Lung cancer,of which non-small lung cancer is the most common subtype,represents the leading cause of cancer related-death worldwide.It is now recognized that a significant proportion of these patients present alterat...Lung cancer,of which non-small lung cancer is the most common subtype,represents the leading cause of cancer related-death worldwide.It is now recognized that a significant proportion of these patients present alterations in certain genes that drive oncogenesis.In recent years,more of these so-called oncogenic drivers have been identified,and a better understanding of their biology has allowed the development new targeted agents.This review aims to provide an update about the current landscape of driver mutation in non-smallcell lung cancer.Alterations in Kirsten rat sarcoma,epidermal growth factor receptor,MET,anaplastic lymphoma kinase,c-ROS oncogene 1,v-raf murine sarcoma viral oncogene homolog B,neurotrophic receptor tyrosine kinase,human epidermal growth factor 2,neuregulin-1 and rearranged during transfection are discussed,as well as agents targeting these alterations.Current standards of treatment as well as promising future strategies are presented.Currently,more than fifteen targeted agents are food and Drug administration-approved for seven oncogenic drivers in non-small-cell lung cancer,highlighting the importance of actively searching for these mutations.Continuous and future efforts made in defining the biology of each of these alterations will help to elucidate their respective resistance mechanisms,and to define the best treatment strategy and therapeutic sequence.展开更多
The aim of this study was to analyze the correlation of the expression of MET and cyclin D1 and MET gene copy number in non-small cell lung cancer (NSCLC) tissues and patient clinicopathologic characteristics and su...The aim of this study was to analyze the correlation of the expression of MET and cyclin D1 and MET gene copy number in non-small cell lung cancer (NSCLC) tissues and patient clinicopathologic characteristics and sur- vival. Sixty-one NSCLC tissue specimens were included in the study. The expression of MET and cyclin D1 was evaluated by immunohistochemistry and MET gene copy number was assessed by quantitative real-time polymer- ase chain reaction (Q-PCR). Positive expression of MET and cyclin D1 protein and increased MET gene copy number occurred in 59.0%, 59.0% and 18.0% of 61 NSCLC tissues, respectively. MET-positivity correlated with poor differentiation (P = 0.009). Increased MET gene copy number was significantly associated with lymph node metastasis (P = 0.004) and advanced tumor stage (P = 0.048), while the expression of cyclin D1 was not associ- ated with any clinicopathologic parameters. There was a significant correlation between the expression of MET and MET gene copy number (P = 0.002). Additionally, the expression of cyclin D1 had a significant association with the expression of MET as well as MET gene copy number (P = 0.002 and P = 0.017, respectively). MET- positivity and increased MET gene copy number were significantly associated with poor overall survival (P = 0.003 and P 〈 0.001, respectively) in univariate analysis. Multivariate Cox proportional hazard analysis confirmed that the expression of MET and MET gene copy number were prognostic indicators of NSCLC (P = 0.003 and P = 0.001, respectively). The overexpression of MET and the increased MET gene copy number might be adverse prognostic factors for NSCLC patients. The activation of the MET/cyclin D1 signaling pathway may contribute to carcino- genesis and the development of NSCLC, and may represent a target for therapy.展开更多
Objective: This study was designed to investigate promoter methylation status and protein expression of p14^ARF gene in non-small cell lung cancer, and value the role of p14^ARF promoter methylation in carcinogenesis...Objective: This study was designed to investigate promoter methylation status and protein expression of p14^ARF gene in non-small cell lung cancer, and value the role of p14^ARF promoter methylation in carcinogenesis of non-small cell lung cancer. Methods: Promoter methylation status and protein expression of p14^ARF gene in 40 cases of non-small cell lung cancer were analyzed by methylation specific polymerase china reaction (MSP), restriction enzyme-related polymerase chain reaction (RE-PCR) and immunohistochemistry (IHC). Results: The positive rates of p14^ARF promoter methylation in tumor tissues and normal tissues adjacent to cancer were 17.5% (7/40) and 2.5% (1/40) respectively. There were statistically significant differences between them, P〈0.05. The results of RE-PCR were consistent with that of MSP. The expression rate of p14^ARF protein in tumor tissues was significantly lower than that in normal tissues adjacent to cancer, p〈0.01. Promoter methylation status and protein expression of p14^ARF gene in non-small cell lung cancer showed significantly an inverse correlation (r=-0.56, P〈0.01), and both of them did not relate statistically with the clinicopathologic characteristics of patients such as histological classification, clinical stage, differentiation grade and lymph node involvement. Conclusion: Promoter methylation is a crucial mechanism of inactivation of p14^ARF gene. Promoter methylation of p14^ARF gene might he involved in carcinogenesis of non-small cell lung cancer, and is an early event in development process of non-small cell lung cancer. It might be used as a new target in gene treatments in the future.展开更多
BACKGROUND The clinical significance of breast cancer susceptibility gene 1(BRCA1)in nonsmall cell lung cancer(NSCLC)patients undergoing surgery remains unclear up to now.AIM To explore the relation of BRCA1 expressio...BACKGROUND The clinical significance of breast cancer susceptibility gene 1(BRCA1)in nonsmall cell lung cancer(NSCLC)patients undergoing surgery remains unclear up to now.AIM To explore the relation of BRCA1 expression with clinicopathological characteristics and survival in patients with resected NSCLC.METHODS EMBASE,PubMed,Web of Science,and The Cochrane Library databases were searched to identify the relevant articles.To assess the correlation between the expression of BRCA1 and clinicopathological characteristics and prognosis of patients with resected NSCLC patients,the combined relative risks or hazard ratios(HRs)with their corresponding 95%confidence intervals[CIs]were estimated.RESULTS Totally,11 articles involving 1041 patients were included in the meta-analysis.The results indicated that the expression of BRCA1 was significantly correlated with prognosis of resected NSCLC.Positive BRCA1 expression signified a shorter overall survival(HR=1.60,95%CI:1.25-2.05;P<0.001)and disease-free survival(HR=1.78,95%CI:1.42-2.23;P<0.001).However,no significant association of BRCA1 expression with any clinicopathological parameters was observed.CONCLUSION BRCA1 expression indicates a poor prognosis in resected NSCLC patients.BRCA1 might serve as an independent biomarker to predict clinical outcomes and help to customize optimal adjuvant chemotherapy for NSCLC patients who had received surgical therapy.展开更多
Vascular endothelial growth factor (VEGF) is one of the most important and specific factors affecting angiogenesis in tumor development. VEGFR2 is a receptor encoded by the KDR gene. VEGF and VEGFR2 transmit a signal ...Vascular endothelial growth factor (VEGF) is one of the most important and specific factors affecting angiogenesis in tumor development. VEGFR2 is a receptor encoded by the KDR gene. VEGF and VEGFR2 transmit a signal to intracellular tyrosine kinase cascades. Polymorphic variants of the VEGF and KDR genes significantly influence the expression levels of the endothelial growth factor and its receptor, which leads to a change in the activation of angiogenesis in oncopathological processes. In this study, the relationship between the polymorphic variants rs2010963, rs699947 and rs3025039 of the VEGF gene and rs1870377 and rs2071559 of the KDR gene was analyzed with the development of a specific histological type of non-small cell lung cancer and its clinical and morphological characteristics. It was established that the development of squamous cell carcinoma is associated with -634CC genotype of the VEGF gene and the genotypes containing -2578A allele of the VEGF gene reduce the likelihood of this cancer type development. The development of adenocarcinoma is associated with +936CC VEGF/1719TT KDR and +936CT VEGF/1719TT KDR combinations. In women with non-small cell lung cancer, -634GC genotype of the VEGF gene is associated with a greater degree of the primary lesion spread. Genotype -2578СС of the VEGF gene is associated with a higher degree of the primary tumor spread in the general group of patients and with regional metastases in women. Haplotypes -634G/-2578C/+936C are risky for the occurrence of metastases in regional lymph nodes in women.展开更多
Objective:To detect the methylation status of MGMT gene promoter in non-small cell lung cancer(NSCLC),and to analyze the relationship between methylation of MGMT gene promoter and the chemosensitivity and prognosis of...Objective:To detect the methylation status of MGMT gene promoter in non-small cell lung cancer(NSCLC),and to analyze the relationship between methylation of MGMT gene promoter and the chemosensitivity and prognosis of adjuvant chemotherapy after NSCLC.Methods:Tumor tissues and adjacent non-tumor tissues of 92 patients with NSCLC who underwent surgery and adjuvant chemotherapy from January 2012 to June 2015 in the thoracic surgery department of our hospital were collected,methylation-specific PCR(MSP)was used to detect the methylation status of MGMT gene promoter in tissues,and the relationship between methylation of MGMT gene promoter and chemosensitivity,progression-free survival(PFS)and 3-year overall survival rate was analyzed.Results:The methylation rate of MGMT gene promoter in cancer tissue was 39.13%(36/92)higher than that in non-cancer tissue 3.26%(3/92)(P<0.05);methylation of MGMT gene promoter was associated with TNM stage,lymph node metastasis and tumor differentiation(P<0.05);the proportion of patients with recurrence,metastasis or death in methylation group was higher than that in non-methylation group(P<0.05);PFS and 3-year overall survival rate in methylated group were lower than those in non-methylated group(P<0.05);multivariate COX regression analysis showed that lymph node metastasis and promoter methylation of MGMT gene were independent risk factors for prognosis of NSCLC patients.Conclusion:MGMT gene promoter methylation is closely related to the chemosensitivity and prognosis of platinum-based adjuvant chemotherapy after NSCLC.It may be an important target to reverse the chemosensitivity of platinum-based chemotherapy and improve the prognosis of NSCLC.展开更多
Summary: To examine the deletion and point mutation of WWOX (WW domain containing oxidoreductase) exons 6-8 in human non-small cell lung cancer and their possible relationship with pathological stages, tumor tissues ...Summary: To examine the deletion and point mutation of WWOX (WW domain containing oxidoreductase) exons 6-8 in human non-small cell lung cancer and their possible relationship with pathological stages, tumor tissues and the corresponding normal tissues were obtained from 44 Chinese patients who had undergone surgery for non-small cell lung cancer. RNA was extracted from each sample and deletion and mutation of WWOX exons 6-8 were analyzed by RT-PCR and DNA sequencing. Our results showed that 28 of 44 (63.6 %) lung cancer samples showed loss of WWOX exons 6-8 transcript and the deletion was detected in only 3 of 44 (6.8 %) corresponding adjacent normal tissues (P<0.05). The transcript sequencing analyses of the 16 lung cancer samples without transcript loss of WWOX exons 6-8 revealed no difference from the sequence of GenBank. Moreover, the deletion of WWOX exons 6-8 was significantly higher in the smokers when compared with the non-smokers. It is also higher in the men and squamous carcinomas than in women and adenocarcinomas (P<0.05). The deletion, however, was not found to be associated with pathological stages of the tumors. Our study documented a high incidence of deletion of WWOX exons 6-8 in non-small cell lung cancer in Chinese patients and suggested that the frequent loss of WWOX exons 6-8 might play an important role in the tumorigenesis of non-small cell lung cancer in Chinese. WWOX exons 6-8 may serves as a candidate molecular target of smoking carcinogenesis, and point mutation is not a predominant way of alteration of WWOX exons 6-8.展开更多
Objective The aim of this study was to study the quantitative expression of circulating tumour DNA(ctDNA) in patients with non-small cell lung cancer(NSCLC) before and after radical operation and to explore the correl...Objective The aim of this study was to study the quantitative expression of circulating tumour DNA(ctDNA) in patients with non-small cell lung cancer(NSCLC) before and after radical operation and to explore the correlation between gene mutations in non-small cell lung cancer tissues and those in ctDNA.Methods We randomly assigned 5 NSCLC patients from the Department of Thoracic Surgery of Fujian Medical University Union Hospital. All the patients had undergone radical surgery. Venous blood samples were collected from the 5 NSCLC patients at two time points(before the operation and 21–37 days after the operation) for monitoring ctDNA levels. This was done by isolating plasma from venous blood using high velocity centrifugation, extracting DNA from the plasma using the QIAamp Circulating Nucleic Acid kit, and then quantifying the ctDNA levels. The results were analyzed using the Wilcoxon Rank Sum Test. Moreover, the ctDNA levels were compared with those of carcinoembryonic antigen(CEA), which was detected simultaneously with the ctDNA. Then, DNA samples from the tumor tissues and peripheral blood cells and ctDNA were sequenced using the Hiseq2000 sequencing platform(Illumina) and the mutant genes were screened out. Mutations that occurred within the tumor tissues were used as positive control, whereas those found in the pre-operative blood cells were used as a negative control. Based on the mutational analysis of ctDNA genes, a total of 508 cancer-related genes were screened. Results The median values of the pre-and post-operative ctDNA levels in the 5 patients with NSCLC were 0.612(0.518–0.876) and 0.430(0.372–0.612) ng/μL, respectively. There was a significant difference between the two groups(P < 0.05). The pre-operative CEA level was slightly higher than the post-operative level(P > 0.05). In one of the cases, LC tissues showed multiple mutations, consistent with pre-operative ctDNA. Moreover, isogenic mutations of the same type were not detected in post-operative ctDNA or peripheral blood cells. Conclusion Mutations found in the lung cancer(LC) ctDNA gene were consistent with the mutation type of LC tissue. Hence, the quantitative and qualitative analysis of ctDNA is a promising novel molecular biomarker for the evaluation of tumor burden changes in NSCLC.展开更多
Objective: To test the expression of HER4 in non-small cell lung cancer (NSCLC) and elucidate the relationship between its over-expression and the clinical pathology of NSCLC. Methods: 70 cases of paraffin-embedded ti...Objective: To test the expression of HER4 in non-small cell lung cancer (NSCLC) and elucidate the relationship between its over-expression and the clinical pathology of NSCLC. Methods: 70 cases of paraffin-embedded tissues from informative NSCLC were tested for the expression of HER4 by means of immunohistochemical assay. Results: HER4 were overexpressed in NSCLC in 91.4%. The overexpression of HER4 correlated only with the lymph node metastasis, TNM staging and survival after operation. Conclusion: ErbB4 is one of the genes to regulate the growth of NSCLC in advanced stages and artificial interference of the overexpression of HER4 in NSCLC might be a good way for the treatment of NSCLC in advanced stages.展开更多
Objective:To investigate the effects of Intron on the EMT capability of non-small cell lung cancer cell line PC-9.Methods:Firstly,using the psiCHECK-2 plasmid as a basic framework to construct the recombinant plasmid ...Objective:To investigate the effects of Intron on the EMT capability of non-small cell lung cancer cell line PC-9.Methods:Firstly,using the psiCHECK-2 plasmid as a basic framework to construct the recombinant plasmid of psiCHECK-2-Intron dual-luciferase reporter gene;secondly,the psiCHECK-2-Intron and psiCHECK-2 were transfected into PC-9 cells respectively.The migration and invasion abilities of PC-9 cells were analyzed by Matrigel assay.The expression changes of EMT related hallmarks,including N-cadherin,β-catenin and snail,were detected by qRT-PCR and Western Blotting.Results:Compared with the control group,the migration and invasion abilities of PC-9 cells in Intron group significantly decreased(p<0.001).The expression of N-cadherin,β-catenin and snail also down-regulated(p<0.001).Conclusion:The introns could inhibit the EMT of PC-9 cells.展开更多
The advent of targeted molecular therapy against the EML4-ALK fusion gene is the latest therapeutic intervention for a subset of patients with non-small cell lung cancer (NSCLC). Crizotinib (Xalkori) is an orally avai...The advent of targeted molecular therapy against the EML4-ALK fusion gene is the latest therapeutic intervention for a subset of patients with non-small cell lung cancer (NSCLC). Crizotinib (Xalkori) is an orally available small molecule tyrosine kinase inhibitor proven in clinical trials to significantly impact progression free survival and overall response rate. We present a case of a 56-year-old male with NSCLC whose lack of a positive treatment response to this therapy led to the clinical suspicion and identification of the underdiagnosed entity known as synchronous multiple primary lung cancer (SMPLC).展开更多
Non-small cell lung cancer (NSCLC) remains to be primary reason of tumor deaths in the past few decades. The mortality of this malignancy could be reduced by developing new prognostic biomarkers and discovering novel ...Non-small cell lung cancer (NSCLC) remains to be primary reason of tumor deaths in the past few decades. The mortality of this malignancy could be reduced by developing new prognostic biomarkers and discovering novel therapeutic biological target. Here, we studied the mRNA expression of FOX gene family and UBE2C in different types of cancer compared with normal tissue through ONCOMINE differential analysis. CCLE analysis was mined to explore the expression profiles of target genes in different tumor cells. GEPIA was used to discover the expression of target genes in different subtypes and the correlations with lung cancer stage. The prognostic values of FOXM1 and UBE2C were further investigated through Kaplan-Meier plotter analysis. It showed that FOXA1, FOXD1 and FOXM1 were dramatically high expressed in NSCLC comparing with normal lung tissues. Besides, the expression of FOXM1 was significantly associated with UBE2C. Furthermore, the overexpression of FOXM1 and UBE2C were correlated to shorter survival in lung adenocarcinoma (LAC) instead of lung squamous cell carcinoma (LSCC). Hence, we could draw a conclusion that FOXM1 and UBE2C are distinguished biomarkers and crucial prognostic indicators for lung adenocarcinoma patients.展开更多
Objective The aim of this study was to explore the mechanism behind lncRNA small nucleolar RNA host gene 19(lncRNA SNHG19)/microrNA-299-5P(miR-299-5p)/mitogen-activated protein kinase 6(MAPK6)signaling axis promoting ...Objective The aim of this study was to explore the mechanism behind lncRNA small nucleolar RNA host gene 19(lncRNA SNHG19)/microrNA-299-5P(miR-299-5p)/mitogen-activated protein kinase 6(MAPK6)signaling axis promoting metastasis of non-small cell lung cancer(NSCLC).Methods To analyze the abnormal expression of lncRNAs in NSCLC,50 surgically resected NSCLC and adjacent tissue samples were collected from August 2021 to August 2022.The mRNA expression levels of lncRNA SNHG19,Mir-299-5p,and MAPK6 were detected by qRT-PCR.The functions of lncRNA SNHG19,Mir-299-5p and MAPK6 were investigated by CCK-8,clone formation,EdU,scratch,Transwell western blotting(WB)and in vivo xenograft assay.RNA fluorescence in-situ hybridization(FISH),RNA pull-down,dual luciferase reporter,and RNA co-immunoprecipitation assays were used to explore the mechanism of action between lncRNA SNHG19,miR-299-5p,and MAPK6.Results High expression of lncRNA SNHG19 was correlated with poor prognosis,tumor size,lymph node metastasis,and TNM stage in NSCLC patients(P<0.05).Cell function experiments showed that lncRNA SNHG19 could improve the proliferation,clone formation,migration,and invasion ability of A549 cells both in vitro and in vivo(all P<0.05)and increased the relative expression levels of vimentin and MAPK6(P<0.05).The relative expression level of E-cadherin was decreased(P<0.05).lncRNA SNHG19 can interact with Mir-299-5p and regulate the expression level of MAPK6.Conclusion lncRNA SNHG19 is upregulated in NSCLC tissues and cells,and its high expression is associated with tumor progression and poor survival.Moreover,it can act as a molecular sponge for Mir-299-5p to regulate MAPK6 expression and promote the proliferation and metastasis of A549 cells.展开更多
To assses the effect of single nucleotide polymorphism of excision repair cross-complementation group 1 C8092A on the clinical outcome and toxicity in advanced stage non-small cell lung cancer patients receiving first...To assses the effect of single nucleotide polymorphism of excision repair cross-complementation group 1 C8092A on the clinical outcome and toxicity in advanced stage non-small cell lung cancer patients receiving first line platinum based chemotherapy.MethodsThis article is a review of the current research on single nucleotide polymorphism and its effect on treatment outcome and toxicity of advanced stage lung cancer.Conclusion The observations indicate that more advanced studies and trials on C8092A SNPs are needed so as to assess if it could be used as a potential biomarker in the future.展开更多
Objective Using gene chip technology to explore the molecular mechanism of euphorbiasteroid in the treatment of non-small cell lung cancer(NSCLC).Methods A549 cells were used as the in vitro model,and they were random...Objective Using gene chip technology to explore the molecular mechanism of euphorbiasteroid in the treatment of non-small cell lung cancer(NSCLC).Methods A549 cells were used as the in vitro model,and they were randomly divided into control group and different concentrations of euphorbiasteroid administration groups.Each group had 3 duplicate wells,after the cells were cultured in vitro,the cell viability was evaluated by CCK-8 method.Gene chip technology was used to screen the differentially expressed genes(DEGs)between the control group and the euphorbiasteroid administration group.The differential genes were further analyzed for Gene Ontology(GO)function enrichment and Kyoto Encyclopedia of Genes and Genome(KEGG)pathway enrichment analysis.The STRING online analysis platform combined with Cytoscape software to construct a target protein interaction(PPI)network and perform topological analysis to screen key targets,and use Real-time PCR(RT-PCR)and molecular docking technology to verify key targets.Results According to the analysis of gene chip data,276 differentially expressed genes were screened,including 117 up-regulated genes and 159 down-regulated genes.GO analysis showed that differentially expressed genes were mainly involved in cell division,cell proliferation,cell cycle and other processes,involving protein binding,protein kinase binding and other functions,and were mainly distributed in nucleoplasm,chromosomes and other parts.KEGG signaling pathway analysis showed that differentially expressed genes were involved in cell cycle,pyrimidine metabolism,p53 signaling pathway and other pathways.PPI network analysis showed that CCNA2,TOP2A,CCNB1,CDC20,and RRM2 may be the key targets of euphorbiasteroid in the treatment of NSCLC.RT-PCR results showed that the expressions of CCNA2,TOP2A,CCNB1,CDC20,and RRM2 were significantly down-regulated in the euphorbiasteroid administered group,which was consistent with the gene chip results.Molecular docking results showed that euphorbiasteroid had good affinity with key targets and could bind spontaneously and stably.Conclusion The combination of gene chip,RT-PCR technology and molecular docking technology can find out the differential genes after the intervention of euphorbiasteroid,which can be used to explore the mechanism of euphorbiasteroid in the treatment of NSCLC.展开更多
With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly t...With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly temporary and incomplete. Moreover, even patients with the same oncogenic driver gene can respond diversely to the same agent. Furthermore, the therapeutic role of immune-checkpoint inhibitors (ICIs) in oncogene-driven NSCLC remains unclear. Therefore, this review aimed to classify the management of NSCLC with driver mutations based on the gene subtype, concomitant mutation, and dynamic alternation. Then, we provide an overview of the resistant mechanism of target therapy occurring in targeted alternations (“target-dependent resistance”) and in the parallel and downstream pathways (“target-independent resistance”). Thirdly, we discuss the effectiveness of ICIs for NSCLC with driver mutations and the combined therapeutic approaches that might reverse the immunosuppressive tumor immune microenvironment. Finally, we listed the emerging treatment strategies for the new oncogenic alternations, and proposed the perspective of NSCLC with driver mutations. This review will guide clinicians to design tailored treatments for NSCLC with driver mutations.展开更多
Background:Anaplastic lymphoma kinase(ALK)test in advanced non-small cell lung cancer(NSCLC)can help physicians provide target therapies for patients harboring ALK gene rearrangement.This study aimed to investigate th...Background:Anaplastic lymphoma kinase(ALK)test in advanced non-small cell lung cancer(NSCLC)can help physicians provide target therapies for patients harboring ALK gene rearrangement.This study aimed to investigate the real-world test patterns and positive rates of ALK gene rearrangements in advanced NSCLC.Methods:In this real-world study(ChiCTR2000030266),patientswith advanced NSCLC who underwent an ALK rearrangement test in 30 medical centers in China between October 1,2018 and December 31,2019 were retrospectively analyzed.Interpretation training was conducted before the study was initiated.Quality controls were performed at participating centers using immunohistochemistry(IHC)-VENTANA-D5F3.The positive ALK gene rearrangement rate and consistency rate were calculated.The associated clinicopathological characteristics of ALK gene rearrangement were investigated as well.Results:The overall ALK gene rearrangement rate was 6.7%in 23,689 patients with advanced NSCLC and 8.2%in 17,436 patients with advanced lung adenocarcinoma.The quality control analysis of IHC-VENTANA-D5F3 revealed an intrahospital consistency rate of 98.2%(879/895)and an inter-hospital consistency rate of 99.2%(646/651).IHC-VENTANA-D5F3 was used in 53.6%,real-time polymerase chain reaction(RT-PCR)in 25.4%,next-generation sequencing(NGS)in 18.3%,and fluorescence in-situ hybridization(FISH)in 15.9%in the adenocarcinoma subgroup.For specimens tested with multiple methods,the consistency rates confirmed by IHC-VENTANA-D5F3 were 98.0%(822/839)for FISH,98.7%(1,222/1,238)forNGS,and 91.3%(146/160)for RT-PCR.The overall ALK gene rearrangement rateswere higher in females,patients of≤35 years old,never smokers,tumor cellularity of>50,and metastatic specimens used for testing in the total NSCLC population and adenocarcinoma subgroup(all P<0.05).Conclusions:This study highlights the real-world variability and challenges of ALK test in advanced NSCLC,demonstrating a predominant use of IHCVENTANA-D5F3 with high consistency and distinct clinicopathological features in ALK-positive patients.These findings underscore the need for a consensus on optimal test practices and support the development of refined ALK test strategies to enhance diagnostic accuracy and therapeutic decision-making in NSCLC.展开更多
Objective: To investigate the expression of novel multidrug resistance transporter (BCRP gene) from human MCF-7/AdrVp breast cancer cells in normal lung tissue and non-small lung cancer tissue. Methods: RNA was extrac...Objective: To investigate the expression of novel multidrug resistance transporter (BCRP gene) from human MCF-7/AdrVp breast cancer cells in normal lung tissue and non-small lung cancer tissue. Methods: RNA was extracted immediately from fresh normal lung tissue and viable tumor tissue harvested from surgically resected specimens of non-small cell lung cancer patients. cDNA of BCRP gene was prepared by RT-PCR and was then amplified by PCR. cDNA products from those specimens were transferred to blotting membrane through electrophoresis and transferring technique and southern blot hybridization was eventually performed to detect the expression of BCRP gene. Results: RNA were extracted from 8 tumor tissue alone and 12 pairs of tumor tissue and normal lung tissue harvested from the same lung. Four patients’ RNA samples with poor quality due to degrading were discarded. cDNA products of BCRP gene were obtained by RT-PCR and were then amplified by PCR in the remain 16 patients’ RNA samples. Through southern blot hybridization, BCRP gene was found to be slightly expressed in various amounts in all normal lung tissue (10/10) and only in a half of tumor tissue samples (8/16). Conclusion: BCRP gene is slightly expressed in different amount in all normal lung tissue and only in a half of tumor tissue of non-small cell lung cancer patients. It is possible to induce it’s overexpression and to develop multidrug resistance during chemotherapy if using anthracycline anticancer drugs.展开更多
Background Personalized medicine becomes essential in lung cancer treatment, however lung-cancer-related gene expression profiles in Chinese patients remain unknown. In this study, the correlation of gene expression p...Background Personalized medicine becomes essential in lung cancer treatment, however lung-cancer-related gene expression profiles in Chinese patients remain unknown. In this study, the correlation of gene expression profiles and clinical characteristics in non-small-cell lung cancer (NSCLC) was investigated. Methods Seventy-six Chinese patients with NSCLC were enrolled in the study to investigate mRNA expression profiles of excision repair cross complement group 1 (ERCC1), thymidylate synthetase (TYMS), ribonucleotide reductase (RRM1), class Ill 13-tubulin (TUBB3), and epidermal growth factor receptor (EGFR) genes and their correlation with patient clinical characteristics. A novel liquidchip technology was used to detect mRNA expression levels in formalin fixed paraffin embedded tumor pathology samples. The relationships between gene expression and clinical characteristics were assessed using the Mann-Whitney test. Results ERCC1 mRNA levels were higher in tumors from patients with metastatic disease than patients with non- metastatic disease (P=-0.021), and higher in adenocarcinomas than squamous cell carcinomas (P=0.006). Increased TUBB3 mRNA expression levels were found in patients with performance status (PS) 1 in comparison with PS 0 (P=0.049), with poorly differentiated tumors in comparison with tumors that were moderately and well differentiated (P 〈0.000 1), and with advanced stage in comparison with early stage disease (P 〈0.000 1). Conclusions ERCC1 mRNA levels were higher in metastatic adenocarcinoma NSCLC; TUBB3 mRNA levels were significantly higher in poorly differentiated tumors and in advanced stage NSCLC, which indicates the poor prognosis.展开更多
Antigen containing, allogeneic cells secreting the genetically modified protein and peptide-chaperone gp96-Ig cross, prime and expand antigen specific CD8 T cells with therapeutic antitumor activity in mice. In a firs...Antigen containing, allogeneic cells secreting the genetically modified protein and peptide-chaperone gp96-Ig cross, prime and expand antigen specific CD8 T cells with therapeutic antitumor activity in mice. In a first in man phase I study, we now report the results of therapeutic vaccination of non-small cell lung cancer (NSCLC) patients with an established, allogeneic non-small cell lung adenocarcinoma cell line secreting gp96-Ig. Advanced NSCLC-patients stage IIIB or IV of any histological subtype were enrolled and treated with up to 36 vaccinations over the course of 18 weeks. Primary endpoint was safety, secondary endpoints tumor response and overall survival. Measurement of tumor antigen specific CD8 CTL responses is precluded by the lack of known NSCLC associated antigens. Therefore, we measured patient CD8 T cell-IFN-γ responses to allo-antigens of the vaccine cells as surrogate for tumor antigen specific CD8 CTL. In 7 of 18 treated patients tumor growth was stabilized, however none of the 18 patients had an objective tumor response by RECIST criteria. Of 15 patients evaluable for immune response, 11 responded to vaccination with more than twofold increase in CD8-IFN-γ frequency above baseline. These patients had a median survival time of 16.5 months. Four patients who had no CD8 response above base line had survival times from 2.1 to 6.7 months. Our data are consistent with the concept that generation of CD8 CTL by therapeutic vaccination may delay tumor growth and progression and mediate prolonged survival even in the absence of objective tumor responses. Further studies will be required to test this concept and promising result.展开更多
文摘Lung cancer,of which non-small lung cancer is the most common subtype,represents the leading cause of cancer related-death worldwide.It is now recognized that a significant proportion of these patients present alterations in certain genes that drive oncogenesis.In recent years,more of these so-called oncogenic drivers have been identified,and a better understanding of their biology has allowed the development new targeted agents.This review aims to provide an update about the current landscape of driver mutation in non-smallcell lung cancer.Alterations in Kirsten rat sarcoma,epidermal growth factor receptor,MET,anaplastic lymphoma kinase,c-ROS oncogene 1,v-raf murine sarcoma viral oncogene homolog B,neurotrophic receptor tyrosine kinase,human epidermal growth factor 2,neuregulin-1 and rearranged during transfection are discussed,as well as agents targeting these alterations.Current standards of treatment as well as promising future strategies are presented.Currently,more than fifteen targeted agents are food and Drug administration-approved for seven oncogenic drivers in non-small-cell lung cancer,highlighting the importance of actively searching for these mutations.Continuous and future efforts made in defining the biology of each of these alterations will help to elucidate their respective resistance mechanisms,and to define the best treatment strategy and therapeutic sequence.
基金supported in part by a grant from the Nature Science Foundation of Health Bureau of Shaanxi Province(#08D28)
文摘The aim of this study was to analyze the correlation of the expression of MET and cyclin D1 and MET gene copy number in non-small cell lung cancer (NSCLC) tissues and patient clinicopathologic characteristics and sur- vival. Sixty-one NSCLC tissue specimens were included in the study. The expression of MET and cyclin D1 was evaluated by immunohistochemistry and MET gene copy number was assessed by quantitative real-time polymer- ase chain reaction (Q-PCR). Positive expression of MET and cyclin D1 protein and increased MET gene copy number occurred in 59.0%, 59.0% and 18.0% of 61 NSCLC tissues, respectively. MET-positivity correlated with poor differentiation (P = 0.009). Increased MET gene copy number was significantly associated with lymph node metastasis (P = 0.004) and advanced tumor stage (P = 0.048), while the expression of cyclin D1 was not associ- ated with any clinicopathologic parameters. There was a significant correlation between the expression of MET and MET gene copy number (P = 0.002). Additionally, the expression of cyclin D1 had a significant association with the expression of MET as well as MET gene copy number (P = 0.002 and P = 0.017, respectively). MET- positivity and increased MET gene copy number were significantly associated with poor overall survival (P = 0.003 and P 〈 0.001, respectively) in univariate analysis. Multivariate Cox proportional hazard analysis confirmed that the expression of MET and MET gene copy number were prognostic indicators of NSCLC (P = 0.003 and P = 0.001, respectively). The overexpression of MET and the increased MET gene copy number might be adverse prognostic factors for NSCLC patients. The activation of the MET/cyclin D1 signaling pathway may contribute to carcino- genesis and the development of NSCLC, and may represent a target for therapy.
文摘Objective: This study was designed to investigate promoter methylation status and protein expression of p14^ARF gene in non-small cell lung cancer, and value the role of p14^ARF promoter methylation in carcinogenesis of non-small cell lung cancer. Methods: Promoter methylation status and protein expression of p14^ARF gene in 40 cases of non-small cell lung cancer were analyzed by methylation specific polymerase china reaction (MSP), restriction enzyme-related polymerase chain reaction (RE-PCR) and immunohistochemistry (IHC). Results: The positive rates of p14^ARF promoter methylation in tumor tissues and normal tissues adjacent to cancer were 17.5% (7/40) and 2.5% (1/40) respectively. There were statistically significant differences between them, P〈0.05. The results of RE-PCR were consistent with that of MSP. The expression rate of p14^ARF protein in tumor tissues was significantly lower than that in normal tissues adjacent to cancer, p〈0.01. Promoter methylation status and protein expression of p14^ARF gene in non-small cell lung cancer showed significantly an inverse correlation (r=-0.56, P〈0.01), and both of them did not relate statistically with the clinicopathologic characteristics of patients such as histological classification, clinical stage, differentiation grade and lymph node involvement. Conclusion: Promoter methylation is a crucial mechanism of inactivation of p14^ARF gene. Promoter methylation of p14^ARF gene might he involved in carcinogenesis of non-small cell lung cancer, and is an early event in development process of non-small cell lung cancer. It might be used as a new target in gene treatments in the future.
文摘BACKGROUND The clinical significance of breast cancer susceptibility gene 1(BRCA1)in nonsmall cell lung cancer(NSCLC)patients undergoing surgery remains unclear up to now.AIM To explore the relation of BRCA1 expression with clinicopathological characteristics and survival in patients with resected NSCLC.METHODS EMBASE,PubMed,Web of Science,and The Cochrane Library databases were searched to identify the relevant articles.To assess the correlation between the expression of BRCA1 and clinicopathological characteristics and prognosis of patients with resected NSCLC patients,the combined relative risks or hazard ratios(HRs)with their corresponding 95%confidence intervals[CIs]were estimated.RESULTS Totally,11 articles involving 1041 patients were included in the meta-analysis.The results indicated that the expression of BRCA1 was significantly correlated with prognosis of resected NSCLC.Positive BRCA1 expression signified a shorter overall survival(HR=1.60,95%CI:1.25-2.05;P<0.001)and disease-free survival(HR=1.78,95%CI:1.42-2.23;P<0.001).However,no significant association of BRCA1 expression with any clinicopathological parameters was observed.CONCLUSION BRCA1 expression indicates a poor prognosis in resected NSCLC patients.BRCA1 might serve as an independent biomarker to predict clinical outcomes and help to customize optimal adjuvant chemotherapy for NSCLC patients who had received surgical therapy.
文摘Vascular endothelial growth factor (VEGF) is one of the most important and specific factors affecting angiogenesis in tumor development. VEGFR2 is a receptor encoded by the KDR gene. VEGF and VEGFR2 transmit a signal to intracellular tyrosine kinase cascades. Polymorphic variants of the VEGF and KDR genes significantly influence the expression levels of the endothelial growth factor and its receptor, which leads to a change in the activation of angiogenesis in oncopathological processes. In this study, the relationship between the polymorphic variants rs2010963, rs699947 and rs3025039 of the VEGF gene and rs1870377 and rs2071559 of the KDR gene was analyzed with the development of a specific histological type of non-small cell lung cancer and its clinical and morphological characteristics. It was established that the development of squamous cell carcinoma is associated with -634CC genotype of the VEGF gene and the genotypes containing -2578A allele of the VEGF gene reduce the likelihood of this cancer type development. The development of adenocarcinoma is associated with +936CC VEGF/1719TT KDR and +936CT VEGF/1719TT KDR combinations. In women with non-small cell lung cancer, -634GC genotype of the VEGF gene is associated with a greater degree of the primary lesion spread. Genotype -2578СС of the VEGF gene is associated with a higher degree of the primary tumor spread in the general group of patients and with regional metastases in women. Haplotypes -634G/-2578C/+936C are risky for the occurrence of metastases in regional lymph nodes in women.
基金Research Project of Traditional Chinese Medicine of Shaanxi Traditional Chinese Medicine Administration in 2017.Project No:LCMS052.
文摘Objective:To detect the methylation status of MGMT gene promoter in non-small cell lung cancer(NSCLC),and to analyze the relationship between methylation of MGMT gene promoter and the chemosensitivity and prognosis of adjuvant chemotherapy after NSCLC.Methods:Tumor tissues and adjacent non-tumor tissues of 92 patients with NSCLC who underwent surgery and adjuvant chemotherapy from January 2012 to June 2015 in the thoracic surgery department of our hospital were collected,methylation-specific PCR(MSP)was used to detect the methylation status of MGMT gene promoter in tissues,and the relationship between methylation of MGMT gene promoter and chemosensitivity,progression-free survival(PFS)and 3-year overall survival rate was analyzed.Results:The methylation rate of MGMT gene promoter in cancer tissue was 39.13%(36/92)higher than that in non-cancer tissue 3.26%(3/92)(P<0.05);methylation of MGMT gene promoter was associated with TNM stage,lymph node metastasis and tumor differentiation(P<0.05);the proportion of patients with recurrence,metastasis or death in methylation group was higher than that in non-methylation group(P<0.05);PFS and 3-year overall survival rate in methylated group were lower than those in non-methylated group(P<0.05);multivariate COX regression analysis showed that lymph node metastasis and promoter methylation of MGMT gene were independent risk factors for prognosis of NSCLC patients.Conclusion:MGMT gene promoter methylation is closely related to the chemosensitivity and prognosis of platinum-based adjuvant chemotherapy after NSCLC.It may be an important target to reverse the chemosensitivity of platinum-based chemotherapy and improve the prognosis of NSCLC.
文摘Summary: To examine the deletion and point mutation of WWOX (WW domain containing oxidoreductase) exons 6-8 in human non-small cell lung cancer and their possible relationship with pathological stages, tumor tissues and the corresponding normal tissues were obtained from 44 Chinese patients who had undergone surgery for non-small cell lung cancer. RNA was extracted from each sample and deletion and mutation of WWOX exons 6-8 were analyzed by RT-PCR and DNA sequencing. Our results showed that 28 of 44 (63.6 %) lung cancer samples showed loss of WWOX exons 6-8 transcript and the deletion was detected in only 3 of 44 (6.8 %) corresponding adjacent normal tissues (P<0.05). The transcript sequencing analyses of the 16 lung cancer samples without transcript loss of WWOX exons 6-8 revealed no difference from the sequence of GenBank. Moreover, the deletion of WWOX exons 6-8 was significantly higher in the smokers when compared with the non-smokers. It is also higher in the men and squamous carcinomas than in women and adenocarcinomas (P<0.05). The deletion, however, was not found to be associated with pathological stages of the tumors. Our study documented a high incidence of deletion of WWOX exons 6-8 in non-small cell lung cancer in Chinese patients and suggested that the frequent loss of WWOX exons 6-8 might play an important role in the tumorigenesis of non-small cell lung cancer in Chinese. WWOX exons 6-8 may serves as a candidate molecular target of smoking carcinogenesis, and point mutation is not a predominant way of alteration of WWOX exons 6-8.
基金Supported by grants from the Key Specialty Discipline Construction Program of Fujian and Nation,P.R.CFujian Provincial Department of Health’s Key Middle-aged and Young Talents Program(No.2013-ZQN-JC-14)
文摘Objective The aim of this study was to study the quantitative expression of circulating tumour DNA(ctDNA) in patients with non-small cell lung cancer(NSCLC) before and after radical operation and to explore the correlation between gene mutations in non-small cell lung cancer tissues and those in ctDNA.Methods We randomly assigned 5 NSCLC patients from the Department of Thoracic Surgery of Fujian Medical University Union Hospital. All the patients had undergone radical surgery. Venous blood samples were collected from the 5 NSCLC patients at two time points(before the operation and 21–37 days after the operation) for monitoring ctDNA levels. This was done by isolating plasma from venous blood using high velocity centrifugation, extracting DNA from the plasma using the QIAamp Circulating Nucleic Acid kit, and then quantifying the ctDNA levels. The results were analyzed using the Wilcoxon Rank Sum Test. Moreover, the ctDNA levels were compared with those of carcinoembryonic antigen(CEA), which was detected simultaneously with the ctDNA. Then, DNA samples from the tumor tissues and peripheral blood cells and ctDNA were sequenced using the Hiseq2000 sequencing platform(Illumina) and the mutant genes were screened out. Mutations that occurred within the tumor tissues were used as positive control, whereas those found in the pre-operative blood cells were used as a negative control. Based on the mutational analysis of ctDNA genes, a total of 508 cancer-related genes were screened. Results The median values of the pre-and post-operative ctDNA levels in the 5 patients with NSCLC were 0.612(0.518–0.876) and 0.430(0.372–0.612) ng/μL, respectively. There was a significant difference between the two groups(P < 0.05). The pre-operative CEA level was slightly higher than the post-operative level(P > 0.05). In one of the cases, LC tissues showed multiple mutations, consistent with pre-operative ctDNA. Moreover, isogenic mutations of the same type were not detected in post-operative ctDNA or peripheral blood cells. Conclusion Mutations found in the lung cancer(LC) ctDNA gene were consistent with the mutation type of LC tissue. Hence, the quantitative and qualitative analysis of ctDNA is a promising novel molecular biomarker for the evaluation of tumor burden changes in NSCLC.
基金Supported by a grant from the Ningbo Health Bureau of Zhejiang province (No. 2002057)
文摘Objective: To test the expression of HER4 in non-small cell lung cancer (NSCLC) and elucidate the relationship between its over-expression and the clinical pathology of NSCLC. Methods: 70 cases of paraffin-embedded tissues from informative NSCLC were tested for the expression of HER4 by means of immunohistochemical assay. Results: HER4 were overexpressed in NSCLC in 91.4%. The overexpression of HER4 correlated only with the lymph node metastasis, TNM staging and survival after operation. Conclusion: ErbB4 is one of the genes to regulate the growth of NSCLC in advanced stages and artificial interference of the overexpression of HER4 in NSCLC might be a good way for the treatment of NSCLC in advanced stages.
基金National Natural Science Foundation of China(No.81660474)。
文摘Objective:To investigate the effects of Intron on the EMT capability of non-small cell lung cancer cell line PC-9.Methods:Firstly,using the psiCHECK-2 plasmid as a basic framework to construct the recombinant plasmid of psiCHECK-2-Intron dual-luciferase reporter gene;secondly,the psiCHECK-2-Intron and psiCHECK-2 were transfected into PC-9 cells respectively.The migration and invasion abilities of PC-9 cells were analyzed by Matrigel assay.The expression changes of EMT related hallmarks,including N-cadherin,β-catenin and snail,were detected by qRT-PCR and Western Blotting.Results:Compared with the control group,the migration and invasion abilities of PC-9 cells in Intron group significantly decreased(p<0.001).The expression of N-cadherin,β-catenin and snail also down-regulated(p<0.001).Conclusion:The introns could inhibit the EMT of PC-9 cells.
文摘The advent of targeted molecular therapy against the EML4-ALK fusion gene is the latest therapeutic intervention for a subset of patients with non-small cell lung cancer (NSCLC). Crizotinib (Xalkori) is an orally available small molecule tyrosine kinase inhibitor proven in clinical trials to significantly impact progression free survival and overall response rate. We present a case of a 56-year-old male with NSCLC whose lack of a positive treatment response to this therapy led to the clinical suspicion and identification of the underdiagnosed entity known as synchronous multiple primary lung cancer (SMPLC).
文摘Non-small cell lung cancer (NSCLC) remains to be primary reason of tumor deaths in the past few decades. The mortality of this malignancy could be reduced by developing new prognostic biomarkers and discovering novel therapeutic biological target. Here, we studied the mRNA expression of FOX gene family and UBE2C in different types of cancer compared with normal tissue through ONCOMINE differential analysis. CCLE analysis was mined to explore the expression profiles of target genes in different tumor cells. GEPIA was used to discover the expression of target genes in different subtypes and the correlations with lung cancer stage. The prognostic values of FOXM1 and UBE2C were further investigated through Kaplan-Meier plotter analysis. It showed that FOXA1, FOXD1 and FOXM1 were dramatically high expressed in NSCLC comparing with normal lung tissues. Besides, the expression of FOXM1 was significantly associated with UBE2C. Furthermore, the overexpression of FOXM1 and UBE2C were correlated to shorter survival in lung adenocarcinoma (LAC) instead of lung squamous cell carcinoma (LSCC). Hence, we could draw a conclusion that FOXM1 and UBE2C are distinguished biomarkers and crucial prognostic indicators for lung adenocarcinoma patients.
文摘Objective The aim of this study was to explore the mechanism behind lncRNA small nucleolar RNA host gene 19(lncRNA SNHG19)/microrNA-299-5P(miR-299-5p)/mitogen-activated protein kinase 6(MAPK6)signaling axis promoting metastasis of non-small cell lung cancer(NSCLC).Methods To analyze the abnormal expression of lncRNAs in NSCLC,50 surgically resected NSCLC and adjacent tissue samples were collected from August 2021 to August 2022.The mRNA expression levels of lncRNA SNHG19,Mir-299-5p,and MAPK6 were detected by qRT-PCR.The functions of lncRNA SNHG19,Mir-299-5p and MAPK6 were investigated by CCK-8,clone formation,EdU,scratch,Transwell western blotting(WB)and in vivo xenograft assay.RNA fluorescence in-situ hybridization(FISH),RNA pull-down,dual luciferase reporter,and RNA co-immunoprecipitation assays were used to explore the mechanism of action between lncRNA SNHG19,miR-299-5p,and MAPK6.Results High expression of lncRNA SNHG19 was correlated with poor prognosis,tumor size,lymph node metastasis,and TNM stage in NSCLC patients(P<0.05).Cell function experiments showed that lncRNA SNHG19 could improve the proliferation,clone formation,migration,and invasion ability of A549 cells both in vitro and in vivo(all P<0.05)and increased the relative expression levels of vimentin and MAPK6(P<0.05).The relative expression level of E-cadherin was decreased(P<0.05).lncRNA SNHG19 can interact with Mir-299-5p and regulate the expression level of MAPK6.Conclusion lncRNA SNHG19 is upregulated in NSCLC tissues and cells,and its high expression is associated with tumor progression and poor survival.Moreover,it can act as a molecular sponge for Mir-299-5p to regulate MAPK6 expression and promote the proliferation and metastasis of A549 cells.
文摘To assses the effect of single nucleotide polymorphism of excision repair cross-complementation group 1 C8092A on the clinical outcome and toxicity in advanced stage non-small cell lung cancer patients receiving first line platinum based chemotherapy.MethodsThis article is a review of the current research on single nucleotide polymorphism and its effect on treatment outcome and toxicity of advanced stage lung cancer.Conclusion The observations indicate that more advanced studies and trials on C8092A SNPs are needed so as to assess if it could be used as a potential biomarker in the future.
基金This study was supported by the National Key Research and Development Program of China(Grant No.2018YFE0197900).
文摘Objective Using gene chip technology to explore the molecular mechanism of euphorbiasteroid in the treatment of non-small cell lung cancer(NSCLC).Methods A549 cells were used as the in vitro model,and they were randomly divided into control group and different concentrations of euphorbiasteroid administration groups.Each group had 3 duplicate wells,after the cells were cultured in vitro,the cell viability was evaluated by CCK-8 method.Gene chip technology was used to screen the differentially expressed genes(DEGs)between the control group and the euphorbiasteroid administration group.The differential genes were further analyzed for Gene Ontology(GO)function enrichment and Kyoto Encyclopedia of Genes and Genome(KEGG)pathway enrichment analysis.The STRING online analysis platform combined with Cytoscape software to construct a target protein interaction(PPI)network and perform topological analysis to screen key targets,and use Real-time PCR(RT-PCR)and molecular docking technology to verify key targets.Results According to the analysis of gene chip data,276 differentially expressed genes were screened,including 117 up-regulated genes and 159 down-regulated genes.GO analysis showed that differentially expressed genes were mainly involved in cell division,cell proliferation,cell cycle and other processes,involving protein binding,protein kinase binding and other functions,and were mainly distributed in nucleoplasm,chromosomes and other parts.KEGG signaling pathway analysis showed that differentially expressed genes were involved in cell cycle,pyrimidine metabolism,p53 signaling pathway and other pathways.PPI network analysis showed that CCNA2,TOP2A,CCNB1,CDC20,and RRM2 may be the key targets of euphorbiasteroid in the treatment of NSCLC.RT-PCR results showed that the expressions of CCNA2,TOP2A,CCNB1,CDC20,and RRM2 were significantly down-regulated in the euphorbiasteroid administered group,which was consistent with the gene chip results.Molecular docking results showed that euphorbiasteroid had good affinity with key targets and could bind spontaneously and stably.Conclusion The combination of gene chip,RT-PCR technology and molecular docking technology can find out the differential genes after the intervention of euphorbiasteroid,which can be used to explore the mechanism of euphorbiasteroid in the treatment of NSCLC.
基金Beijing Natural Science Foundation(No.7222144)National Key Research and Development Project(No.2019YFC1315700)CAMS Key Laboratory of Translational Research on Lung Cancer(No.2018PT31035).
文摘With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly temporary and incomplete. Moreover, even patients with the same oncogenic driver gene can respond diversely to the same agent. Furthermore, the therapeutic role of immune-checkpoint inhibitors (ICIs) in oncogene-driven NSCLC remains unclear. Therefore, this review aimed to classify the management of NSCLC with driver mutations based on the gene subtype, concomitant mutation, and dynamic alternation. Then, we provide an overview of the resistant mechanism of target therapy occurring in targeted alternations (“target-dependent resistance”) and in the parallel and downstream pathways (“target-independent resistance”). Thirdly, we discuss the effectiveness of ICIs for NSCLC with driver mutations and the combined therapeutic approaches that might reverse the immunosuppressive tumor immune microenvironment. Finally, we listed the emerging treatment strategies for the new oncogenic alternations, and proposed the perspective of NSCLC with driver mutations. This review will guide clinicians to design tailored treatments for NSCLC with driver mutations.
基金CAMS Innovation Fund for Medical Sciences,Grant/Award Numbers:2021-1-I2M-012,2022-I2M-C&T-B-078Beijing Hope Run Special Fund of Cancer Foundation of the People’s Republic of China,Grant/Award Number:LC2019L04+1 种基金National Key Research and Development Program,Grant/Award Number:2022YFC2409902Capital’s Funds for Health Improvement and Research,Grant/Award Number:2020-2Z-4028。
文摘Background:Anaplastic lymphoma kinase(ALK)test in advanced non-small cell lung cancer(NSCLC)can help physicians provide target therapies for patients harboring ALK gene rearrangement.This study aimed to investigate the real-world test patterns and positive rates of ALK gene rearrangements in advanced NSCLC.Methods:In this real-world study(ChiCTR2000030266),patientswith advanced NSCLC who underwent an ALK rearrangement test in 30 medical centers in China between October 1,2018 and December 31,2019 were retrospectively analyzed.Interpretation training was conducted before the study was initiated.Quality controls were performed at participating centers using immunohistochemistry(IHC)-VENTANA-D5F3.The positive ALK gene rearrangement rate and consistency rate were calculated.The associated clinicopathological characteristics of ALK gene rearrangement were investigated as well.Results:The overall ALK gene rearrangement rate was 6.7%in 23,689 patients with advanced NSCLC and 8.2%in 17,436 patients with advanced lung adenocarcinoma.The quality control analysis of IHC-VENTANA-D5F3 revealed an intrahospital consistency rate of 98.2%(879/895)and an inter-hospital consistency rate of 99.2%(646/651).IHC-VENTANA-D5F3 was used in 53.6%,real-time polymerase chain reaction(RT-PCR)in 25.4%,next-generation sequencing(NGS)in 18.3%,and fluorescence in-situ hybridization(FISH)in 15.9%in the adenocarcinoma subgroup.For specimens tested with multiple methods,the consistency rates confirmed by IHC-VENTANA-D5F3 were 98.0%(822/839)for FISH,98.7%(1,222/1,238)forNGS,and 91.3%(146/160)for RT-PCR.The overall ALK gene rearrangement rateswere higher in females,patients of≤35 years old,never smokers,tumor cellularity of>50,and metastatic specimens used for testing in the total NSCLC population and adenocarcinoma subgroup(all P<0.05).Conclusions:This study highlights the real-world variability and challenges of ALK test in advanced NSCLC,demonstrating a predominant use of IHCVENTANA-D5F3 with high consistency and distinct clinicopathological features in ALK-positive patients.These findings underscore the need for a consensus on optimal test practices and support the development of refined ALK test strategies to enhance diagnostic accuracy and therapeutic decision-making in NSCLC.
文摘Objective: To investigate the expression of novel multidrug resistance transporter (BCRP gene) from human MCF-7/AdrVp breast cancer cells in normal lung tissue and non-small lung cancer tissue. Methods: RNA was extracted immediately from fresh normal lung tissue and viable tumor tissue harvested from surgically resected specimens of non-small cell lung cancer patients. cDNA of BCRP gene was prepared by RT-PCR and was then amplified by PCR. cDNA products from those specimens were transferred to blotting membrane through electrophoresis and transferring technique and southern blot hybridization was eventually performed to detect the expression of BCRP gene. Results: RNA were extracted from 8 tumor tissue alone and 12 pairs of tumor tissue and normal lung tissue harvested from the same lung. Four patients’ RNA samples with poor quality due to degrading were discarded. cDNA products of BCRP gene were obtained by RT-PCR and were then amplified by PCR in the remain 16 patients’ RNA samples. Through southern blot hybridization, BCRP gene was found to be slightly expressed in various amounts in all normal lung tissue (10/10) and only in a half of tumor tissue samples (8/16). Conclusion: BCRP gene is slightly expressed in different amount in all normal lung tissue and only in a half of tumor tissue of non-small cell lung cancer patients. It is possible to induce it’s overexpression and to develop multidrug resistance during chemotherapy if using anthracycline anticancer drugs.
文摘Background Personalized medicine becomes essential in lung cancer treatment, however lung-cancer-related gene expression profiles in Chinese patients remain unknown. In this study, the correlation of gene expression profiles and clinical characteristics in non-small-cell lung cancer (NSCLC) was investigated. Methods Seventy-six Chinese patients with NSCLC were enrolled in the study to investigate mRNA expression profiles of excision repair cross complement group 1 (ERCC1), thymidylate synthetase (TYMS), ribonucleotide reductase (RRM1), class Ill 13-tubulin (TUBB3), and epidermal growth factor receptor (EGFR) genes and their correlation with patient clinical characteristics. A novel liquidchip technology was used to detect mRNA expression levels in formalin fixed paraffin embedded tumor pathology samples. The relationships between gene expression and clinical characteristics were assessed using the Mann-Whitney test. Results ERCC1 mRNA levels were higher in tumors from patients with metastatic disease than patients with non- metastatic disease (P=-0.021), and higher in adenocarcinomas than squamous cell carcinomas (P=0.006). Increased TUBB3 mRNA expression levels were found in patients with performance status (PS) 1 in comparison with PS 0 (P=0.049), with poorly differentiated tumors in comparison with tumors that were moderately and well differentiated (P 〈0.000 1), and with advanced stage in comparison with early stage disease (P 〈0.000 1). Conclusions ERCC1 mRNA levels were higher in metastatic adenocarcinoma NSCLC; TUBB3 mRNA levels were significantly higher in poorly differentiated tumors and in advanced stage NSCLC, which indicates the poor prognosis.
文摘Antigen containing, allogeneic cells secreting the genetically modified protein and peptide-chaperone gp96-Ig cross, prime and expand antigen specific CD8 T cells with therapeutic antitumor activity in mice. In a first in man phase I study, we now report the results of therapeutic vaccination of non-small cell lung cancer (NSCLC) patients with an established, allogeneic non-small cell lung adenocarcinoma cell line secreting gp96-Ig. Advanced NSCLC-patients stage IIIB or IV of any histological subtype were enrolled and treated with up to 36 vaccinations over the course of 18 weeks. Primary endpoint was safety, secondary endpoints tumor response and overall survival. Measurement of tumor antigen specific CD8 CTL responses is precluded by the lack of known NSCLC associated antigens. Therefore, we measured patient CD8 T cell-IFN-γ responses to allo-antigens of the vaccine cells as surrogate for tumor antigen specific CD8 CTL. In 7 of 18 treated patients tumor growth was stabilized, however none of the 18 patients had an objective tumor response by RECIST criteria. Of 15 patients evaluable for immune response, 11 responded to vaccination with more than twofold increase in CD8-IFN-γ frequency above baseline. These patients had a median survival time of 16.5 months. Four patients who had no CD8 response above base line had survival times from 2.1 to 6.7 months. Our data are consistent with the concept that generation of CD8 CTL by therapeutic vaccination may delay tumor growth and progression and mediate prolonged survival even in the absence of objective tumor responses. Further studies will be required to test this concept and promising result.