262 results on '"Wuguo Deng"'
Search Results
2. FLI1 promotes IFN-γ-induced kynurenine production to impair anti-tumor immunity
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Enni Chen, Jiawei Wu, Jiajia Huang, Wancui Zhu, Haohui Sun, Xiaonan Wang, Dagui Lin, Xiaodi Li, Dingbo Shi, Zhiqiao Liu, Jinsheng Huang, Miao Chen, Fangyun Xie, and Wuguo Deng
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Science - Abstract
Abstract Nasopharyngeal carcinoma (NPC)-mediated immunosuppression within the tumor microenvironment (TME) frequently culminates in the failure of otherwise promising immunotherapies. In this study, we identify tumor-intrinsic FLI1 as a critical mediator in impairing T cell anti-tumor immunity. A mechanistic inquiry reveals that FLI1 orchestrates the expression of CBP and STAT1, facilitating chromatin accessibility and transcriptional activation of IDO1 in response to T cell-released IFN-γ. This regulatory cascade ultimately leads to augmented IDO1 expression, resulting in heightened synthesis of kynurenine (Kyn) in tumor cells. This, in turn, fosters CD8+ T cell exhaustion and regulatory T cell (Treg) differentiation. Intriguingly, we find that pharmacological inhibition of FLI1 effectively obstructs the CBP/STAT1-IDO1-Kyn axis, thereby invigorating both spontaneous and checkpoint therapy-induced immune responses, culminating in enhanced tumor eradication. In conclusion, our findings delineate FLI1-mediated Kyn metabolism as an immune evasion mechanism in NPC, furnishing valuable insights into potential therapeutic interventions.
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- 2024
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3. TERC promotes non-small cell lung cancer progression by facilitating the nuclear localization of TERT
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Haohui Sun, Xiaodi Li, Qian Long, Xiaonan Wang, Wancui Zhu, Enni Chen, Wenhao Zhou, Han Yang, Chuyang Huang, Wuguo Deng, and Miao Chen
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cancer ,cell biology ,molecular biology ,Science - Abstract
Summary: The core of telomerase consists of the protein subunit telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC). So far, the role of TERC in cancer development has remained elusive. Here, we found TERC expression elevated in non-small cell lung cancer (NSCLC) tissues, which was associated with disease progression and poor prognosis in patients. Using NSCLC cell lines and xenograft models, we showed that knockdown of TERC caused cell cycle arrest, and inhibition of cell proliferation and migration. Mechanistically, TERC was exported to the cytoplasm by nuclear RNA export factor 1 (NXF1), where it mediated the interaction of TERT with other telomerase subunits. Depletion of TERC hindered the assembly and subsequent nuclear localization of the telomerase complex, preventing TERT from functioning in telomere maintenance and transcription regulation. Our findings suggest that TERC is a potential biomarker for NSCLC diagnosis and prognosis and can be a target for NSCLC treatment.
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- 2024
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4. Neurotransmitter receptor-related gene signature as potential prognostic and therapeutic biomarkers in colorectal cancer
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Linjie Zhang, Yizhang Deng, Jingbang Yang, Wuguo Deng, and Liren Li
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colorectal cancer ,neurotransmitter receptor ,TCGA ,prognosis ,biomarker ,immune infiltration ,Biology (General) ,QH301-705.5 - Abstract
Background: Colorectal cancer is one of the most common malignant tumors worldwide. A various of neurotransmitter receptors have been found to be expressed in tumor cells, and the activation of these receptors may promote tumor growth and metastasis. This study aimed to construct a novel neurotransmitter receptor-related genes signature to predict the survival, immune microenvironment, and treatment response of colorectal cancer patients.Methods: RNA-seq and clinical data of colorectal cancer from The Cancer Genome Atlas database and Gene Expression Omnibus were downloaded. Neurotransmitter receptor-related gene were collected from publicly available data sources. The Weighted Gene Coexpression Network Analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression, Support Vector Machine-Recursive Feature Elimination (SVM-RFE), and Random Forest (RF) algorithms were employed to construct the Neurotransmitter receptor-related gene prognostic signature. Further analyses, functional enrichment, CIBERSORTx, The Tumor Immune Single Cell Center (TISCH), survival analysis, and CellMiner, were performed to analyze immune status and treatment responses. Quantitative real-time polymerase chain reaction (qRT-PCR) assays were carried out to confirm the expression levels of prognostic genes.Results: By combining machine learning algorithm and WGCNA, we identified CHRNA3, GABRD, GRIK3, and GRIK5 as Neurotransmitter receptor-related prognostic genes signature. Functional enrichment analyses showed that these genes were enriched with cellular metabolic-related pathways, such as organic acid, inorganic acid, and lipid metabolism. CIBERSORTx and Single cell analysis showed that the high expression of genes were positively correlated with immunosuppressive cells infiltration, and the genes were mainly expressed in cancer-associated fibroblasts and endothelial cells. A nomogram was further built to predict overall survival (OS). The expression of CHRNA3, GABRD, GRIK3, and GRIK5 in cancer cells significantly impacted their response to chemotherapy.Conclusion: A neurotransmitter receptor-related prognostic gene signature was developed and validated in the current study, giving novel sights of neurotransmitter in predicting the prognostic and improving the treatment of CRC.
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- 2023
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5. Computational profiling and prognostic modeling based on lysosome-related genes in colorectal cancer
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Linjie Zhang, Jingbang Yang, Yizhang Deng, Wuguo Deng, and Liren Li
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colorectal cancer ,lysosome related genes ,immunotherapy ,TME ,bioinformatic ,Genetics ,QH426-470 - Abstract
Background: Despite significant advances over the past decade, patients diagnosed with advanced colorectal cancer (CRC) continue to face unfavorable prognoses. Recent studies have underscored the pivotal role of lysosomes in tumor development and progression. This led us to postulate and develop a novel lysosomal-centric model for predicting CRC risk and therapeutic response.Methods: CRC tissue samples were sourced from the TCGA database, while lysosome-associated genes were collated from the GSEA database. Differentially expressed lysosome-related genes (DE-LRGs) were discerned by contrasting tumor samples with normal tissue. Based on the expression profile of DE-LRGs, patients were stratified into two distinct clusters. Survival disparities between the clusters were delineated using Kaplan-Meier estimators. For tumor microenvironment assessment, we employed ESTIMATE and ssGSEA. Functional pathway enrichment was ascertained using both GSVA and GSEA. Subsequent uni- and multi-variate Cox regression analyses pinpointed risk-associated DE-LRGs. Leveraging these genes, we constructed a novel risk prediction model and derived risk scores. The model’s prognostic capability was externally validated using dataset GSE39084. The mutational landscape across risk categories was evaluated using the Maftools algorithm. The potential efficacy of targeted and immunotherapeutic interventions for each patient cohort was gauged using pRRophetic, CYT, and IMvigor210.Results: We identified 46 DE-LRGs. Tumor Immune MicroEnvironment (TIME) assessment revealed that cluster 2 patients exhibited elevated ESTIMATE, Immunocore, and stromal scores, yet diminished tumor purity relative to cluster 1. Notable differences in immune cell infiltration patterns were observed between clusters, and distinct pathway enrichments were evident. Cluster 2 manifested a pronounced expression of immune checkpoint-related genes. Four DE-LRGs (ATP6V0A4, GLA, IDUA, and SLC11A1) were deemed critical for risk association, leading to the formulation of our novel risk model. The model exhibited commendable predictive accuracy, which was corroborated in an external validation cohort. A palpable survival advantage was observed in high-TMB, low-risk subgroups. Moreover, the low-risk cohort displayed heightened sensitivity to both targeted and immunotherapeutic agents.Conclusion: Our findings underscore the potential of lysosome-associated genes as robust prognostic and therapeutic response markers in CRC patients.
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- 2023
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6. Single-stage transplantation combined with epidermal stem cells promotes the survival of tissue-engineered skin by inducing early angiogenesis
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Zhiyong Wang, Hailin Xu, Hao Yang, Yi Zhang, Xiaoyan Wang, Peng Wang, Zhongye Xu, Dongming Lv, Yanchao Rong, Yunxian Dong, Bing Tang, Zhicheng Hu, Wuguo Deng, and Jiayuan Zhu
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Epidermal stem cells ,Acellular dermal matrix ,Tissue-engineered skin ,Vascularization ,Angiogenesis ,Medicine (General) ,R5-920 ,Biochemistry ,QD415-436 - Abstract
Abstract Background The composite transplantation of a split-thickness skin graft (STSG) combined with an acellular dermal matrix (ADM) is a promising repair method for full-thickness skin defects. Due to delayed vascularization of the ADM, no currently available engineered skin tissue is able to permanently cover full-thickness skin defects via a single-stage procedure. Epidermal stem cells (EpSCs) have been found to promote angiogenesis in the wound bed. Whether EpSCs can induce early angiogenesis of dermal substitutes and promote the survival of single-stage tissue-engineered skin transplantation needs to be further studied. Methods In vitro, rat vascular endothelial cells (RVECs) were treated with the supernatant of EpSCs cultured in ADM and stimulated for 48 h. RVECs were analysed by RNA sequencing and tube formation assays. For the in vivo experiment, 75 rats were randomly divided into five groups: ADM, ADM + EpSCs (AE), STSG, ADM + STSG (AS), and ADM + STSG + EpSCs (ASE) groups. The quality of wound healing was estimated by general observation and H&E and Masson staining. The blood perfusion volume was evaluated using the LDPI system, and the expression of vascular markers was determined by immunohistochemistry (IHC). Results The active substances secreted by EpSCs cultured in ADM promoted angiogenesis, as shown by tube formation experiments and RNA-seq. EpSCs promoted epithelialization of the ADM and vascularization of the ADM implant. The ASE group showed significantly increased skin graft survival, reduced skin contraction, and an improved cosmetic appearance compared with the AS group and the STSG control group. Conclusions In summary, our findings suggest that EpSCs promote the formation of new blood vessels in dermal substitutes and support one-step transplantation of tissue-engineered skin, and thereby provide new ideas for clinical application.
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- 2023
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7. FLI1 regulates radiotherapy resistance in nasopharyngeal carcinoma through TIE1-mediated PI3K/AKT signaling pathway
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Enni Chen, Jiajia Huang, Miao Chen, Jiawei Wu, Puyun Ouyang, Xiaonan Wang, Dingbo Shi, Zhiqiao Liu, Wancui Zhu, Haohui Sun, Shanshan Yang, Baoyu Zhang, Wuguo Deng, Huijuan Qiu, and Fangyun Xie
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FLI1 ,TIE1 ,Nasopharyngeal carcinoma (NPC) ,Radiotherapy resistance ,Medicine - Abstract
Abstract Background Radiotherapy resistance is the main cause of treatment failure in nasopharyngeal carcinoma (NPC), which leads to poor prognosis. It is urgent to elucidate the molecular mechanisms underlying radiotherapy resistance. Methods RNA-seq analysis was applied to five paired progressive disease (PD) and complete response (CR) NPC tissues. Loss-and gain-of-function assays were used for oncogenic function of FLI1 both in vitro and in vivo. RNA-seq analysis, ChIP assays and dual luciferase reporter assays were performed to explore the interaction between FLI1 and TIE1. Gene expression with clinical information from tissue microarray of NPC were analyzed for associations between FLI1/TIE1 expression and NPC prognosis. Results FLI1 is a potential radiosensitivity regulator which was dramatically overexpressed in the patients with PD to radiotherapy compared to those with CR. FLI1 induced radiotherapy resistance and enhanced the ability of DNA damage repair in vitro, and promoted radiotherapy resistance in vivo. Mechanistic investigations showed that FLI1 upregulated the transcription of TIE1 by binding to its promoter, thus activated the PI3K/AKT signaling pathway. A decrease in TIE1 expression restored radiosensitivity of NPC cells. Furthermore, NPC patients with high levels of FLI1 and TIE1 were correlated with poor prognosis. Conclusion Our study has revealed that FLI1 regulates radiotherapy resistance of NPC through TIE1-mediated PI3K/AKT signaling pathway, suggesting that targeting the FLI1/TIE1 signaling pathway could be a potential therapeutic strategy to enhance the efficacy of radiotherapy in NPC.
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- 2023
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8. The prognostic value and immune correlation of IL18 expression and promoter methylation in renal cell carcinoma
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Xiaonan Wang, Wancui Zhu, Qian Long, Enni Chen, Haohui Sun, Xiaodi Li, Hailin Xu, Weizhao Li, Pei Dong, Liru He, Miao Chen, and Wuguo Deng
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Renal cell carcinoma (RCC) ,IL18 ,DNA methylation ,Epigenetic biomarker ,Tumor immune cell infiltration ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Renal cell carcinoma (RCC) is not sensitive to immunotherapy and has poor prognosis. DNA methylation regulates gene expression, and its abnormal changes are related to many human diseases. Recently, DNA methylation has been found to participate in immune infiltration in various cancers. However, its pattern in RCC remains poorly understood. Results We found that IL18 was significantly over-expressed in RCC tumor tissues compared to normal adjacent tissues The IL18 promoter region was hypomethylated, which was strongly correlated with elevated IL18 mRNA expression, and predicted advanced clinicopathological characteristics and shorter overall survival. Furthermore, we found that IL18 promoter methylation was significantly related to the down-regulation of immune checkpoint molecules and increase of CD8 + T cell infiltration in RCC tumor tissues. Conclusions We have identified the important role of IL18 promoter methylation and expression, which are associated with clinicopathological characteristics, overall survival, immune cell infiltration and expression of immune checkpoint molecules in RCC. We present the rationale for IL18 promoter methylation as a molecular biomarker for predicting the response of RCC to immune checkpoint inhibitors.
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- 2023
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9. A novel TOX3-WDR5-ABCG2 signaling axis regulates the progression of colorectal cancer by accelerating stem-like traits and chemoresistance.
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Jiaojiao Hao, Jinsheng Huang, Chunyu Hua, Yan Zuo, Wendan Yu, Xiaojun Wu, Liren Li, Guoqing Xue, Xinyu Wan, Liyuan Ru, Ziyue Guo, Shilong Han, Wuguo Deng, Fei Lin, and Wei Guo
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Biology (General) ,QH301-705.5 - Abstract
The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem-like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up-regulated in CRC CSCs (cCSCs) expansion and chemo-resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to -261 to -141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri-methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem-like traits and chemoresistance to CRC by co-regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo-resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3-WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem-like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2-deregulated tumors.
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- 2023
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10. Prognostic value and immune landscapes of TERT promoter methylation in triple negative breast cancer
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Fei Lin, Jiajia Huang, Wancui Zhu, Tongchao Jiang, Jia Guo, Wen Xia, Miao Chen, Ling Guo, Wuguo Deng, and Huanxin Lin
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triple negative breast cancer (TNBC) ,telomerase reverse transcriptase (TERT) ,methylation ,prognostic value ,immune infiltration ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundTreatment options for patients with triple-negative breast cancer (TNBC) remain limited to mainstay therapies owing to a lack of efficacious therapeutic targets. Accordingly, there is an urgent need to discover and identify novel molecular targets for the treatment and diagnosis of this disease. In this study, we analyzed the correlation of telomerase reverse transcriptase (TERT) methylation status with TERT expression, prognosis, and immune infiltration in TNBC and identified the role of TERT methylation in the regulation TNBC prognosis and immunotherapy.MethodsData relating to the transcriptome, clinicopathological characteristics and methylation of TNBC patients were obtained from The Cancer Genome Atlas (TCGA) database. TERT expression levels and differential methylation sites (DMSs) were detected. The correlations between TERT expression and DMSs were calculated. Kaplan–Meier curves was plotted to analyze the relationship between the survival of TNBC patients and the DMSs. The correlations of DMSs and TERT expression with several immunological characteristics of immune microenvironment (immune cell infiltration, immunomodulators, immune-related biological pathways, and immune checkpoints) were assessed. The results were validated using 40 TNBC patients from Sun Yat-sen University Cancer Center (SYSUCC).ResultsSix DMSs were identified. Among them, four sites (cg11625005, cg07380026, cg17166338, and cg26006951) were within the TERT promoter, in which two sites (cg07380026 and cg26006951) were significantly related to the prognosis of patients with TNBC. Further validation using 40 TNBC samples from SYSUCC showed that the high methylation of the cg26006951 CpG site was associated with poor survival prognosis (P=0.0022). TERT expression was significantly correlated with pathological N stage and clinical stage, and cg07380026 were significantly associated with pathological T and N stages in the TCGA cohort. Moreover, the methylation site cg26006951, cg07380026 and TERT expression were significantly correlated with immune cell infiltration, common immunomodulators, and the level of the immune checkpoint receptor lymphocyte activation gene 3 (LAG-3) in TNBC patients.ConclusionTERT promotertypermethylation plays an important role in TERT expression regulation and tumor microenvironment in TNBC. It is associated with overall survival and LAG-3 expression. TERT promoter hypermethylation may be a potential molecular biomarker for predicting response to the TERT inhibitors and immune checkpoint inhibitors in TNBC.
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- 2023
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11. Prognostic value of JAK3 promoter methylation and mRNA expression in clear cell renal cell carcinoma
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Qian Long, Chunyu Huang, Jinsheng Huang, Qi Meng, Yanjun Cheng, Yilin Li, Liru He, Miao Chen, Changlin Zhang, Xiaonan Wang, Wancui Zhu, Jin Peng, Dingbo Shi, Fufu Zheng, Pei Dong, and Wuguo Deng
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Janus kinase 3 ,Renal cell carcinoma ,Epigenetic biomarker ,Tumor immune microenvironment ,Tumor immune cell infiltration ,Medicine (General) ,R5-920 ,Science (General) ,Q1-390 - Abstract
Introduction: Janus kinase 3 (JAK3) is a well-established oncogene in clear cell renal cell carcinoma (ccRCC). The methylation status of oncogene promoters has emerged as biomarkers for cancer diagnosis and prognosis. Objective: This study aims to investigate the biological and clinical significance of JAK3 promoter methylation in ccRCC. Methods: We analyzed the relationship of JAK3 promoter methylation with its mRNA expression, overall survival, and immune cell infiltration in a cohort obtained from The Cancer Genome Atlas (TCGA), which was further validated by another independent cohort. We further validated correlations of JAK3 promoter methylation with JAK3 expression, overall survival, and immune cell infiltration in an independent ccRCC cohort (Sun Yat-sen University Cancer Center (SYSUCC) cohort) by methods of immunohistochemistry (IHC) and pyrosequencing. Results: We found JAK3 promoter was significantly hypomethylated in tumor tissues compared to normal adjacent tissues in ccRCC, and JAK3 promoter hypomethylation was strongly correlated with high JAK3 mRNA expression in all three ccRCC cohorts we examined. JAK3 promoter hypomethylation predicted advanced clinicopathological characteristics and shorter overall survival (TCGA cohort and SYSUCC cohort). Furthermore, we found that JAK3 promoter methylation was significantly associated with immune cell infiltration and expression of immune checkpoint molecules (TCGA cohort and CPTAC cohort). Finally, our SYSUCC cohort validated that JAK3 promoter methylation was correlated with CD4+ and CD8+ T cell infiltration in ccRCC tumor tissues. Conclusion: Our data demonstrated that the crucial role of JAK3 promoter methylation in its expression regulation and tumor microenvironment. JAK3 promoter methylation and expression are associated with clinicopathological characteristics, overall survival, and immune cell infiltration in ccRCC. We propose a rationale for further validation of JAK3 promoter methylation as a molecular biomarker for predicting responses to immune checkpoint inhibitors in ccRCC.
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- 2022
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12. Correction: Gamabufotalin, a bufadienolide compound from toad venom, suppresses COX-2 expression through targeting IKKβ/NF-κB signaling pathway in lung cancer cells
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Zhenlong Yu, Wei Guo, Xiaochi Ma, Baojing Zhang, Peipei Dong, Lin Huang, Xiuli Wang, Chao Wang, Xiaokui Huo, Wendan Yu, Canhui Yi, Yao Xiao, Wenjing Yang, Yu Qin, Yuhui Yuan, Songshu Meng, Quentin Liu, and Wuguo Deng
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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13. Human umbilical cord mesenchymal stem cells derived extracellular vesicles alleviate salpingitis by promoting M1–to–M2 transformation
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Changlin Zhang, Wei Liao, Weizhao Li, Mengxiong Li, Xiaoyu Xu, Haohui Sun, Yaohua Xue, Lixiang Liu, Jiehong Qiu, Chi Zhang, Xunzhi Zhang, Juntong Ye, Jingran Du, David Y. B. Deng, Wuguo Deng, and Tian Li
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chronic salpingitis ,macrophage polarization ,NF-κB signaling pathway ,mesenchymal stem cell (MSC) ,extracellular vesicles ,Physiology ,QP1-981 - Abstract
Background: With an increasing number of patients experiencing infertility due to chronic salpingitis after Chlamydia trachomatis (CT) infection, there is an unmet need for tissue repair or regeneration therapies. Treatment with human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hucMSC-EV) provides an attractive cell-free therapeutic approach.Methods: In this study, we investigated the alleviating effect of hucMSC-EV on tubal inflammatory infertility caused by CT using in vivo animal experiments. Furthermore, we examined the effect of hucMSC-EV on inducing macrophage polarization to explore the molecular mechanism.Results: Our results showed that tubal inflammatory infertility caused by Chlamydia infection was significantly alleviated in the hucMSC-EV treatment group compared with the control group. Further mechanistic experiments showed that the application of hucMSC-EV induced macrophage polarization from the M1 to the M2 type via the NF-κB signaling pathway, improved the local inflammatory microenvironment of fallopian tubes and inhibited tube inflammation.Conclusion: We conclude that this approach represents a promising cell-free avenue to ameliorate infertility due to chronic salpingitis.
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- 2023
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14. The NRF2-dependent transcriptional axis, XRCC5/hTERT drives tumor progression and 5-Fu insensitivity in hepatocellular carcinoma
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Tianze Liu, Qian Long, Luting Li, Hairun Gan, Xinyan Hu, Haoyu Long, Lukun Yang, Pengfei Pang, Siyang Wang, and Wuguo Deng
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HCC ,XRCC5 ,transcription ,hTERT ,5-fluorouracil ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Human telomerase reverse transcriptase (hTERT) is highly expressed in many tumors and is essential for tumorigenesis and metastasis in multiple cancers. However, the molecular mechanisms underlying its high expression level in hepatocellular carcinoma (HCC) remain unclear. In this study, we identified X-ray repair cross-complementing 5 (XRCC5), a novel hTERT promoter-binding protein in HCC cells, using biotin-streptavidin-agarose pull-down assay. We found that XRCC5 was highly expressed in HCC cells, in which it transcriptionally upregulated hTERT. Functionally, the transgenic expression of XRCC5 promoted HCC progression and 5-fluorouracil resistance, whereas short hairpin RNA knockdown of XRCC5 had converse effects in vitro and in vivo. Moreover, hTERT overexpression reversed XRCC5 knockdown- or 5-fluorouracil (5-Fu)-mediated HCC inhibition. Mechanistically, nuclear-factor-erythroid-2-related factor 2 (NRF2) interacted with XRCC5, which in turn upregulated hTERT. However, the upregulation was insignificant when NRF2 was reduced, suggesting that the XRCC5-mediated hTERT expression was NRF2 dependent. The HCC patients with high expression levels of XRCC5 and hTERT had shorter overall survival times compared with those with low XRCC5 and hTERT levels in their tumor tissues. Collectively, our study demonstrates the molecular mechanisms of the XRCC5/NRF2/hTERT signaling in HCC metastasis, which will aid in the identification of novel strategies for the diagnosis and treatment of HCC.
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- 2022
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15. CPT1A promotes anoikis resistance in esophageal squamous cell carcinoma via redox homeostasis
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Tian Tian, Yunxin Lu, Jinfei Lin, Miao Chen, Huijuan Qiu, Wancui Zhu, Haohui Sun, Jinsheng Huang, Han Yang, and Wuguo Deng
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CPT1A ,Fatty acid oxidation ,Anoikis resistance ,Esophageal squamous cell carcinoma ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Anoikis resistance was a prominent hallmark of cancer metastasis, and lipo-genic characteristics have been identified as another metabolic alteration during tumorigenesis. However, their crosstalk has not been fully elucidated, especially in advanced esophageal squamous cell carcinoma (ESCC). In this study, we showed, for the first time, that the key enzyme carnitine O-palmitoyl transferase 1 (CPT1A), which is involved in fatty acid oxidation (FAO), was markedly upregulated in ESCC cells upon detached culture via a metabolism PCR array. Overexpression of CPT1A was associated with poor survival of ESCC patients and could protect ESCC cells from apoptosis via maintaining redox homeostasis through supply of GSH and NADPH. Mechanistically, detached culture conditions enhanced the expression of the transcription factor ETV4 and suppressed the expression of the ubiquitin enzyme RNF2, which were responsible for the elevated expression of CPT1A at the mRNA and protein levels, respectively. Moreover, genetic or pharmacologic disruption of CPT1A switched off the NADPH supply and therefore prevented the anchorage-independent growth of ESCC cells in vitro and lung metastases of xenografted tumor models in vivo. Collectively, our results provide novel insights into how ESCC cancer cells exploit metabolic switching to form distant metastases and some evidence for the link between anoikis and FAO.
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- 2022
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16. BPTF inhibition antagonizes colorectal cancer progression by transcriptionally inactivating Cdc25A
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Ping Guo, Shijia Zu, Shilong Han, Wendan Yu, Guoqing Xue, Xiaona Lu, Hua Lin, Xinrui Zhao, Haibo Lu, Chunyu Hua, Xinyu Wan, Liyuan Ru, Ziyue Guo, Hanxiao Ge, Kuan Lv, Guohui Zhang, Wuguo Deng, Cheng Luo, and Wei Guo
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Colorectal cancer ,BPTF ,Cdc25A ,c-Myc ,Cell cycle ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
As the largest subunit of the nuclear remodeling factor complex, Bromodomain PHD Finger Transcription Factor (BPTF) has been reported to be involved in tumorigenesis and development in several cancers. However, to date, its functions and related molecular mechanisms in colorectal cancer (CRC) are still poorly defined and deserve to be revealed. In this study, we uncovered that, under the expression regulation of c-Myc, BPTF promoted CRC progression by targeting Cdc25A. BPTF was found to be highly expressed in CRC and promoted the proliferation and metastasis of CRC cells through BPTF specific siRNAs, shRNAs or inhibitors. Based on RNA-seq, combined with DNA-pulldown, ChIP and luciferase reporter assay, we proved that, by binding to −178/+107 region within Cdc25A promoter, BPTF transcriptionally activated Cdc25A, thus accelerating the cell cycle process of CRC cells. Meanwhile, BPTF itself was found to be transcriptionally regulated by c-Myc. Moreover, BPTF knockdown or inactivation was verified to sensitize CRC cells to chemotherapeutics, 5-Fluorouracil (5FU) and Oxaliplatin (Oxa), c-Myc inhibitor and cell cycle inhibitor not just at the cellular level in vitro, but in subcutaneous xenografts or AOM/DSS-induced in situ models of CRC in mice, while Cdc25A overexpression partially reversed BPTF silencing-caused tumor growth inhibition. Clinically, BPTF, c-Myc and Cdc25A were highly expressed in CRC tissues simultaneously, the expression of any two of the three was positively correlated, and their expressions were highly relevant to tumor differentiation, TNM staging and poor prognosis of CRC patients. Thus, our study indicated that the targeted inhibition of BPTF alone, or together with chemotherapy and/or cell cycle-targeted therapy, might act as a promising new strategy for CRC treatment, while c-Myc/BPTF/Cdc25A signaling axis is expected to be developed as an associated set of candidate biomarkers for CRC diagnosis and prognosis prediction.
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- 2022
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17. SPT6 recruits SND1 to co‐activate human telomerase reverse transcriptase to promote colon cancer progression
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Chaoliang Diao, Ping Guo, Wenjing Yang, Yao Sun, Yina Liao, Yue Yan, Anshi Zhao, Xin Cai, Jiaojiao Hao, Sheng Hu, Wendan Yu, Manyu Chen, Ruozhu Wang, Wenyang Li, Yan Zuo, Jinjin Pan, Chunyu Hua, Xiaona Lu, Wenhua Fan, Zongheng Zheng, Wuguo Deng, Guangyu Luo, and Wei Guo
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colorectal cancer ,hTERT ,SND1 ,SPT6 ,transcription regulation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Human telomerase reverse transcriptase (hTERT) plays an extremely important role in cancer initiation and development, including colorectal cancer (CRC). However, the precise upstream regulatory mechanisms of hTERT in different cancer types remain poorly understood. Here, we uncovered the candidate transcriptional factor of hTERT in CRC and explored its role and the corresponding molecular mechanisms in regulating hTERT expression and CRC survival with an aim of developing mechanism‐based combinational targeting therapy. The possible binding proteins at the hTERT promoter were uncovered using pull‐down/mass spectrometry analysis. The regulation of SPT6 on hTERT expression and CRC survival was evaluated in human CRC cell lines and mouse models. Mechanistic studies focusing on the synergy between SPT6 and staphylococcal nuclease and Tudor domain containing 1 (SND1) in controlling hTERT expression and CRC progression were conducted also in the above two levels. The expression correlation and clinical significance of SPT6, SND1, and hTERT were investigated in tumor tissues from murine models and patients with CRC in situ. SPT6 was identified as a possible transcriptional factor to bind to the hTERT promoter. SPT6 knockdown decreased the activity of hTERT promoter, downregulated the protein expression level of hTERT, suppressed proliferation, invasion, and stem‐like properties, promoted apoptosis induction, and enhanced chemotherapeutic drug sensitivity in vitro. SPT6 silencing also led to the delay of tumor growth and metastasis in mice carrying xenografts of human‐derived colon cancer cells. Mechanistically, SND1 interacted with SPT6 to co‐control hTERT expression and CRC cell proliferation, stemness, and growth in vitro and in vivo. SPT6, SND1, and hTERT were highly expressed simultaneously in CRC tissues, both from the murine model and patients with CRC in situ, and pairwise expression among these three factors showed a significant positive correlation. In brief, our research demonstrated that SPT6 synergized with SND1 to promote CRC development by targeting hTERT and put forward that inhibiting the SPT6‐SND1‐hTERT axis may create a therapeutic vulnerability in CRC.
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- 2021
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18. Type 1 T Helper Cell-Based Molecular Subtypes and Signature Are Associated with Clinical Outcome in Pancreatic Ductal Adenocarcinoma
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Ran Wei, Huihui Zhang, Jianzhong Cao, Dailei Qin, Wuguo Deng, and Shengping Li
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pancreatic ductal adenocarcinoma ,type 1 T helper cell ,lymph node metastasis ,immunotherapy ,prognosis ,Biology (General) ,QH301-705.5 - Abstract
Lymph node metastasis in pancreatic ductal adenocarcinoma (PDAC) is shown to be related with poor prognosis. To construct an immune-related gene prognostic risk model for PDAC and clarify the molecular and immune characteristics and the benefit of immune checkpoint inhibitor (ICI) therapy in prognostic risk model-defined subgroups of PDAC, we analyze the association between the density of immune cell infiltration and lymph node metastatic status and further study the potential role of immune cells, immune cell–related genes, and immunotherapy outcomes in PDAC patients using bioinformatics models and machine learning methods. Based on The Cancer Genome Atlas (TCGA), PACA-AU and PACA-CA data sets, 62 immune-related hub genes were identified by weighted gene co-expression network analysis (WGCNA). Four genes were selected to construct a molecular subtype identification based on the type 1 T helper cell–related hub genes by using the Cox regression method. We found that lower type 1 T helper cell abundance was correlated with prolonged survival in PDAC patients. Further, prognostic risk score model constructed with the type 1 T helper cell-related signature showed high accuracy in predicting overall survival and response to immunotherapy. This study might improve the understanding of the role of type 1 T helper cells in PDAC patients and aid in the development of immunotherapy and personalized treatments for these patients.
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- 2022
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19. Targeting the NCOA3-SP1-TERT axis for tumor growth in hepatocellular carcinoma
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Wenbin Li, Yue Yan, Zongheng Zheng, Qiaohua Zhu, Qian Long, Silei Sui, Meihua Luo, Miao Chen, Yizhuo Li, Yijun Hua, Wuguo Deng, Renchun Lai, and Liren Li
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Cytology ,QH573-671 - Abstract
Abstract Hepatocellular carcinoma (HCC) has a high mortality rate and lacks an effective therapeutic target. Elevated expression of human telomerase reverse transcriptase (TERT) is an important hallmark in cancers, but the mechanism by which TERT is activated differentially in cancers is poorly understood. Here, we have identified nuclear receptor coactivator-3 (NCOA3) as a new modulator of TERT expression and tumor growth in HCC. NACO3 specifically binds to the TERT promoter at the -234 to -144 region and transcriptionally activates TERT expression. NCOA3 promotes HCC cell growth and tumor progression in vitro and in vivo through upregulating the TERT signaling. Knockdown of NACO3 suppresses HCC cell viability and colony formation, whereas TERT overexpression rescues this suppression. NCOA3 interacts with and recruits SP1 binding on the TERT promoter. Knockdown of NCOA3 also inhibits the expression of the Wnt signaling-related genes but has no effect on the Notch signaling-targeting genes. Moreover, NCOA3 is positively correlated with TERT expression in HCC tumor tissues, and high expression of both NCOA3 and TERT predicts a poor prognosis in HCC patients. Our findings indicate that targeting the NCOA3-SP1-TERT signaling axis may benefit HCC patients.
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- 2020
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20. Targeting HMGB3/hTERT axis for radioresistance in cervical cancer
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Zongjuan Li, Yang Zhang, Silei Sui, Yijun Hua, Anshi Zhao, Xiaoyuan Tian, Ruonan Wang, Wei Guo, Wendan Yu, Kun Zou, Wuguo Deng, Liru He, and Lijuan Zou
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Cervical cancer ,HMGB3 ,hTERT ,Radioresistance ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Radiotherapy is regarded as a milestone for the cure of cervical cancer. However, clinical outcome heavily be hindered by radioresistance. So, exploring the underlying mechanism of radioresistance, and find potential target, well deserve fully emphasis. Methods In this study, we developed two novel radiation resistance cervical cancer cell lines, which could mimic clinical radioresistance. In order to find new potential targets, RNA-Seq, database analysis, streptavidin-agarose and LC/MS were used. Pull-down, luciferase and rescue assays were conducted to explore the regulatory mechanisms. To further evaluate the correlation between therapeutic responses and HMGB3/hTERT expression, 172 cervical cancer patients were recruited. Results Knockdown of HMGB3 significantly inhibit the DNA damage repair and induced more γH2AX foci, leading to enhanced chemo- and radio-sensitivity in vitro and in vivo, whereas HMGB3 overexpression has the opposite effects. HMGB3 promotes cell growth and radioresistance by transcriptionally up-regulating hTERT via the specifical binding of HMGB3 at the hTERT promoter region from − 902 to − 321. HMGB3 knockdown-mediated radiosensitization could be reversed by the overexpressed hTERT in both cervical cancer cell lines and xenograft tumor mouse model. Furthermore, clinical data from 172 cervical cancer patients proved that there was a positive correlation between HMGB3 and hTERT expression, and high expression of HMGB3/hTERT predicted poor response to radiotherapy, worse TNM stages and shorter survival time. Conclusion Here, we have identified HMGB3/hTERT signaling axis as a new target for cervical cancer radioresistance. Our results provide new insights into the mechanism of cervical cancer radioresistance and indicate that targeting the HMGB3/hTERT signaling axis may benefit cervical cancer patients.
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- 2020
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21. CPSF4 promotes triple negative breast cancer metastasis by upregulating MDM4
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Kaping Lee, Qiufan Zheng, Qianyi Lu, Fei Xu, Ge Qin, Qinglian Zhai, Ruoxi Hong, Miao Chen, Wuguo Deng, and Shusen Wang
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Medicine ,Biology (General) ,QH301-705.5 - Published
- 2021
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22. NPM1 upregulates the transcription of PD-L1 and suppresses T cell activity in triple-negative breast cancer
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Ge Qin, Xin Wang, Shubiao Ye, Yizhuo Li, Miao Chen, Shusen Wang, Tao Qin, Changlin Zhang, Yixin Li, Qian Long, Huabin Hu, Dingbo Shi, Jiaping Li, Kai Zhang, Qinglian Zhai, Yanlai Tang, Tiebang Kang, Ping Lan, Fangyun Xie, Jianjun Lu, and Wuguo Deng
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Science - Abstract
PD-L1 is highly expressed in triple-negative breast cancers (TNBC). Here, the authors show that nucleophosmin 1 (NPM1) transcriptionally activates PD-L1 expression and inhibits T cell activity in TNBC.
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- 2020
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23. YBX1 Enhances Metastasis and Stemness by Transcriptionally Regulating MUC1 in Lung Adenocarcinoma
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Qiang Xie, Shilei Zhao, Wenzhi Liu, Yanwei Cui, Fengzhou Li, Zhuoshi Li, Tao Guo, Wendan Yu, Wei Guo, Wuguo Deng, and Chundong Gu
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YBX1 ,MUC1 ,prognosis ,transcriptional regulation ,metastasis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abnormal expression of the transcription factor Y-box-binding protein-1 (YBX1) is associated with the proliferation, migration, aggressiveness, and stem-like properties of various cancers. These characteristics contribute to the tumorigenesis and metastasis of cancer. We found that the expression levels of Mucin-1 (MUC1) and YBX1 were positively correlated in lung adenocarcinoma cells and lung adenocarcinoma tissue. Our retrospective cohort study of 176 lung adenocarcinoma patients after surgery showed that low expression of both YBX1 and MUC1 was an independent predictor of the prognosis and recurrence of lung adenocarcinoma. In lung adenocarcinoma cells, the silencing/overexpression of YBX1 caused a simultaneous change in MUC1, and MUC1 overexpression partially reversed the decreased tumor cell migration, aggressiveness, and stemness caused by YBX1 silencing. Moreover, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays proved that MUC1 was the downstream target of YBX1 and that YBX1 bound to the -1480~-1476 position in the promoter region of MUC1 to regulate its transcription. Furthermore, in mouse xenograft models and a lung cancer metastasis model, MUC1, which is downstream of YBX1, partially reversed the decreased number and size of tumors caused by YBX1 silencing. In conclusion, our findings indicated a novel mechanism by which YBX1 promotes the stemness and metastasis of lung adenocarcinoma by targeting MUC1 and provided a combination approach for diagnosis different from traditional single tumor biomarkers to predict patient prognosis and provide clinical treatment targets.
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- 2021
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24. Nucleoporin TPR promotes tRNA nuclear export and protein synthesis in lung cancer cells.
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Miao Chen, Qian Long, Melinda S Borrie, Haohui Sun, Changlin Zhang, Han Yang, Dingbo Shi, Marc R Gartenberg, and Wuguo Deng
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Genetics ,QH426-470 - Abstract
The robust proliferation of cancer cells requires vastly elevated levels of protein synthesis, which relies on a steady supply of aminoacylated tRNAs. Delivery of tRNAs to the cytoplasm is a highly regulated process, but the machinery for tRNA nuclear export is not fully elucidated. In this study, using a live cell imaging strategy that visualizes nascent transcripts from a specific tRNA gene in yeast, we identified the nuclear basket proteins Mlp1 and Mlp2, two homologs of the human TPR protein, as regulators of tRNA export. TPR expression is significantly increased in lung cancer tissues and correlated with poor prognosis. Consistently, knockdown of TPR inhibits tRNA nuclear export, protein synthesis and cell growth in lung cancer cell lines. We further show that NXF1, a well-known mRNA nuclear export factor, associates with tRNAs and mediates their transport through nuclear pores. Collectively, our findings uncover a conserved mechanism that regulates nuclear export of tRNAs, which is a limiting step in protein synthesis in eukaryotes.
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- 2021
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25. TNF Patterns and Tumor Microenvironment Characterization in Head and Neck Squamous Cell Carcinoma
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Qian Long, Chunyu Huang, Qi Meng, Jin Peng, Fan Yao, Dingfu Du, Xiaonan Wang, Wancui Zhu, Dingbo Shi, Xiangdong Xu, Xiang Qi, Wuguo Deng, Miao Chen, Yizhuo Li, and Ankui Yang
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TNF ,head and neck cancer ,tumor immune microenvironment ,immunotherapy ,bioinformatics and biomarkers ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundHNSCC is a heterogeneous disease, which arises from distinct anatomic subsites, associates with various risk factors and possesses diverse molecular pathological features. Generally, HNSCC is considered as an immunosuppressive disease, characterized by abnormal tumor immune microenvironment. The TNF family plays a crucial role in the survival, proliferation, differentiation, and effector functions in both immune and non-immune cells. However, the expression patterns of TNF in HNSCC remains to be systematically analyzed.MethodsWe downloaded transcriptional profile data of HNSCC from TCGA and GEO datasets. Unsupervised clustering methods were used to identify different TNF patterns and classify patients for further analysis. PCA was conducted to construct a TNF relevant score, which we called risk score.ResultsIn this study, we systematically evaluated the patterns of TNF family and tumor immune microenvironment characteristics of HNSCC patients by clustering the expression of 46 members of TNF family. We identified two subtypes with distinct clinical and immune characteristics in HNSCC and constructed a risk scoring system based on the expression profile of TNF family genes.ConclusionRisk score serves as a reliable predictor of overall survival, clinical characteristics, and immune cell infiltration, which has the potential to be applied as a valuable biomarker for HNSCC immunotherapy.
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- 2021
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26. Prognostic, clinicopathological, and immune correlation of NLRP3 promoter methylation in kidney renal clear cell carcinoma
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Qian Long, Liru He, Jin Peng, Qi Meng, Changlin Zhang, Miao Chen, Xiaonan Wang, Wancui Zhu, Fufu Zheng, Pei Dong, and Wuguo Deng
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Medicine (General) ,R5-920 - Published
- 2021
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27. A Prognostic Model Based on Nutritional Risk Index in Operative Breast Cancer
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Fei Lin, Wen Xia, Miao Chen, Tongchao Jiang, Jia Guo, Yi Ouyang, Haohui Sun, Xiaoyu Chen, Wuguo Deng, Ling Guo, and Huanxin Lin
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breast cancer ,nutritional risk index (NRI) ,prognosis ,nomogram ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Background: The nutritional risk index (NRI) is an independent prognostic factor for overall survival in various cancers, but its prognostic value in breast cancer remains unclear. This study aimed to explore the relationship between the NRI and overall survival (OS) in breast cancer and to develop a predictive nomogram. Methods: We retrospectively enrolled 1347 breast cancer patients who underwent mastectomy or lumpectomy between January 2011 and November 2012. Using a cutoff value of 110.59, patients were divided into a high-NRI group and a low-NRI group. OS was compared between the two groups. Clinicopathological factors independently associated with survival were used to construct a predictive nomogram. Results: Of the 1347 patients, 534 patients were classified as high NRI and 813 as low NRI. OS was significantly shorter in low-NRI patients. The 3- and 5-year OS rates were 87.3% and 73.4%, respectively, in the high-NRI group whereas they were 83.0% and 67.2%, respectively, in the low-NRI group. Cox regression analysis found that histopathological type, tumor size, lymph node status, progesterone receptor (PR) status, Ki-67, and NRI were independently associated with OS. Conclusions: NRI is an independent prognostic factor of OS in breast cancer patients. The proposed nomogram model may be a useful tool for individualized survival prediction.
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- 2022
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28. Sequence-dependent synergistic cytotoxicity of icotinib and pemetrexed in human lung cancer cell lines in vitro and in vivo
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Tianze Liu, Lizi Jin, Wenjing Lu, Hairun Gan, Zhidong Lin, Miao Chen, Jiani Liu, Fan Zhang, Siyang Wang, Hongyu Zhang, Wuguo Deng, and Hongtao Chen
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Icotinib ,Lung cancer ,EGFR mutation ,Synergy ,Washout period ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Recent Clinical trials of administration of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in combination with standard first-line chemotherapy have failed to improve survival in patients with advanced NSCLC, However, the sequential treatment with EGFR-TKIs and chemotherapy is expected to improve survival of NSCLC. The aim of this study is to test the antiproliferative effect of pemetrexed combined with icotinib in different sequences on non-small cell lung cancer (NSCLC) cell lines to determine the optimal combination schedule, and subsequently elaborated the potential mechanisms. Methods Six human lung cancer cell lines with wild-type or mutant EGFR gene were exposed to pemetrexed and icotinib combined in different sequences. Cell proliferation was examined by cell counting kit-8 (CCK-8) and colony formation assay; cell cycle and apoptosis were evaluated by flow cytometry; cell migration and invasion were measured by wound healing and transwell invasion assays respectively; protein expression was by detected by Western blot. Results The growth inhibition effect of pemetrexed combined with icotinib on NSCLC cells were schedule-dependent in vitro and in vivo. Treatment with pemetrexed followed by icotinib (P-I) had significantly stronger anticancer ability than treatment with icotinib followed by pemetrexed (I-P) and concomitant treatment with pemetrexed and icotinib (P + I). Cell cycle analysis revealed that pemetrexed blocked cells in S phase, whereas icotinib arrested cells in G1 phase. We also found that icotinib markedly enhanced the pro-apoptotic activity of pemetrexed via cytochrome-C/Caspase/Bcl-2 signaling pathway. In addition, our results showed that pemetrexed alone increased the levels of p-EGFR, p-AKT and p-MAPK, which were inhibited by icotinib. Finally, we showed that the washout period of icotinib was no less than 96 h. Conclusions Sequential treatment of NSCLC cells with pemetrexed followed by icotinib had powerful antiproliferative effect, and it could become a novel effective combination therapy for NSCLC patients.
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- 2019
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29. Melatonin synergizes BRAF-targeting agent vemurafenib in melanoma treatment by inhibiting iNOS/hTERT signaling and cancer-stem cell traits
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Jiaojiao Hao, Wenhua Fan, Yizhuo Li, Ranran Tang, Chunfang Tian, Qian Yang, Tianhua Zhu, Chaoliang Diao, Sheng Hu, Manyu Chen, Ping Guo, Qian Long, Changlin Zhang, Ge Qin, Wendan Yu, Miao Chen, Liren Li, Lijun Qin, Jingshu Wang, Xiuping Zhang, Yandong Ren, Penghui Zhou, Lijuan Zou, Kui Jiang, Wei Guo, and Wuguo Deng
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Melatonin ,Vemurafenib ,NF-κB ,iNOS ,hTERT ,Cancer stem cell ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background As the selective inhibitor of BRAF kinase, vemurafenib exhibits effective antitumor activities in patients with V600 BRAF mutant melanomas. However, acquired drug resistance invariably develops after its initial treatment. Methods Immunohistochemical staining was performed to detect the expression of iNOS and hTERT, p-p65, Epcam, CD44, PCNA in mice with melanoma xenografts. The proliferation and migration of melanoma cells were detected by MTT, tumorsphere culture, cell cycle, cell apoptosis, AO/EB assay and colony formation, transwell assay and scratch assay in vitro, and tumor growth differences were observed in xenograft nude mice. Changes in the expression of key molecules in the iNOS/hTERT signaling pathways were detected by western blot. Nucleus-cytoplasm separation, and immunofluorescence analyses were conducted to explore the location of p50/p65 in melanoma cell lines. Flow cytometry assay were performed to determine the expression of CD44. Pull down assay and ChIP assay were performed to detect the binding ability of p65 at iNOS and hTERT promoters. Additionally, hTERT promoter-driven luciferase plasmids were transfected in to melanoma cells with indicated treatment to determine luciferase activity of hTERT. Results Melatonin significantly and synergistically enhanced vemurafenib-mediated inhibitions of proliferation, colony formation, migration and invasion and promoted vemurafenib-induced apoptosis, cell cycle arresting and stemness weakening in melanoma cells. Further mechanism study revealed that melatonin enhanced the antitumor effect of vemurafenib by abrogating nucleus translocation of NF-κB p50/p65 and their binding at iNOS and hTERT promoters, thereby suppressing the expression of iNOS and hTERT. The elevated anti-tumor capacity of vemurafenib upon co-treatment with melatonin was also evaluated and confirmed in mice with melanoma xenografts. Conclusions Collectively, our results demonstrate melatonin synergizes the antitumor effect of vemurafenib in human melanoma by inhibiting cell proliferation and cancer-stem cell traits via targeting NF-κB/iNOS/hTERT signaling pathway, and suggest the potential of melatonin in antagonizing the toxicity of vemurafenib and augmenting its sensitivities in melanoma treatment.
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- 2019
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30. BPTF promotes hepatocellular carcinoma growth by modulating hTERT signaling and cancer stem cell traits
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Xinrui Zhao, Fufu Zheng, Yizhuo Li, Jiaojiao Hao, Zhipeng Tang, Chunfang Tian, Qian Yang, Tianhua Zhu, Chaoliang Diao, Changlin Zhang, Manyu Chen, Sheng Hu, Ping Guo, Lizhi Zhang, Yina Liao, Wendan Yu, Miao Chen, Lijuan Zou, Wei Guo, and Wuguo Deng
- Subjects
Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Bromodomain PHD finger transcription factor (BPTF), a core subunit of nucleosome-remodeling factor (NURF) complex, plays an important role in chromatin remodeling. However, its precise function and molecular mechanism involved in hepatocellular carcinoma (HCC) growth are still poorly defined. Here, we demonstrated the tumor-promoting role of BPTF in HCC progression. BPTF was highly expressed in HCC cells and tumor tissues of HCC patients compared with normal liver cells and tissues. Knockdown of BPTF inhibited cell proliferation, colony formation and stem cell-like traits in HCC cells. In addition, BPTF knockdown effectively sensitized the anti-tumor effect of chemotherapeutic drugs and induced more apoptosis in HCC cells. Consistently, knockdown of BPTF in a xenograft mouse model also suppressed tumor growth and metastasis accompanied by the suppression of cancer stem cells (CSC)-related protein markers. Moreover, the mechanism study showed that the tumor-promoting role of BPTF in HCC was realized by transcriptionally regulating the expression of human telomerase reverse transcriptase (hTERT). Furthermore, we found that HCC patients with high BPTF expression displayed high hTERT expression, and high BPTF or hTERT expression level was positively correlated with advanced malignancy and poor prognosis in HCC patients. Collectively, our results demonstrate that BPTF promotes HCC growth by targeting hTERT and suggest that the BPTF-hTERT axis maybe a novel and potential therapeutic target in HCC. Keywords: BPTF, hTERT, Hepatocellular carcinoma, Cancer stem cell, Stemness
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- 2019
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31. Sample-Specific Perturbation of Gene Interactions Identifies Pancreatic Cancer Subtypes
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Ran Wei, Huihui Zhang, Jianzhong Cao, Dailei Qin, Shengping Li, and Wuguo Deng
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pancreatic adenocarcinoma ,gene interactions ,prognosis ,network-based subtypes ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Pancreatic cancer is a highly fatal disease and an increasing common cause of cancer mortality. Mounting evidence now indicates that molecular heterogeneity in pancreatic cancer significantly impacts its clinical features. However, the dynamic nature of gene expression pattern makes it difficult to rely solely on gene expression alterations to estimate disease status. By contrast, biological networks tend to be more stable over time under different situations. In this study, we used a gene interaction network from a new point of view to explore the subtypes of pancreatic cancer based on individual-specific edge perturbations calculated by relative gene expression value. Our study shows that pancreatic cancer patients from the TCGA database could be separated into four subtypes based on gene interaction perturbations at the individual level. The new network-based subtypes of pancreatic cancer exhibited substantial heterogeneity in many aspects, including prognosis, phenotypic traits, genetic mutations, the abundance of infiltrating immune cell, and predictive therapeutic efficacy (chemosensitivity and immunotherapy efficacy). The new network-based subtypes were closely related to previous reported molecular subtypes of pancreatic cancer. This work helps us to better understand the heterogeneity and mechanisms of pancreatic cancer from a network perspective.
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- 2022
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32. Melatonin increases the chemosensitivity of diffuse large B-cell lymphoma cells to epirubicin by inhibiting P-glycoprotein expression via the NF-κB pathway
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Kaili Liu, Jincheng Song, Yue Yan, Kun Zou, Yuxuan Che, Beichen Wang, Zongjuan Li, Wendan Yu, Wei Guo, Lijuan Zou, Wuguo Deng, and Xiuhua Sun
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Epirubicin is a first-line chemotherapeutic drug for the clinical treatment of diffuse large B cell lymphoma (DLBCL), but the overexpression of multidrug resistance (MDR) transporter proteins, especially P-glycoprotein (P-gp), renders epirubicin ineffective. Some studies reveal the potential role of melatonin in chemotherapeutic synergy and MDR. Methods: The cell viability and apoptosis were determined by CCK-8 assay and acridine orange/ethidium bromide (AO/EB) fluorescence staining assay. Immunofluorescence and immunohistochemical staining were used to detect the expression of P-gp in DLBCL cells and tissues. Rhodamine-123 accumulation assay was used to evaluate the pump function of P-gp. The possible mechanisms of melatonin sensitize DLBCL cells to epirubicin were explored by western blotting, cytochrome C release, and pulldown assay. Results: Melatonin significantly enhanced the epirubicin-induced cell proliferation suppression, epirubicin-induced apoptosis, and reduced the IC50 value of epirubicin. Further, melatonin synergized with epirubicin to promote the activation of the mitochondria-mediated apoptosis pathway and increased the accumulation of epirubicin in DLBCL cells by inhibiting the expression and function of P-gp. Immunohistochemical staining studies revealed that P-gp expression was positively correlated with P65 expression. Epirubicin was subsequently discovered to upregulate the expression of P-gp by activating the NF-κB pathway in the DLBCL cells. Melatonin reduced the amount of P65 protein in the nucleus and abrogated the ability of P65 to bind to the ABCB1 promoter, decisively suppressing P-gp expression. Conclusions: Our results demonstrated that melatonin inactivates the NF-κB pathway and downregulates the expression of P-gp, ultimately sensitizing DLBCL cells to the epirubicin that suppresses their growth.
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- 2021
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33. Investigating Mechanisms of Response or Resistance to Immune Checkpoint Inhibitors by Analyzing Cell-Cell Communications in Tumors Before and After Programmed Cell Death-1 (PD-1) Targeted Therapy: An Integrative Analysis Using Single-cell RNA and Bulk-RNA Sequencing Data
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Yi-Quan Jiang, Zi-Xian Wang, Ming Zhong, Lu-Jun Shen, Xue Han, Xuxiazi Zou, Xin-Yi Liu, Yi-Nan Deng, Yang Yang, Gui-Hua Chen, Wuguo Deng, and Jin-Hua Huang
- Subjects
single-cell rna sequencing ,programmed cell death-1 ,immunotherapy ,immune checkpoint blockade ,cell-cell interaction ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Currently, a significant proportion of cancer patients do not benefit from programmed cell death-1 (PD-1)-targeted therapy. Overcoming drug resistance remains a challenge. In this study, single-cell RNA sequencing and bulk RNA sequencing data from samples collected before and after anti-PD-1 therapy were analyzed. Cell-cell interaction analyses were performed to determine the differences between pretreatment responders and nonresponders and the relative differences in changes from pretreatment to posttreatment status between responders and nonresponders to ultimately investigate the specific mechanisms underlying response and resistance to anti-PD-1 therapy. Bulk-RNA sequencing data were used to validate our results. Furthermore, we analyzed the evolutionary trajectory of ligands/receptors in specific cell types in responders and nonresponders. Based on pretreatment data from responders and nonresponders, we identified several different cell-cell interactions, like WNT5A-PTPRK, EGFR-AREG, AXL-GAS6 and ACKR3-CXCL12. Furthermore, relative differences in the changes from pretreatment to posttreatment status between responders and nonresponders existed in SELE-PSGL-1, CXCR3-CCL19, CCL4-SLC7A1, CXCL12-CXCR3, EGFR-AREG, THBS1-a3b1 complex, TNF-TNFRSF1A, TNF-FAS and TNFSF10-TNFRSF10D interactions. In trajectory analyses of tumor-specific exhausted CD8 T cells using ligand/receptor genes, we identified a cluster of T cells that presented a distinct pattern of ligand/receptor expression. They highly expressed suppressive genes like HAVCR2 and KLRC1, cytotoxic genes like GZMB and FASLG and the tissue-residence-related gene CCL5. These cells had increased expression of survival-related and tissue-residence-related genes, like heat shock protein genes and the interleukin-7 receptor (IL-7R), CACYBP and IFITM3 genes, after anti-PD-1 therapy. These results reveal the mechanisms underlying anti-PD-1 therapy response and offer abundant clues for potential strategies to improve immunotherapy.
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- 2021
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34. PUF60/AURKA Axis Contributes to Tumor Progression and Malignant Phenotypes in Bladder Cancer
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Qian Long, Xin An, Miao Chen, Nan Wang, Silei Sui, Yixin Li, Changlin Zhang, Kaping Lee, Xiaonan Wang, Tian Tian, Yangxun Pan, Huijuan Qiu, Fangyun Xie, Wuguo Deng, Fufu Zheng, and Liru He
- Subjects
PUF60 ,AURKA ,bladder cancer ,transcriptional regulation ,biomarker ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abnormal expression or mutation of RNA splicing proteins are widely observed in human cancers. Here, we identified poly(U) binding splicing factor 60 (PUF60) as one of the most differentially expressed genes out of 97 RNA splicing proteins between normal and bladder cancer tissues by bioinformatics analysis of TCGA bladder cancer expression data. The expression of PUF60 was significantly higher in tumor tissues, while high PUF60 expression was associated with malignant phenotypes of bladder cancer and shorter survival time. Moreover, we identified aurora kinase A (AURKA) as a new downstream target of PUF60 in bladder cancer cells. PUF60 knockdown significantly inhibited cell viability and colony formation capacity in bladder cancer cells, whereas AURKA overexpression reversed this inhibition effect. Overexpression of PUF60 significantly promoted cell viability and colony formation in bladder cancer cells, while treatment with AURKA specific inhibitor reversed this promotive effect. Mechanistically, PUF60 specifically bound to the AURKA promoter, thereby activating its transcription and expression. Furthermore, we showed that there was a significant positive correlation between PUF60 and AURKA expression in bladder cancer tissues, and PUF60 and AURKA expression contributed to tumor progression and malignant phenotypes in the patients with bladder cancer. Collectively, these results indicate that the PUF60/AURKA axis plays a key role in regulating tumorigenesis and progression of bladder cancer, and may be a potential prognostic biomarker and therapeutic target for bladder cancer patients.
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- 2020
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35. Activator Protein-2β Promotes Tumor Growth and Predicts Poor Prognosis in Breast Cancer
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Zhenglin Li, Xiangdong Xu, Meihua Luo, Jiaojiao Hao, Shilei Zhao, Wendan Yu, Xiangsheng Xiao, Jiali Wu, Fufu Zheng, Miao Chen, Yizhuo Li, Ge Qin, Yina Liao, Xinrui Zhao, Xinfa Yu, Wei Guo, Lijuan Zou, and Wuguo Deng
- Subjects
Ap-2β ,Breast cancer ,Prognosis ,Physiology ,QP1-981 ,Biochemistry ,QD415-436 - Abstract
Background/Aims: Activator protein-2 (AP-2) transcription factors have been proved to be essential in maintaining cellular homeostasis and regulating the transformation from normal growth to neoplasia. However, the role of AP-2β, a key member of AP-2 family, in breast cancer is rarely reported. Methods: The effect of AP-2 on cell growth, migration and invasion in breast cancer cells were measured by MTT, colony formation, wound-healing and transwell assays, respectively. The expression levels of AP-2β and other specific markers in breast cancer cell lines and tissue microarrays from the patients were detected using RT-PCR, Western blot and immunohistochemical staining. The regulation of AP-2β on tumor growth in vivo was analyzed in a mouse xenograft model. Results: We demonstrated the tumor-promoting function of AP-2β in breast cancer. AP-2β was found to be highly expressed in breast cancer cell lines and tumor tissues of breast cancer patients. The shRNA-mediated silencing of AP-2β led to the dramatic inhibition of cell proliferation, colony formation ability, migration and invasiveness in breast cancer cells accompanied by the down-regulated expression of some key proteins involved in cancer progression, including p75, MMP-2, MMP-9, C-Jun, p-ERK and STAT3. Overexpression of AP-2β markedly up-regulated the levels of these proteins. Consistent with the in vitro study, the silencing or overexpression of AP-2β blocked or promoted tumor growth in the mice with xenografts of breast cancers. Notably, the high AP-2β expression levels was correlated with poor prognosis and advanced malignancy in patients with breast cancer. Conclusions: Our study demonstrates that AP-2β promotes tumor growth and predicts poor prognosis, and may represent a potential therapeutic target for breast cancer.
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- 2018
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36. RBFOX3 Regulates the Chemosensitivity of Cancer Cells to 5-Fluorouracil via the PI3K/AKT, EMT and Cytochrome-C/Caspase Pathways
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Tianze Liu, Xiaojun Wu, Yizhuo Li, Wenjing Lu, Fufu Zheng, Changlin Zhang, Qian Long, Huijuan Qiu, Yixin Li, Qin Ge, Miao Chen, Xinfa Yu, Wangbing Chen, Hongyang Zhang, Wenlin Huang, Meihua Luo, Wuguo Deng, and Liren Li
- Subjects
Rbfox3 ,5-fuorouracil (5-FU) ,Hepatocellular carcinoma (HCC) ,Physiology ,QP1-981 ,Biochemistry ,QD415-436 - Abstract
Background/Aims: RBFOX3, an RNA-binding fox protein, plays an important role in the differentiation of neuronal development, but its role in the chemosensitivity of hepatocellular carcinoma (HCC) to 5-FU is unknown. Methods: In this study, we examined the biological functions of RBFOX3 and its effect on the chemosensitivity of HCC cells to 5-FU in vitro and in a mouse xenograft model. Results: RBFOX3 was found to have elevated expression in HCC cell lines and tissue samples, and its knockdown inhibited HCC cell proliferation. Moreover, knockdown of RBFOX3 improved the inhibitory effect of 5-fluorouracil (5-FU) on cell proliferation, migration and invasion, and enhanced the apoptosis induced by 5-FU. However, overexpression of RBFOX3 reduced the inhibitory effect of 5-fluorouracil (5-FU) on cell proliferation, migration and invasion, and decreased the apoptosis induced by 5-FU. We further elucidated that RBFOX3 knockdown synergized with 5-FU to inhibit the growth and invasion of HCC cells through PI3K/AKT and epithelial-mesenchymal transition (EMT) signaling, and promote apoptosis by activating the cytochrome-c/caspase signaling pathway. Finally, we validated that RBFOX3 regulated 5-FU-mediated cytotoxicity in HCC in mouse xenograft models. Conclusions: The findings from this study indicate that RBFOX3 regulates the chemosensitivity of HCC to 5-FU in vitro and in vivo. Therefore, targeting RBFOX3 may improve the inhibition of HCC growth and progression by 5-FU, and provide a novel potential therapeutic strategy for HCC.
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- 2018
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37. MAD2L2 inhibits colorectal cancer growth by promoting NCOA3 ubiquitination and degradation
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Yixin Li, Liren Li, Miao Chen, Xinfa Yu, Zhuoyu Gu, Huijuan Qiu, Ge Qin, Qian Long, Xiaoyan Fu, Tianze Liu, Wenbin Li, Wenlin Huang, Dingbo Shi, Tiebang Kang, Meihua Luo, Xiaojun Wu, and Wuguo Deng
- Subjects
colorectal cancer ,degradation ,MAD2L2 ,NCOA3 ,ubiquitination ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Nuclear receptor coactivator 3 (NCOA3) is a transcriptional coactivator that has elevated expression in multiple tumor types, including colorectal cancer (CRC). However, the molecular mechanisms that regulate the tumorigenic functions of NCOA3 in CRC remain largely unknown. In this study, we aimed to discover and identify the novel regulatory proteins of NCOA3 and explore their mechanisms of action. Immunoprecipitation (IP) coupled with mass spectrometry (IP‐MS) analysis was used to detect, identify, and verify the proteins that interacted with NCOA3 in CRC cells. The biological functions of the candidate proteins and the underlying molecular mechanism were investigated in CRC cells and mouse model in vitro and in vivo. The clinical significance of NCOA3 and its interaction partner protein in CRC patients was also studied. We identified mitotic arrest deficient 2‐like protein 2 (MAD2L2, also known as MAD2B or REV7), with two signal peptide sequences of LIPLK and EVYPVGIFQK, to be an interaction partner of NCOA3. Overexpression of MAD2L2 suppressed the proliferation, migration, and clonogenicity of CRC cells by inducing the degradation of NCOA3. The mechanism study showed that increased MAD2L2 expression in CRC cells activated p38, which was required for the phosphorylation of NCOA3 that led to its ubiquitination and degradation by the proteasome. Moreover, we found that MAD2L2 predicted favorable prognosis in CRC patients. We have discovered a novel role of MAD2L2 in the regulation of NCOA3 degradation and proposed that MAD2L2 serves as a tumor suppressor in CRC.
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- 2018
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38. β-Catenin Cooperates with CREB Binding Protein to Promote the Growth of Tumor Cells
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Wendan Yu, Liren Li, Fufu Zheng, Wenjing Yang, Shilei Zhao, Chunfang Tian, Wenwen Yin, Yiming Chen, Wei Guo, Lijuan Zou, and Wuguo Deng
- Subjects
Prognosis ,β-catenin ,CBP ,Lung cancer ,Physiology ,QP1-981 ,Biochemistry ,QD415-436 - Abstract
Background/Aims: β-catenin is an integral component of the canonical Wnt signaling pathway, and its mutations are an autosomal recessive cause of colorectal cancer (CRC), medulloblastoma (MDB), and ovarian cancer. Nevertheless, little is known about its function in lung cancers. Methods: We first knocked down β-catenin by siRNA to investigate its effects on lung cancer cell proliferation, migration and apoptosis. Then we verified the interaction between β-catenin and CREB binding protein (CBP) by immunofluoresence and co-immunoprecipition assays. Finally, the expression of β-catenin and CBP in human lung adenocarcinoma specimens were analyzed by immunohistochemistry assay. Results: β-catenin knockdown inhibited cell proliferation, promoted apoptosis and suppressed cell migration in A549 and H460 cells accompanied by the decreased expression of Myc, PCNA, VEGF, CD44, MMP-9, MMP-13 and activated bax/caspase-3 pathway. Furthermore, co-immunoprecipition and immunofluoresence analyses revealed that CBP interacted with β-catenin and contributed to β-catenin-mediated lung cancer cell growth. Abolishment of their interaction by the Wnt/β-catenin inhibitor ICG-001 remarkably suppressed cell proliferation. Immunohistochemistry assay of tissue microarrays from patients with lung cancer indicated that both CBP and β-catenin were highly expressed in tumor tissues and predicted poor prognosis in lung adenocarcinoma patients. Conclusions: Our study has provided new evidence for the role of β-catenin in promoting the growth of lung cancer cells through cooperation with CBP, and suggested that dual targeting of β-catenin and CBP could be a potential therapeutic strategy in lung cancer treatment.
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- 2017
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39. Downregulation of NMI promotes tumor growth and predicts poor prognosis in human lung adenocarcinomas
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Jingshu Wang, Kun Zou, Xu Feng, Miao Chen, Cong Li, Ranran Tang, Yang Xuan, Meihua Luo, Wangbing Chen, Huijuan Qiu, Ge Qin, Yixin Li, Changlin Zhang, Binyi Xiao, Lan Kang, Tiebang Kang, Wenlin Huang, Xinfa Yu, Xiaojun Wu, and Wuguo Deng
- Subjects
NMI ,COX-2 ,NF-κB ,p300 ,Lung cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background N-myc (and STAT) interactor (NMI) plays vital roles in tumor growth, progression, and metastasis. In this study, we identified NMI as a potential tumor suppressor in lung cancer and explored its molecular mechanism involved in lung cancer progression. Methods Human lung cancer cell lines and a mouse xenograft model was used to study the effect of NMI on tumor growth. The expression of NMI, COX-2 and relevant signaling proteins were examined by Western blot. Tissue microarray immunohistochemical analysis was performed to assess the correlation between NMI and COX-2 expression in lung cancer patients. Results NMI was highly expressed in normal lung cells and tissues, but lowly expressed in lung cancer cells and tissues. Overexpression of NMI induced apoptosis, suppressed lung cancer cell growth and migration, which were mediated by up-regulation of the cleaved caspase-3/9 and down-regulation of phosphorylated PI3K/AKT, MMP2/MMP9, β-cadherin, and COX-2/PGE2. In contrast, knockdown of NMI promoted lung cancer cell colony formation and migration, which were correlated with the increased expression of phosphorylated PI3K/AKT, MMP2/MMP9, β-cadherin and COX-2/PGE2. Further study showed that NMI suppressed COX-2 expression through inhibition of the p50/p65 NF-κB acetylation mediated by p300. The xenograft lung cancer mouse models also confirmed the NMI-mediated suppression of tumor growth by inhibiting COX-2 signaling. Moreover, tissue microarray immunohistochemical analysis of lung adenocarcinomas also demonstrated a negative correlation between NMI and COX-2 expression. Kaplan-Meier analysis indicated that the patients with high level of NMI had a significantly better prognosis. Conclusions Our study showed that NMI suppressed tumor growth by inhibiting PI3K/AKT, MMP2/MMP9, COX-2/PGE2 signaling pathways and p300-mediated NF-κB acetylation, and predicted a favorable prognosis in human lung adenocarcinomas, suggesting that NMI was a potential tumor suppressor in lung cancer.
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- 2017
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40. CDC5L Promotes hTERT Expression and Colorectal Tumor Growth
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Jia Li, Ningning Zhang, Rui Zhang, Longmei Sun, Wendan Yu, Wei Guo, Yingying Gao, Mei Li, Wei Liu, Pin Liang, Wuguo Deng, and Xiaonan Cui
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CDC5L ,hTERT ,CRC ,Migration ,Prognosis ,Physiology ,QP1-981 ,Biochemistry ,QD415-436 - Abstract
Background/Aims: Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide because the survival rate remains low. Cell division cycle 5-like (CDC5L) is highly expressed in some cancer cells, but the mechanism requires clarification. Human telomerase reverse transcriptase (hTERT) plays important roles in CRC. Methods: This study aimed to identify a link between CDC5L and hTERT and to determine their effects on the signaling pathways, migration and prognosis of CRC cells. We first treated LoVo cells with biotin-labeled hTERT and identified CDC5L. Then, pulldown and ChIP assays were used to verify whether CDC5L was a promoter of hTERT. The roles of CDC5L and hTERT in cell growth and migration were studied using siRNA in vivo and in vitro. 130 human CRC specimens were analyzed using immunohistochemistry. Western blot and wound scratch analyses were used to determine the signaling pathway for CDC5L-mediated activation of CRC growth and migration. Results: We identified CDC5L as a new hTERT promoter-binding protein. Clinically, CDC5L and hTERT expression levels were key factors in the prognosis of CRC patients. CDC5L knockdown inhibited tumor growth by down-regulating hTERT expression, and CDC5L was shown to be a transcriptional activator of hTERT in a luciferase reporter assay. Conclusion: Altogether, the above results demonstrated that CDC5L was positively correlated with hTERT as a key promoter of CRC cells. To some extent, our findings suggest that CDC5L may serve as a novel therapeutic target for human colorectal cancer.
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- 2017
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41. Bufalin Inhibits hTERT Expression and Colorectal Cancer Cell Growth by Targeting CPSF4
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Ningning Zhang, Yunpeng Xie, Yidi Tai, Yingying Gao, Wei Guo, Wendan Yu, Jia Li, Xu Feng, Jiaojiao Hao, Yue Gao, Xinrui Zhao, Yina Liao, Wei Jiang, Ge Liu, Wuguo Deng, and Xiaonan Cui
- Subjects
hTERT ,CPSF4 ,Proliferation ,Apoptosis ,Migration ,Bufalin ,Physiology ,QP1-981 ,Biochemistry ,QD415-436 - Abstract
Background/Aims: Bufalin can induce apoptosis in certain human cancer cell lines, but bufalin has not yet been thoroughly evaluated in colorectal cancer cells. Cleavage and polyadenylation specific factor 4 (CPSF4) and human telomerase reverse transcriptase (hTERT) play important roles in colorectal cancer growth. The aim of this study was to investigate the roles and interactions of bufalin, CPSF4 and hTERT and the effects of bufalin in human colorectal cancer. Methods: We treated LoVo and SW620 cells with bufalin to investigate the effect of bufalin on proliferation, apoptosis and migration. We verified the relationship between CPSF4 and hTERT using pulldown assays, luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays. Results: Bufalin inhibited the proliferation and migration of and induced apoptosis in LoVo and SW620 cells. We identified CPSF4 as an hTERT promoter-binding protein in colorectal cancer cells. Conclusion: Our study identified bufalin as a potential small molecule inhibitor for cancer therapy.
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- 2016
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42. Ku80 promotes melanoma growth and regulates antitumor effect of melatonin by targeting HIF1-α dependent PDK-1 signaling pathway
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Tianze Liu, Lizi Jin, Miao Chen, Zongheng Zheng, Wenjing Lu, Wenhua Fan, Liren Li, Fufu Zheng, Qiaohua Zhu, Huijuan Qiu, Jiani Liu, Manyu Chen, Chunfang Tian, Zheng Hu, Changlin Zhang, Meihua Luo, Jian Li, Tiebang Kang, Lukun Yang, Yizhuo Li, and Wuguo Deng
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Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Melanoma is one of the most malignant and aggressive cancers with high cancer-related deaths. However, it is unclear whether Ku80 regulates tumor growth in human melanoma. In this study, we screened a siRNA library targeting 6024 human genes and identified Ku80 as a potential therapeutic target in melanoma cells. Knockdown of Ku80 significantly suppressed melanoma cell proliferation and induced apoptosis, as well as enhanced the antitumor effect of melatonin in melanoma in vitro and in vivo. Overexpression of Ku80, however, promoted melanoma growth and increased the insensitivity of melanoma cells to melatonin. Mechanistically, we found that Ku80 bound to the PDK1 promoter and activated the transcription of PDK1. Moreover, we showed that the binding of Ku80 at the PDK-1 promoter was HIF1-α dependent, and melatonin degraded HIF1-α in melanoma cells. Furthermore, clinical data revealed that the expression of Ku80 and PDK-1 proteins were positively correlated and elevated in the tumor tissues of melanoma patients, and high expression of Ku80 predicted a poor prognosis in melanoma. Collectively, our study demonstrated that Ku80 promoted melanoma growth and regulated antitumor activity of melatonin by targeting HIF1-α dependent PDK-1 signaling pathway, suggesting that Ku80 may be a potential molecular target for melanoma treatment. Keywords: Ku80, PDK-1, Melatonin, HIF1-α, Melanoma
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- 2019
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43. Outcomes of Induction Chemotherapy Plus Intensity-Modulated Radiotherapy (IMRT) Versus IMRT Plus Concurrent Chemotherapy for Locoregionally Advanced Nasopharyngeal Carcinoma: A Propensity Matched Study
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Pu-Yun OuYang, Zhuo-Fei Bi, Lu-Ning Zhang, Kai-Yun You, Yao Xiao, Xiao-Wen Lan, Jie Tang, Xi-Cheng Wang, Wuguo Deng, and Fang-Yun Xie
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
PURPOSE: It deserves investigation whether induction chemotherapy (IC) followed by intensity-modulated radiotherapy (IMRT) is inferior to the current standard of IMRT plus concurrent chemotherapy (CC) in locoregionally advanced nasopharyngeal carcinoma. METHODS: Patients who received IC (94 patients) or CC (302 patients) plus IMRT at our center between March 2003 and November 2012 were retrospectively analyzed. Propensity-score matching method was used to match patients in both arms at equal ratio. Failure-free survival (FFS), overall survival (OS), distant metastasis–free survival (DMFS), and locoregional relapse–free survival (LRFS) were assessed with Kaplan-Meier method, log-rank test, and Cox regression. RESULTS: In the original cohort of 396 patients, IC plus IMRT resulted in similar FFS (P = .565), OS (P = .334), DMFS (P = .854), and LRFS (P = .999) to IMRT plus CC. In the propensity-matched cohort of 188 patients, no significant survival differences were observed between the two treatment approaches (3-year FFS 80.3% vs 81.0%, P = .590; OS 93.4% vs 92.1%, P = .808; DMFS 85.9% vs 87.7%, P = .275; and LRFS 93.1% vs 92.0%, P = .763). Adjusting for the known prognostic factors in multivariate analysis, IC plus IMRT did not cause higher risk of treatment failure, death, distant metastasis, or locoregional relapse. CONCLUSIONS: IC plus IMRT appeared to achieve comparable survival to IMRT plus CC in locoregionally advanced nasopharyngeal carcinoma. Further investigations were warranted.
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- 2016
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44. XRCC5 cooperates with p300 to promote cyclooxygenase-2 expression and tumor growth in colon cancers.
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Zhifeng Zhang, Fufu Zheng, Zhenlong Yu, Jiajiao Hao, Miao Chen, Wendan Yu, Wei Guo, Yiming Chen, Wenlin Huang, Zhijun Duan, and Wuguo Deng
- Subjects
Medicine ,Science - Abstract
Cyclooxygenase (COX) is the rate-limiting enzyme in prostaglandins (PGs) biosynthesis. Previous studies indicate that COX-2, one of the isoforms of COX, is highly expressed in colon cancers and plays a key role in colon cancer carcinogenesis. Thus, searching for novel transcription factors regulating COX-2 expression will facilitate drug development for colon cancer. In this study, we identified XRCC5 as a binding protein of the COX-2 gene promoter in colon cancer cells with streptavidin-agarose pulldown assay and mass spectrometry analysis, and found that XRCC5 promoted colon cancer growth through modulation of COX-2 signaling. Knockdown of XRCC5 by siRNAs inhibited the growth of colon cancer cells in vitro and of tumor xenografts in a mouse model in vivo by suppressing COX-2 promoter activity and COX-2 protein expression. Conversely, overexpression of XRCC5 promoted the growth of colon cancer cells by activating COX-2 promoter and increasing COX-2 protein expression. Moreover, the role of p300 (a transcription co-activator) in acetylating XRCC5 to co-regulate COX-2 expression was also evaluated. Immunofluorescence assay and confocal microscopy showed that XRCC5 and p300 proteins were co-located in the nucleus of colon cancer cells. Co-immunoprecipitation assay also proved the interaction between XRCC5 and p300 in nuclear proteins of colon cancer cells. Cell viability assay indicated that the overexpression of wild-type p300, but not its histone acetyltransferase (HAT) domain deletion mutant, increased XRCC5 acetylation, thereby up-regulated COX-2 expression and promoted the growth of colon cancer cells. In contrast, suppression of p300 by a p300 HAT-specific inhibitor (C646) inhibited colon cancer cell growth by suppressing COX-2 expression. Taken together, our results demonstrated that XRCC5 promoted colon cancer growth by cooperating with p300 to regulate COX-2 expression, and suggested that the XRCC5/p300/COX-2 signaling pathway was a potential target in the treatment of colon cancers.
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- 2017
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45. Friend Leukemia Virus Integration 1 Expression Has Prognostic Significance in Nasopharyngeal Carcinoma
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Xuexia Liang, Dingbo Shi, Jingping Yun, Yanping Mao, Puyun Ouyang, Zhen Su, Jia Fu, Jinghui Hou, Wuguo Deng, and Fangyun Xie
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
This study aimed to investigate the expression pattern and prognostic value of friend leukemia virus integration 1 (FLI-1) in nasopharyngeal carcinoma (NPC). Immunohistochemistry (IHC) staining of FLI-1 was performed in specimens from 198 untreated NPC patients. Ninety-nine patients were randomly assigned to the training set to analyze the prognostic value of FLI-1 and other clinicopathological characteristics, while the others were assigned to the testing set for validation. Clinicopathological data were compared using the Pearson chi-square test. Univariate and multivariate analyses were performed using the Cox proportional hazards model to test independent prognostic factors and calculate the hazard ratio (HR) and 95% confidence interval (CI). Cytoplasmic FLI-1 expression positively correlated with N stage, distant metastasis and death (P
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- 2014
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46. Effects of social isolation and re-socialization on cognition and ADAR1 (p110) expression in mice
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Wei Chen, Dong An, Hong Xu, Xiaoxin Cheng, Shiwei Wang, Weizhi Yu, Deqin Yu, Dan Zhao, Yiping Sun, Wuguo Deng, Yiyuan Tang, and Shengming Yin
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Cognitive ability ,ADAR1 ,Social isolation ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
It has been reported that social isolation stress could be a key factor that leads to cognitive deficit for both humans and rodent models. However, detailed mechanisms are not yet clear. ADAR1 (Adenosine deaminase acting on RNA) is an enzyme involved in RNA editing that has a close relation to cognitive function. We have hypothesized that social isolation stress may impact the expression of ADAR1 in the brain of mice with cognitive deficit. To test our hypothesis, we evaluated the cognition ability of mice isolated for different durations (2, 4, and 8 weeks) using object recognition and object location tests; we also measured ADAR1 expression in hippocampus and cortex using immunohistochemistry and western blot. Our study showed that social isolation stress induced spatial and non-spatial cognition deficits of the tested mice. In addition, social isolation significantly increased both the immunoreactivity and protein expression of ADAR1 (p110) in the hippocampus and frontal cortex. Furthermore, re-socialization could not only recover the cognition deficits, but also bring ADAR1 (p110) immunoreactivity of hippocampus and frontal cortex, as well as ADAR1 (p110) protein expression of hippocampus back to the normal level for the isolated mice in adolescence. In conclusion, social isolation stress significantly increases ADAR1 (p110) expression in the hippocampus and frontal cortex of the mice with cognitive deficit. This finding may open a window to better understand the reasons (e.g., epigenetic change) that are responsible for social isolation-induced cognitive deficit and help the development of novel therapies for the resulted diseases.
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- 2016
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47. Effusanin E suppresses nasopharyngeal carcinoma cell growth by inhibiting NF-κB and COX-2 signaling.
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Mingzhu Zhuang, Mouming Zhao, Huijuan Qiu, Dingbo Shi, Jingshu Wang, Yun Tian, Lianzhu Lin, and Wuguo Deng
- Subjects
Medicine ,Science - Abstract
Rabdosia serra is well known for its antibacterial, anti-inflammatory and antitumor activities, but no information has been available for the active compounds derived from this plant in inhibiting human nasopharyngeal carcinoma (NPC) cell growth. In this study, we isolated and purified a natural diterpenoid from Rabdosia serra and identified its chemical structure as effusanin E and elucidated its underlying mechanism of action in inhibiting NPC cell growth. Effusanin E significantly inhibited cell proliferation and induced apoptosis in NPC cells. Effusanin E also induced the cleavage of PARP, caspase-3 and -9 proteins and inhibited the nuclear translocation of p65 NF-κB proteins. Moreover, effusanin E abrogated the binding of NF-κB to the COX-2 promoter, thereby inhibiting the expression and promoter activity of COX-2. Pretreatment with a COX-2 or NF-κB-selective inhibitor (celecoxib or ammonium pyrrolidinedithiocarbamate) had an additive effect on the effusanin E-mediated inhibition of proliferation, while pretreatment with an activator of NF-κB/COX-2 (lipopolysaccharides) abrogated the effusanin E-mediated inhibition of proliferation. Effusanin E also significantly suppressed tumor growth in a xenograft mouse model without obvious toxicity, furthermore, the expression of p50 NF-κB and COX-2 were down-regulated in the tumors of nude mice. These data suggest that effusanin E suppresses p50/p65 proteins to down-regulate COX-2 expression, thereby inhibiting NPC cell growth. Our findings provide new insights into exploring effusanin E as a potential therapeutic compound for the treatment of human nasopharyngeal carcinoma.
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- 2014
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48. Lasiodin inhibits proliferation of human nasopharyngeal carcinoma cells by simultaneous modulation of the Apaf-1/caspase, AKT/MAPK and COX-2/NF-κB signaling pathways.
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Lianzhu Lin, Wuguo Deng, Yun Tian, Wangbing Chen, Jingshu Wang, Lingyi Fu, Dingbo Shi, Mouming Zhao, and Wei Luo
- Subjects
Medicine ,Science - Abstract
Rabdosia serra has been widely used for the treatment of the various human diseases. However, the antiproliferative effects and underlying mechanisms of the compounds in this herb remain largely unknown. In this study, an antiproliferative compound against human nasopharyngeal carcinoma (NPC) cells from Rabdosia serra was purified and identified as lasiodin (a diterpenoid). The treatment with lasiodin inhibited cell viability and migration. Lasiodin also mediated the cell morphology change and induced apoptosis in NPC cells. The treatment with lasiodin induced the Apaf-1 expression, triggered the cytochrome-C release, and stimulated the PARP, caspase-3 and caspase-9 cleavages, thereby activating the apoptotic pathways. The treatment with lasiodin also significantly inhibited the phosphorylations of the AKT, ERK1/2, p38 and JNK proteins. The pretreatment with the AKT or MAPK-selective inhibitors considerably blocked the lasiodin-mediated inhibition of cell proliferation. Moreover, the treatment with lasiodin inhibited the COX-2 expression, abrogated NF-κB binding to the COX-2 promoter, and promoted the NF-κB translocation from cell nuclei to cytosol. The pretreatment with a COX-2-selective inhibitor abrogated the lasiodin-induced inhibition of cell proliferation. These results indicated that lasiodin simultaneously activated the Apaf-1/caspase-dependent apoptotic pathways and suppressed the AKT/MAPK and COX-2/NF-κB signaling pathways. This study also suggested that lasiodin could be a promising natural compound for the prevention and treatment of NPC.
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- 2014
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49. Diabetes, prediabetes and the survival of nasopharyngeal carcinoma: a study of 5,860 patients.
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Pu-Yun OuYang, Zhen Su, Jie Tang, Xiao-Wen Lan, Yan-Ping Mao, Wuguo Deng, and Fang-Yun Xie
- Subjects
Medicine ,Science - Abstract
BACKGROUND:The incidence of diabetes is increasing. But the impact of diabetes and prediabetes on survival of patients with nasopharyngeal carcinoma (NPC) has received little evaluation. METHODS:In a cohort of 5,860 patients, we compared the disease specific survival (DSS), locoregional relapse-free survival (LRFS) and distant metastasis-free survival (DMFS) of patients with diabetes, prediabetes and normoglycemia defined by pretreatment fasting plasma glucose (FPG) using Kaplan-Meier method, log-rank test and Cox proportional hazards model. RESULTS:Comparing to normoglycemic patients, the diabetic and the prediabetic were generally older, fatter, had hypertension, heart diseases and hyperlipaemia and usually received radiotherapy alone. But both the diabetic and the prediabetic had similar DSS, LRFS and DMFS to normoglycemic patients, even adjusting for such important factors as age, gender, smoking, drinking, hypertension, heart diseases, body mass index, hyperlipaemia, titer of VCA-IgA and EA-IgA, pathology, T-stage, N-stage, chemotherapy and radiotherapy (P>0.05 for all). Additionally, the findings remained unchanged in sensitivity analysis by excluding patients with known diabetes history and in subgroups of the various factors. CONCLUSIONS:The diabetic and prediabetic NPC patients had similar survival to normoglycemic NPC patients. These data, in the largest reported cohort, are the first to evaluate the association between diabetes, prediabetes and the survival in NPC. The findings are relevant to patient management and provided evidence of the effect on this disease exerted by comorbidities.
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- 2014
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50. Melatonin enhances the anti-tumor effect of fisetin by inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways.
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Canhui Yi, Yong Zhang, Zhenlong Yu, Yao Xiao, Jingshu Wang, Huijuan Qiu, Wendan Yu, Ranran Tang, Yuhui Yuan, Wei Guo, and Wuguo Deng
- Subjects
Medicine ,Science - Abstract
Melatonin is a hormone identified in plants and pineal glands of mammals and possesses diverse physiological functions. Fisetin is a bio-flavonoid widely found in plants and exerts antitumor activity in several types of human cancers. However, the combinational effect of melatonin and fisetin on antitumor activity, especially in melanoma treatment, remains unclear. Here, we tested the hypothesis that melatonin could enhance the antitumor activity of fisetin in melanoma cells and identified the underlying molecular mechanisms. The combinational treatment of melanoma cells with fisetin and melatonin significantly enhanced the inhibitions of cell viability, cell migration and clone formation, and the induction of apoptosis when compared with the treatment of fisetin alone. Moreover, such enhancement of antitumor effect by melatonin was found to be mediated through the modulation of the multiply signaling pathways in melanoma cells. The combinational treatment of fisetin with melatonin increased the cleavage of PARP proteins, triggered more release of cytochrome-c from the mitochondrial inter-membrane, enhanced the inhibition of COX-2 and iNOS expression, repressed the nuclear localization of p300 and NF-κB proteins, and abrogated the binding of NF-κB on COX-2 promoter. Thus, these results demonstrated that melatonin potentiated the anti-tumor effect of fisetin in melanoma cells by activating cytochrome-c-dependent apoptotic pathway and inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways, and our study suggests the potential of such a combinational treatment of natural products in melanoma therapy.
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- 2014
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