental group was significantly longer than that of the control group (30.00 months vs 14.00 months, P=0.010).â© Conclusion: Stereotactic radiation therapy combined with temozolomide for recurrent glioma is effective, and it has positive effect on improving the clinical efficacy and survival rate for the patients.
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Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Dacarbazina/análogos & derivados , Glioma/terapia , Recidiva Local de Neoplasia/terapia , Radiocirurgia/métodos , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Encefálicas/mortalidade , Quimiorradioterapia/efeitos adversos , Terapia Combinada , Dacarbazina/efeitos adversos , Dacarbazina/uso terapêutico , Glioma/mortalidade , Humanos , Radiocirurgia/efeitos adversos , Estudos Retrospectivos , Taxa de Sobrevida , Temozolomida , Resultado do TratamentoRESUMO
Plant hormones ethylene and auxin synergistically regulate plant root growth and development. Ubiquitin-mediated proteolysis of Aux/IAA transcriptional repressors by the E3 ubiquitin ligase SCFTIR1/AFB triggers a transcription-based auxin signaling. Here we show that rice (Oryza sativa L.) soil-surface rooting 1 (SOR1), which is a RING finger E3 ubiquitin ligase identified from analysis of a rice ethylene-insensitive mutant mhz2/sor1-2, controls root-specific ethylene responses by modulating Aux/IAA protein stability. SOR1 physically interacts with OsIAA26 and OsIAA9, which are atypical and canonical Aux/IAA proteins, respectively. SOR1 targets OsIAA26 for ubiquitin/26S proteasome-mediated degradation, whereas OsIAA9 protects the OsIAA26 protein from degradation by inhibiting the E3 activity of SOR1. Auxin promotes SOR1-dependent degradation of OsIAA26 by facilitating SCFOsTIR1/AFB2-mediated and SOR1-assisted destabilization of OsIAA9 protein. Our study provides a candidate mechanism by which the SOR1-OsIAA26 module acts downstream of the OsTIR1/AFB2-auxin-OsIAA9 signaling to modulate ethylene inhibition of root growth in rice seedlings.
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Proteínas de Ligação a DNA/metabolismo , Etilenos/metabolismo , Oryza/metabolismo , Proteínas de Plantas/metabolismo , Raízes de Plantas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas de Ligação a DNA/genética , Ácidos Indolacéticos/metabolismo , Oryza/genética , Proteínas de Plantas/genética , Raízes de Plantas/genética , Plântula/genética , Plântula/metabolismo , Transdução de Sinais/fisiologia , Ubiquitina-Proteína Ligases/genéticaRESUMO
High-fat diets (HFDs) and excess adiposity increase proinflammatory cytokines in the colon, altering gene expression in a manner that promotes the development of colorectal cancer (CRC). Thus, compounds that reduce this biochemical inflammation are potential chemopreventive agents. Curcumin (CUR), a dietary polyphenol, and salsalate (SAL), a non-steroidal anti-inflammatory drug, are both anti-inflammatories. We investigated the inhibitory effects of CUR with or without SAL on inflammatory cytokines and procarcinogenic signaling in azoxymethane (AOM)-treated A/J mice. A sub-tumorigenic AOM dose was chosen to produce a biochemical and molecular procarcinogenic colonic environment without tumors. Mice were fed either a HFD (60% of kilocalories) or low-fat diet (LFD) (10% of kilocalories). One HFD treatment group received 0.2% CUR in the diet; one received 0.2% CUR + 0.15% SAL; and one received 0.4% CUR + 0.3% SAL. The HFD mice developed 30% greater fat mass than the LFD mice (p < 0.05). The colonic concentrations of interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in the HFD mice were decreased by 50-69% by the high-dose combination regimen (p < 0.015). Only the combination regimens significantly suppressed phosphorylation of protein kinase B (Akt) and nuclear factor-κB (NF-κB) p65 (p < 0.044). The combination of CUR and SAL reduces the concentration of proinflammatory cytokines and diminishes activation of Akt and NF-κB more effectively than CUR alone, providing a scientific basis for examining whether this combination mitigates the risk of CRC in obese individuals.
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Neoplasias Colorretais/tratamento farmacológico , Curcumina/administração & dosagem , Salicilatos/administração & dosagem , Animais , Anti-Inflamatórios , Azoximetano/efeitos adversos , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Dieta Hiperlipídica/efeitos adversos , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , NF-kappa B/genética , NF-kappa B/imunologiaRESUMO
Following the detection of pathogen cognate effectors, plant Nod-like receptors (NLRs) trigger isolate-specific immunity that is generally associated with cell death. The regulation of NLR stability is important to ensure effective immunity. In barley (Hordeum vulgare), the allelic Mildew locus A (MLA) receptors mediate isolate-specific disease resistance against powdery mildew fungus (Blumeria graminis f. sp. hordei). Currently, how MLA stability is controlled remains unknown. Here, we identified an MLA-interacting RING-type E3 ligase, MIR1, that interacts with several MLAs. We showed that the carboxyl-terminal TPR domain of MIR1 mediates the interaction with the coiled-coil domain-containing region of functional MLAs, such as MLA1, MLA6, and MLA10, but not with that of the nonfunctional MLA18-1. MIR1 can ubiquitinate the amino-terminal region of MLAs in vitro and promotes the proteasomal degradation of MLAs in vitro and in planta. Both proteasome inhibitor treatment and virus-induced gene silencing-mediated MIR1 silencing significantly increased MLA abundance in barley transgenic lines. Furthermore, overexpression of MIR1 specifically compromised MLA-mediated disease resistance in barley, while coexpression of MIR1 and MLA10 attenuated MLA10-induced cell death signaling in Nicotiana benthamiana Together, our data reveal a mechanism for the control of the stability of MLA immune receptors and for the attenuation of MLA-triggered defense signaling by a RING-type E3 ligase via the ubiquitin proteasome system.
Assuntos
Ascomicetos/fisiologia , Hordeum/enzimologia , Hordeum/microbiologia , Doenças das Plantas/imunologia , Imunidade Vegetal , Proteínas de Plantas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Morte Celular , Resistência à Doença , Loci Gênicos , Hordeum/imunologia , Doenças das Plantas/microbiologia , Proteínas de Plantas/química , Plantas Geneticamente Modificadas , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Proteólise , UbiquitinaçãoRESUMO
Early epidemiologic studies have reported that tobacco smoking, which is causally associated with liver cancer, is an independent risk factor for non-alcoholic fatty liver diseases (NAFLD). Lycopene from tomatoes has been shown to be a potential preventive agent against NAFLD and hepatocellular carcinoma (HCC). In the present study, we investigated whether the tobacco carcinogen 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces lesions in both lungs and livers of ferrets with or without lycopene intervention. Male ferrets (6 groups, n = 8-10) were treated either with NNK (50 mg/kg BW, i.p., once a month for four consecutive months) or saline with or without dietary lycopene supplementation (2.2 and 6.6 mg/kg BW/day, respectively) for 26 weeks. Results demonstrate that NNK exposure results in higher incidences of lung tumors, HCC and steatohepatitis (which is characterized by severe inflammatory cell infiltration with concurrent fat accumulation in liver, hepatocellular ballooning degeneration and increased NF-κB expression), as well as elevations in bilirubin and AST levels in ferrets. Lycopene supplementation at two doses prevented NNK-induced expressions of α7 nicotinic acetylcholine receptor in the lung and NF-κB and CYP2E1 in the liver and attenuated the NNK-induced mortality and pathological lesions in both the lungs and livers of ferrets. The present study provided strong experimental evidence that the tobacco carcinogen NNK can induce both HCC and steatohepatitis in the ferrets and can be a useful model for studying tobacco carcinogen-associated NAFLD and liver cancer. Furthermore, lycopene could provide potential benefits against smoke carcinogen-induced pulmonary and hepatic injury.
Assuntos
Anticarcinógenos/administração & dosagem , Carcinógenos/toxicidade , Carotenoides/administração & dosagem , Neoplasias/induzido quimicamente , Neoplasias/prevenção & controle , Nicotiana/química , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Biomarcadores , Peso Corporal/efeitos dos fármacos , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/prevenção & controle , Carotenoides/farmacocinética , Furões , Testes de Função Hepática , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/prevenção & controle , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/prevenção & controle , Licopeno , Masculino , Neoplasias/mortalidade , Neoplasias/patologia , Hepatopatia Gordurosa não Alcoólica/mortalidade , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
During the life cycle of a plant, one of the major biological processes is the transition from the vegetative to the reproductive stage. In Arabidopsis, flowering time is precisely controlled by extensive environmental and internal cues. Gibberellins (GAs) promote flowering, while abscisic acid (ABA) is considered as a flowering suppressor. However, the detailed mechanism through which ABA inhibits the floral transition is poorly understood. Here, we report that ABSCISIC ACID-INSENSITIVE 4 (ABI4), a key component in the ABA signalling pathway, negatively regulates floral transition by directly promoting FLOWERING LOCUS C (FLC) transcription. The abi4 mutant showed the early flowering phenotype whereas ABI4-overexpressing (OE-ABI4) plants had delayed floral transition. Consistently, quantitative reverse transcription-PCR (qRT-PCR) assay revealed that the FLC transcription level was down-regulated in abi4, but up-regulated in OE-ABI4. The change in FT level was consistent with the pattern of FLC expression. Chromatin immunoprecipitation-qPCR (ChIP-qPCR), electrophoretic mobility shift assay (EMSA), and tobacco transient expression analysis showed that ABI4 promotes FLC expression by directly binding to its promoter. Genetic analysis demonstrated that OE-ABI4::flc-3 could not alter the flc-3 phenotype. OE-FLC::abi4 showed a markedly delayed flowering phenotype, which mimicked OE-FLC::WT, and suggested that ABI4 acts upstream of FLC in the same genetic pathway. Taken together, these findings suggest that ABA inhibits the floral transition by activating FLC transcription through ABI4.
Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/genética , Regulação da Expressão Gênica de Plantas , Proteínas de Domínio MADS/genética , Fatores de Transcrição/genética , Ácido Abscísico/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Flores/crescimento & desenvolvimento , Proteínas de Domínio MADS/metabolismo , Fatores de Transcrição/metabolismoRESUMO
OBJECTIVE: To find the largest screw path in the acetabular anterior column using a novel method of axial perspective and test the clinical feasibility of the anterior column axial view projection. METHODS: 3D models with the inner triangular patches deleted were created from the pelvic CT scan data of 58 normal pelvises. The transparency of each 3D model was downgraded at the axial perspective (the view perpendicular to the cross section of the anterior column axis) so that a translucent area was seen clearly. The orientations of each 3D model were adjusted until a triangle-like translucent area that could accommodate the largest virtual screw (Screw I) was present and then an ellipse-like translucent area that could accommodate the two largest virtual screws (Screw II) was present. The maximum diameter, direction of Screw I and the maximum diameter Screw II were measured. Clinical feasibility of the axial view projection was next tested in five cadaveric specimens. RESULTS: The mean maximum diameters of Screw I and Screw II were 11.20 ± 1.73 (7.80-14.60 mm) and 8.71 ± 0.91 (6.60-10.60 mm), respectively. The angles of Screw I to the transverse, coronal and sagittal planes were 41.16° ± 4.59°, 18.18° ± 1.15° and 44.33° ± 4.31°, respectively. Translucent areas were successfully observed in all the cadaveric hemi-pelves and guide pins were successfully inserted in all the cadaveric hemi-pelves with the assistance of the anterior column axial view projection without cortex penetration or joint violation. CONCLUSIONS: The acetabular anterior column could safely accommodate not only one 7.3-mm screw, but also two 6.5-mm screws. The anterior column axial projection may be clinically feasible.
Assuntos
Acetábulo/diagnóstico por imagem , Parafusos Ósseos , Fixação Interna de Fraturas/métodos , Fraturas Ósseas/diagnóstico por imagem , Pelve/diagnóstico por imagem , Acetábulo/lesões , Acetábulo/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Fraturas Ósseas/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Pelve/lesões , Pelve/cirurgia , Tomografia Computadorizada por Raios X/métodos , Adulto JovemRESUMO
miR-185 has been identified as an important factor in several cancers such as breast cancer, ovarial cancer, and prostate cancer. However, its effect and prognostic value in gastric cancer are still poorly known. In this study, we found that the expression levels of miR-185 were strongly downregulated in gastric cancer and associated with clinical stage and the presence of lymph node metastases. Moreover, miR-185 might independently predict OS and RFS in gastric cancer. We further found that upregulation of miR-185 inhibited the proliferation and metastasis of gastric cancer cells in vitro and in vivo. Taken together, our findings demonstrate that the miR-185 is important for gastric cancer initiation and progression and holds promise as a prognostic biomarker to predict survival and relapse in gastric cancer. It is also a potential therapeutic tool to improve clinical outcomes in the above disease.