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Article ; Online: Construction and validation of a two-gene signature based on SUMOylation regulatory genes in non-small cell lung cancer patients.

Sheng, Hongxu / Hao, Zhexue / Zhu, Linhai / Zeng, Yuan / He, Jianxing

2022 Volume 22, Issue 1, Page(s) 572

Abstract: Background: Post-translational modification plays an important role in the occurrence and development of various tumors. However, few researches were focusing on the SUMOylation regulatory genes as tumor biomarkers to predict the survival for specific ... ...

Abstract	Background: Post-translational modification plays an important role in the occurrence and development of various tumors. However, few researches were focusing on the SUMOylation regulatory genes as tumor biomarkers to predict the survival for specific patients. Here, we constructed and validated a two-gene signature to predict the overall survival (OS) of non-small cell lung cancer (NSCLC) patients. Methods: The datasets analyzed in this study were downloaded from TCGA and GEO databases. The least absolute shrinkage and selection operator (LASSO) Cox regression was used to construct the two-gene signature. Gene set enrichment analysis (GSEA) and Gene Ontology (GO) was used to identify hub pathways associated with risk genes. The CCK-8 assay, cell cycle analysis, and transwell assay was used to validate the function of risk genes in NSCLC cell lines. Results: Firstly, most of the SUMOylation regulatory genes were highly expressed in various tumors through the R package 'limma' in the TCGA database. Secondly, our study found that the two gene signature constructed by LASSO regression analysis, as an independent prognostic factor, could predict the OS in both the TCGA training cohort and GEO validation cohorts (GSE68465, GSE37745, and GSE30219). Furthermore, functional enrichment analysis suggests that high-risk patients defined by the risk score system were associated with the malignant phenomenon, such as DNA replication, cell cycle regulation, p53 signaling pathway. Finally, the results of the CCK-8 assay, cell cycle analysis, and transwell assay demonstrated that the two risk genes, SAE1 and UBA2, could promote proliferation and migration in non-small cell lung cancer cells. Conclusions: The two-gene signature constructed in our study could predict the OS and may provide valuable clinical guidance for the treatment of NSCLC patients.
MeSH term(s)	Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Genes, Regulator ; Humans ; Lung Neoplasms/genetics ; Prognosis ; Sumoylation/genetics ; Ubiquitin-Activating Enzymes/genetics
Chemical Substances	UBA2 protein, human ; Ubiquitin-Activating Enzymes (EC 6.2.1.45)
Language	English
Publishing date	2022-05-23
Publishing country	England
Document type	Journal Article
ZDB-ID	2041352-X
ISSN	1471-2407 ; 1471-2407
ISSN (online)	1471-2407
ISSN	1471-2407
DOI	10.1186/s12885-022-09575-4
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Article ; Online: Schizandrin A can inhibit non‑small cell lung cancer cell proliferation by inducing cell cycle arrest, apoptosis and autophagy.

Zhu, Linhai / Wang, Ying / Lv, Wang / Wu, Xiao / Sheng, Hongxu / He, Cheng / Hu, Jian

International journal of molecular medicine

2021 Volume 48, Issue 6

Abstract: Schizandrin A (SchA) can be extracted from the vine ... ...

Abstract	Schizandrin A (SchA) can be extracted from the vine plant
MeSH term(s)	Adenosine Triphosphate/metabolism ; Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/drug effects ; Apoptosis/physiology ; Autophagy/drug effects ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cyclooctanes/pharmacology ; Humans ; Lignans/pharmacology ; Lung Neoplasms/drug therapy ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Membrane Potential, Mitochondrial/drug effects ; Polycyclic Compounds/pharmacology ; Proteins/genetics ; Proteins/metabolism ; Reactive Oxygen Species/metabolism
Chemical Substances	Antineoplastic Agents, Phytogenic ; Cyclooctanes ; Lignans ; Polycyclic Compounds ; Proteins ; Reactive Oxygen Species ; schizandrin A (74XQL5DO3S) ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2021-10-13
Publishing country	Greece
Document type	Journal Article
ZDB-ID	1444428-8
ISSN	1791-244X ; 1107-3756
ISSN (online)	1791-244X
ISSN	1107-3756
DOI	10.3892/ijmm.2021.5047
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Article ; Online: Liriopesides B induces apoptosis and cell cycle arrest in human non‑small cell lung cancer cells.

Sheng, Hongxu / Lv, Wang / Zhu, Linhai / Wang, Luming / Wang, Zhitian / Han, Jia / Hu, Jian

International journal of molecular medicine

2020 Volume 46, Issue 3, Page(s) 1039–1050

Abstract: Although significant progress has been made in the treatment of lung cancer, it remains the leading cause of cancer‑associated mortality. Liriopesides B (LPB) is a natural product isolated from the tuber of Liriope platyphylla, whose effective substances ...

Abstract	Although significant progress has been made in the treatment of lung cancer, it remains the leading cause of cancer‑associated mortality. Liriopesides B (LPB) is a natural product isolated from the tuber of Liriope platyphylla, whose effective substances have exhibited antitumor activity in several types of cancer. However, the functions of LPB in non‑small cell lung cancer (NSCLC) require further investigation. Therefore, the present study aimed to investigate whether LPB influences the pathogenic effects of NSCLC. In the present study, it was demonstrated that LPB reduced proliferation, and induced apoptosis and cell cycle arrest in non‑small cell lung cancer cells. CCK‑8 and colony formation assays demonstrated that LPB decreased cell viability and proliferation of H460 and H1975 cells in a dose‑dependent manner. Flow cytometry revealed that LPB significantly induced apoptosis of NSCLC cells, along with changes in the expression of apoptosis‑associated proteins, including an increase in Bax, caspase‑3, and caspase‑8 expression, and a decrease in Bcl‑2 and Bcl‑xl expression. LPB inhibited the progression of the cell cycle from the G1 to the S phase. Furthermore, autophagy was increased in cells treated with LPB. Finally, the expression of programmed death‑ligand 1 was significantly decreased by LPB. In conclusion, the results of the present study highlight a potential novel strategy for the clinical treatment of NSCLC.
MeSH term(s)	Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/drug effects ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Heterocyclic Compounds, 4 or More Rings/chemistry ; Heterocyclic Compounds, 4 or More Rings/pharmacology ; Humans ; Liriope Plant/chemistry ; Lung Neoplasms/drug therapy ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Spiro Compounds/chemistry ; Spiro Compounds/pharmacology
Chemical Substances	Antineoplastic Agents, Phytogenic ; Heterocyclic Compounds, 4 or More Rings ; Spiro Compounds ; liriopesides B
Language	English
Publishing date	2020-06-16
Publishing country	Greece
Document type	Journal Article
ZDB-ID	1444428-8
ISSN	1791-244X ; 1107-3756
ISSN (online)	1791-244X
ISSN	1107-3756
DOI	10.3892/ijmm.2020.4645
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Article ; Online: [Clinical Evaluation of Absorbable Regenerated Oxidized Cellulose in Lung Cancer Surgery].

Yu, Wenfeng / Xu, Jinming / Sheng, Hongxu / Cao, Jinlin / Wang, Zhitian / Lv, Wang / Hu, Jian

Zhongguo fei ai za zhi = Chinese journal of lung cancer

2020 Volume 23, Issue 6, Page(s) 492–495

Abstract: Background: Thoracoscopic safe and effective hemostasis is an important condition for rapid rehabilitation of thoracic surgery. Placing hemostatic materials during surgery is a commonly used method in lung cancer laparoscopic surgery. Among them, ... ...

Abstract	Background: Thoracoscopic safe and effective hemostasis is an important condition for rapid rehabilitation of thoracic surgery. Placing hemostatic materials during surgery is a commonly used method in lung cancer laparoscopic surgery. Among them, resorbable oxidized cellulose is a commonly used hemostatic material. This research aims to observe the hemostatic effect of resorbable oxidized cellulose in lung cancer surgery. Methods: A retrospective analysis of 42 patients with thoracoscopic lung cancer undergoing radical surgery in the Department of Thoracic Surgery, First Affiliated Hospital of Zhejiang University School of Medicine from July 1, 2018 to December 1, 2018, and intraoperative use of regenerative oxidized cellulose to stop bleeding The clinical and pathological data were selected and the perioperative indicators were selected as the outcome events for statistical analysis. Results: The mean operative time was (120.5±57.3) min. The mean intraoperative blood loss was (26.8±21.6) mL. The average postoperative drainage volume was (513.6±359.5) mL. The average postoperative chest tube indwelling time was (2.6±1.2) d. Conclusions: The use of absorbable regenerated oxidized cellulose in the radical operation of thoracoscopic lung cancer has a good hemostasis effect, and is suitable for hemostasis of wounds after lymph node dissection.
MeSH term(s)	Absorption, Physicochemical ; Cellulose, Oxidized/pharmacology ; Female ; Hemostatics/pharmacology ; Humans ; Lung Neoplasms/physiopathology ; Lung Neoplasms/surgery ; Male ; Middle Aged ; Retrospective Studies ; Treatment Outcome
Chemical Substances	Cellulose, Oxidized ; Hemostatics
Language	Chinese
Publishing date	2020-06-03
Publishing country	China
Document type	Journal Article
ZDB-ID	2438672-8
ISSN	1999-6187 ; 1009-3419
ISSN (online)	1999-6187
ISSN	1009-3419
DOI	10.3779/j.issn.1009-3419.2020.101.10
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Article ; Online: Construction and Validation of a Prognostic Model Based on Novel Senescence-Related Genes in Non-Small Cell Lung Cancer Patients with Drug Sensitivity and Tumor Microenvironment.

Liu, Xiwen / Lin, Lixuan / Cai, Qi / Sheng, Hongxu / Zeng, Ruiqi / Zhao, Yi / Qiu, Xinyi / Liu, Huiting / Huang, Linchong / Liang, Wenhua / He, Jianxing

Advanced biology

2023 Volume 7, Issue 12, Page(s) e2300190

Abstract: Cellular senescence contributes to cancer pathogenesis and immune regulation. Using the LASSO Cox regression, we developed a 12-gene prognostic signature for lung adenocarcinoma (LUAD) from The Cancer Genome Atlas (TCGA) and a Gene Expression Omnibus ( ... ...

Abstract	Cellular senescence contributes to cancer pathogenesis and immune regulation. Using the LASSO Cox regression, we developed a 12-gene prognostic signature for lung adenocarcinoma (LUAD) from The Cancer Genome Atlas (TCGA) and a Gene Expression Omnibus (GEO) dataset. We assessed gene expression, drug sensitivity, immune infiltration, and conducted cell line experiments. High-risk LUAD patients showed increased mortality risk and shorter survival (P < 0.001). Senescence-related gene analysis indicated differences in protein phosphorylation and DNA methylation between normal individuals and LUAD patients. The high-risk group showed a positive association with PD-L1 expression (P = 0.003). Single-cell sequencing data suggested PEBP1 might significantly impact T cell infiltration. We predicted potential sensitive compounds for 12 senescence genes and found GAPDH promoted cell line proliferation. We established a novel prognostic system based on a newly identified senescence gene. High-risk patients had elevated immunosuppressive markers, and PEBP1 might influence T cell infiltration significantly. GAPDH, expressed at higher levels in tumors, could affect cancer progression. Our drug prediction model may guide treatment selection.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Tumor Microenvironment/genetics ; Prognosis ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Adenocarcinoma of Lung/drug therapy ; Adenocarcinoma of Lung/genetics
Language	English
Publishing date	2023-07-30
Publishing country	Germany
Document type	Journal Article
ISSN	2701-0198
ISSN (online)	2701-0198
DOI	10.1002/adbi.202300190
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Article ; Online: A five-m6A regulatory gene signature is a prognostic biomarker in lung adenocarcinoma patients.

Wu, Xiao / Sheng, Hongxu / Wang, Luming / Xia, Pinghui / Wang, Yiqing / Yu, Li / Lv, Wang / Hu, Jian

Aging

2021 Volume 13, Issue 7, Page(s) 10034–10057

Abstract: We analyzed the prognostic value of N6-methyladenosine (m6A) regulatory genes in lung adenocarcinoma (LADC) and their association with tumor immunity and immunotherapy response. Seventeen of 20 m6A regulatory genes were differentially expressed in LDAC ... ...

Abstract	We analyzed the prognostic value of N6-methyladenosine (m6A) regulatory genes in lung adenocarcinoma (LADC) and their association with tumor immunity and immunotherapy response. Seventeen of 20 m6A regulatory genes were differentially expressed in LDAC tissue samples from the TCGA and GEO databases. We developed a five-m6A regulatory gene prognostic signature based on univariate and Lasso Cox regression analysis. Western blot analysis confirmed that the five prognostic m6A regulatory proteins were highly expressed in LADC tissues. We constructed a nomogram with five-m6A regulatory gene prognostic risk signature and AJCC stages. ROC curves and calibration curves showed that the nomogram was well calibrated and accurately distinguished high-risk and low-risk LADC patients. Weighted gene co-expression analysis showed significant correlation between prognostic risk signature genes and the turquoise module enriched with cell cycle genes. The high-risk LADC patients showed significantly higher PD-L1 levels, increased tumor mutational burden, and a lower proportion of CD8
MeSH term(s)	Adenocarcinoma of Lung/genetics ; Adenocarcinoma of Lung/mortality ; Adenocarcinoma of Lung/pathology ; Aged ; Biomarkers, Tumor/genetics ; Databases, Factual ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/mortality ; Lung Neoplasms/pathology ; Male ; Middle Aged ; Prognosis ; Survival Rate
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2021-03-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1945-4589
ISSN (online)	1945-4589
DOI	10.18632/aging.202761
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Article ; Online: A competing risk nomogram predicting cause-specific mortality in patients with lung adenosquamous carcinoma.

Wu, Xiao / Yu, Wenfeng / Petersen, R H / Sheng, Hongxu / Wang, Yiqing / Lv, Wang / Hu, Jian

BMC cancer

2020 Volume 20, Issue 1, Page(s) 429

Abstract: Background: Adenosquamous carcinoma (ASC) is an uncommon histological subtype of lung cancer. The purpose of this study was to assess the cumulative incidences of lung cancer-specific mortality (LC-SM) and other cause-specific mortality (OCSM) in lung ... ...

Abstract	Background: Adenosquamous carcinoma (ASC) is an uncommon histological subtype of lung cancer. The purpose of this study was to assess the cumulative incidences of lung cancer-specific mortality (LC-SM) and other cause-specific mortality (OCSM) in lung ASC patients, and construct a corresponding competing risk nomogram for LC-SM. Methods: Data on 2705 patients with first primary lung ASC histologically diagnosed between 2004 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The cumulative incidence function (CIF) was utilized to calculate the 3-year and 5-year probabilities of LC-SM and OCSM, and a competing risk model was built. Based on the model, we developed a competing risk nomogram to predict the 3-year and 5-year cumulative probabilities of LC-SM and the corresponding concordance indexes (C-indexes) and calibration curves were derived to assess the model performance. To evaluate the clinical usefulness of the nomogram, decision curve analysis (DCA) was conducted. Furthermore, patients were categorized into three groups according to the tertile values of the nomogram-based scores, and their survival differences were assessed using CIF curves. Results: The 3-year and 5-year cumulative mortalities were 49.6 and 55.8% for LC-SM and 8.2 and 11.8% for OCSM, respectively. In multivariate analysis, increasing age, male sex, no surgery, and advanced T, N and M stages were related to a significantly higher likelihood of LC-SM. The nomogram showed good calibration, and the 3-year and 5-year C-indexes for predicting the probabilities of LC-SM in the validation cohort were both 0.79, which were almost equal to those of the ten-fold cross validation. DCA demonstrated that using the nomogram gained more benefit when the threshold probabilities were set within the ranges of 0.24-0.89 and 0.25-0.91 for 3-year and 5-year LCSM, respectively. In both the training and validation cohorts, the high-risk group had the highest probabilities of LC-SM, followed by the medium-risk and low-risk groups (both P < 0.0001). Conclusions: The competing risk nomogram displayed excellent discrimination and calibration for predicting LC-SM. With the aid of this individualized predictive tool, clinicians can more expediently devise appropriate treatment protocols and follow-up schedules.
MeSH term(s)	Aged ; Carcinoma, Adenosquamous/mortality ; Carcinoma, Adenosquamous/pathology ; Cause of Death ; Female ; Follow-Up Studies ; Humans ; Lung Neoplasms/mortality ; Lung Neoplasms/pathology ; Male ; Middle Aged ; Neoplasm Staging ; Nomograms ; Risk Assessment/methods ; SEER Program ; Survival Rate
Language	English
Publishing date	2020-05-16
Publishing country	England
Document type	Journal Article
ISSN	1471-2407
ISSN (online)	1471-2407
DOI	10.1186/s12885-020-06927-w
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Article: Ecliptasaponin A induces apoptosis through the activation of ASK1/JNK pathway and autophagy in human lung cancer cells.

Han, Jia / Lv, Wang / Sheng, Hongxu / Wang, Yiqing / Cao, Longxiang / Huang, Sha / Zhu, Linhai / Hu, Jian

Annals of translational medicine

2019 Volume 7, Issue 20, Page(s) 539

Abstract: Background: Non-small cell lung cancer (NSCLC) is one of the causes of carcinomas mortality worldwide. Ecliptasaponin A (ES), a natural product extracted from the plant known as Eclipta prostrata, has been reported as an anti-cancer drug against various ...

Abstract	Background: Non-small cell lung cancer (NSCLC) is one of the causes of carcinomas mortality worldwide. Ecliptasaponin A (ES), a natural product extracted from the plant known as Eclipta prostrata, has been reported as an anti-cancer drug against various cancer cell lines. However, the exact mechanisms of ES have not yet been fully characterized. Methods: Numerous studies have been done to support that ES has a powerful inhibiting effect on the growth of cancers via the activation of apoptosis and autophagy. To explore the underlying mechanisms of anti-cancer and investigate the relationships of the apoptosis and autophagy, we used apoptosis signal-regulating kinase 1 (ASK1) inhibitor (GS-4997), c-Jun N-terminal kinase (JNK) inhibitor (SP600125), and autophagy inhibitor [chloroquine (CQ) and 3-methyladenine (3-MA)]. Results: ES could potently suppress cell viability and induces apoptotic cell death of human lung cancer cells H460 and H1975. ES activated apoptosis via ASK1/JNK pathway, GS-4997 and SP600125 can attenuated these effects. Furthermore, ES could triggered autophagy in lung cancer cell lines, and the autophagy inhibitor 3-MA and CQ reversed ES-induced apoptosis in H460 and H1975 cells. Furthermore, SP600125 can inhibit autophagy. Conclusions: This study showed that ES induces apoptosis in human lung cancer cells by triggering enhanced autophagy and ASK1/JNK pathway, which may thus be a promising agent against lung cancer.
Language	English
Publishing date	2019-11-01
Publishing country	China
Document type	Journal Article
ZDB-ID	2893931-1
ISSN	2305-5847 ; 2305-5839
ISSN (online)	2305-5847
ISSN	2305-5839
DOI	10.21037/atm.2019.10.07
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Article ; Online: Discriminating association of a common telomerase reverse transcriptase promoter polymorphism with telomere parameters in non-small cell lung cancer with or without epidermal growth factor receptor mutation.

Yuan, Ping / Huang, Sha / Bao, Fei-Chao / Cao, Jin-Lin / Sheng, Hong-Xu / Shi, Liang / Lv, Wang / Hu, Jian

European journal of cancer (Oxford, England : 1990)

2019 Volume 120, Page(s) 10–19

Abstract: Background: The role of epidermal growth factor receptor (EGFR) pathways in regulating telomerase is increasingly being recognised. We analysed the impact of rs2853669 single nucleotide polymorphism (SNP) on telomere parameters and its prognostic value ... ...

Abstract	Background: The role of epidermal growth factor receptor (EGFR) pathways in regulating telomerase is increasingly being recognised. We analysed the impact of rs2853669 single nucleotide polymorphism (SNP) on telomere parameters and its prognostic value for non-small cell lung cancer (NSCLC) with or without EGFR mutation. Methods: The association of rs2853669 with telomerase reverse transcriptase (TERT) mRNA level and relative telomere length (RTL) was analysed using resected tumour samples from 250 NSCLC patients. We also investigated the patients' clinical outcomes with a median follow-up of 57 months (2-99 months). Results: The rs2853669 T/C allele was significantly associated with lower TERT mRNA expression (versus C/C and versus T/T; p < 0.001 for both) and shorter RTL (versus C/C and versus T/T; p = 0.039 and 0.023) in patients without EGFR mutation. Such difference was not observed in their counterparts harbouring EGFR mutation. When considering the cohort as a whole, T/C allele was significantly associated with shortest overall survival compared with T/T or C/C allele (mean: 61.8, 80.9 and 88.7 months, p Conclusion: Our study revealed significant associations of a common SNP within TERT promoter region on telomere parameters and survival in NSCLC patients without EGFR mutation. The result may help providing instruction for therapeutic interventions targeting telomerase and evidence for investigation of TERT-EGFR interacting mechanism in telomere biology.
MeSH term(s)	Biomarkers, Tumor/genetics ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Carcinoma, Non-Small-Cell Lung/surgery ; ErbB Receptors/genetics ; Female ; Follow-Up Studies ; Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Lung Neoplasms/surgery ; Male ; Middle Aged ; Mutation ; Polymorphism, Single Nucleotide ; Prognosis ; Promoter Regions, Genetic ; Retrospective Studies ; Survival Rate ; Telomerase/genetics ; Telomere Homeostasis/genetics
Chemical Substances	Biomarkers, Tumor ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; TERT protein, human (EC 2.7.7.49) ; Telomerase (EC 2.7.7.49)
Language	English
Publishing date	2019-08-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	82061-1
ISSN	1879-0852 ; 0277-5379 ; 0959-8049 ; 0964-1947
ISSN (online)	1879-0852
ISSN	0277-5379 ; 0959-8049 ; 0964-1947
DOI	10.1016/j.ejca.2019.06.024
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Article: Metformin reverses chemoresistance in non-small cell lung cancer via accelerating ubiquitination-mediated degradation of Nrf2.

Huang, Sha / He, Tianyu / Yang, Sijia / Sheng, Hongxu / Tang, Xiuwen / Bao, Feichao / Wang, Yiqing / Lin, Xu / Yu, Wenfeng / Cheng, Fei / Lv, Wang / Hu, Jian

Translational lung cancer research

2020 Volume 9, Issue 6, Page(s) 2337–2355

Abstract: Background: The therapeutic efficacy of cisplatin-based chemotherapy for non-small cell lung cancer (NSCLC) is limited by drug resistance. In NSCLC, hyperactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) counteracts oxidative stress to ... ...

Abstract	Background: The therapeutic efficacy of cisplatin-based chemotherapy for non-small cell lung cancer (NSCLC) is limited by drug resistance. In NSCLC, hyperactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) counteracts oxidative stress to promote chemoresistance. Metformin-mediated downregulation of Nrf2 plays a pivotal role in overcoming drug resistance in NSCLC cells. Therefore, a deeper understanding of the molecular mechanisms of combination therapy and the role of Nrf2 in chemotherapeutic response is critical to clinical translation. Methods: The effects of combination therapy with metformin and cisplatin on cell proliferation and apoptosis, intracellular reactive oxygen species (ROS) levels, and xenograft tumor formation were analyzed in NSCLC cells. Co-immunoprecipitation (co-IP) and Phos-tag assays were used to explore the mechanism of metformin-mediated Nrf2 suppression. Immunohistochemical (IHC) staining was performed to detect Nrf2 expression in matched tumor samples before and after neoadjuvant chemotherapy. Results: Metformin was observed to synergistically augment cisplatin-induced cytotoxicity by strongly inhibiting the level of Nrf2, thereby weakening the antioxidant system and detoxification ability of Nrf2 and enhancing ROS-mediated apoptosis in NSCLC. The synergistic antitumor effect of combination therapy is blocked by treatment with the ROS scavenger N-acetyl cysteine (NAC) as well as overexpression of Nrf2 and its downstream antioxidant protein. Mechanistically, metformin extensively dephosphorylates Nrf2 by attenuating the interaction between Nrf2 and extracellular signal-regulated kinases 1/2 (ERK1/2), which then restores its polyubiquitination and accelerates its proteasomal degradation. Moreover, for the first time, an association of non-decreased Nrf2 expression in patients after neoadjuvant chemotherapy with poor survival and chemoresistance in NSCLC was revealed. Conclusions: Our findings illustrate the mechanism of metformin-mediated Nrf2 degradation through posttranslational modifications (PTMs), which weakens the ROS defense system in NSCLC. Fluctuations in Nrf2 expression have a strong predictive ability for chemotherapeutic response in neoadjuvant NSCLC patients. Targeting of the Nrf2 pathway could be a therapeutic strategy for overcoming chemoresistance, with metformin as the first choice for this strategy.
Language	English
Publishing date	2020-12-26
Publishing country	China
Document type	Journal Article
ZDB-ID	2754335-3
ISSN	2226-4477 ; 2218-6751
ISSN (online)	2226-4477
ISSN	2218-6751
DOI	10.21037/tlcr-20-1072
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