Mechanism Of Lung Cancer Development Research Articles

Deciphering the Role of miR-30a-5p and DLGAP1 Gene in Non-small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the deadliest form of cancer worldwide. Understanding the mechanisms of lung cancer development is vital for targeted therapy advancements. This article explores the little-known role of the guanylate kinase-associated protein (GKAP), encoded by the Disks large-associated protein 1 (DLGAP1) gene, in NSCLC along with assessing microRNA-30a-5p's influence on DLGAP1 gene expression in the A549 cell line. Experiments were conducted on A549 cells transfected with synthetic oligonucleotides. The luciferase assay was employed to confirm the binding site of miR-30a-5p to the 3'UTR of DLGAP1 mRNA. The role of miRNA-30a-5p mimic in regulating potential target gene expression at the protein and mRNA levels was studied by performing RT-qPCR and western blot analyses. The effects of DLGAP1 knockdown and miRNA-30a-5p mimic on cell viability and the cell cycle were evaluated using the MTT test and flow cytometry with annexin/iodide cell staining. The luciferase assay indicated that miR-30a-5p has the ability to bind to the 3'UTR of DLGAP1 mRNA. RT-qPCR revealed that the overexpression of miR-30a-5p down-regulates DLGAP1 mRNA. Western blot analysis indicated that miR-30a-5p slightly reduces the level of the GKAP protein. Knockdown of DLGAP1 with synthetic oligonucleotides, as well as transfection with a miR-30a-5p mimic, significantly attenuates cell proliferation and increases the number of cells in the early and late stages of apoptosis. Our findings reveal the antiproliferative effect of miR-30a-5p and DLGAP1 gene knockdown on A549 cancer cells, implying that these elements could be considered as therapeutic targets for personalized medicine in NSCLC patients.

Abstract 3643: Molecular pathogenesis of lung cancer associated with interstitial pneumonia

Abstract Background: Interstitial pneumonia (IP) is known to be associated with a high risk of developing lung cancer. While common mechanisms have been reported to be involved in the pathogenesis of IP and lung cancer, including genetic and epigenomic alterations or specific signaling pathway activations, many of the molecular mechanisms of lung cancer development in IP lesions remain unknown. Methods: To clarify the detailed mechanisms of the pathogenesis of lung cancer associated with IP, we performed spatially resolved transcriptomics on lung cancer specimens obtained from usual interstitial pneumonia (UIP) associated lung cancer patients. In a total of 10 patients, including five lung cancers that developed inside the UIP and five lung cancers that originated outside the UIP, regions of interest (ROIs) were selected in the tumoral tissues and their adjacent non-tumor tissues. Then, gene expression profiles were comprehensively analyzed by using GeoMx digital spatial profiler in each ROI. Results: In the UIP lesions adjacent to lung cancer, increased gene expressions associated with pulmonary fibrosis, such as COL1A1, COL3A1, and APOE, were observed, and gene set enrichment analysis (GSEA) revealed that they were associated with autoimmunity-related pathways. When we compared the tumor lesions developed inside the UIP with outside the UIP, increased gene expressions related to IP mortality were observed in the tumor cells developed inside the UIP. Interestingly, GSEA revealed that the gene set for neutrophil extracellular trap (NETs) formation was found to be upregulated in the tumor cells developed inside the UIP, suggesting that NETs plays an important role in the pathogenesis of lung cancer developed in IP lesion. Conclusions: In our study, spatially resolved transcriptomics revealed a novel pathway related to the pathogenesis of lung cancer associated with IP. Citation Format: Daisuke Mizuno, Kazuhiko Shien, Atsushi Matsuoka, Masayoshi Ohki, Shuta Tomida, Ryo Yoshichika, Tomoaki Higashihara, Fumiaki Mukohara, Naohiro Hayashi, Tomohiro Habu, Mao Yoshikawa, Ken Suzawa, Hiromasa Yamamoto, Daisuke Ennishi, Shinichi Toyooka. Molecular pathogenesis of lung cancer associated with interstitial pneumonia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3643.

Abstract 784: Proteome-wide mendelian randomization identifies causal association between plasma proteins and lung cancer

Abstract Background: Lung cancer is one of the world's main health issues, and the exploration of novel protein markers can help to understand the mechanisms of lung cancer development and the discovery of therapeutic targets. Based on this, we used proteome-wide Mendelian Randomization to determine causal associations between plasma protein levels and the risk of developing lung cancer and subtypes. Methods: We performed a two-sample Mendelian Randomization analysis using genome-wide association data for 4907 proteins from the deCODE genetics study and five lung cancer and its subtypes from the FinnGen database. Causal effects were estimated using the Wald-ratio method or the inverse variance weighted (IVW) method, with additional analyses using the other four common methods when the number of SNPs was more than one. The Steiger filter method was used to test the correct direction of the causal effect. Multiple corrections were utilized by the Benjamini-Hochberg method. Results: After filtering, we finally analyzed 4645 proteins for the causal association with lung cancer, and the F-statistic of the instrumental variable for each protein was more than 10. After multiple tests, the levels of four genetically predictive proteins were found to be associated with the risk of lung cancer, and one protein was associated with the risk of small-cell lung cancer. In detail, elevated levels of three genetically predicted proteins were significantly associated with increased risk of lung cancer, namely, SYSC (OR:4.75, 95%CI: 2.47-9.16, FDR=0.007), TM11D (OR: 1.34, 95%CI: 1.17-1.53, FDR=0.02), and PDC6I (OR: 2.35, 95%CI: 1.58-3.49, FDR=0.03). Elevated levels of FASLG (OR: 0.87, 95%CI: 0.82-0.92, FDR=0.007) were associated with a reduced risk of lung cancer. In addition, genetically predicted elevated levels of GRP (OR: 0.05, 95%CI: 0.01-0.17, FDR=0.02) were associated with an increased risk of small-cell lung cancer. The Steiger filter test showed that all directions were from proteins to lung cancer. Conclusion: In this study, we found that five proteins may have effects on the risk of lung cancer, in which genetically predicted SYSC, TM11D, and PDC6I were significantly associated with an increased risk of lung cancer, whereas FASLG and GRP were associated with a decreased risk of lung cancer and small-cell lung cancer, respectively. The above may help to explore the pathogenesis of lung cancer, but further comprehensive studies are still needed. Citation Format: Guojin Si, Wenxuan Li, Yacong Zhang, Zhangyan Lyu, Fengju Song, Kexin Chen. Proteome-wide mendelian randomization identifies causal association between plasma proteins and lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 784.

Applications of CRISPR screening to lung cancer treatment.

Lung cancer is an extremely aggressive and highly prevalent disease worldwide, and it is one of the leading causes of cancer death. Deciphering intrinsic genetic mechanism, finding new targets, and overcoming drug resistance are the key to lung cancer treatment. High-throughput CRISPR screening has been extensively used to obtain the genes related to cancers including lung cancer. This review describes CRISPR/Cas9 or CRISPR/dCas9-based technologies for high-throughput screening. We summarize the applications of CRISPR screening technology in exploring the mechanism of lung cancer development in vivo or in vitro, overcoming drug resistance, improving the effect of immunotherapy, and discovering new therapeutic targets. This review highlights the potential of CRISPR screening in combination with tumor barcoding and high-throughput sequencing (Tuba-seq) to precisely quantify the impact of alterations in many tumor suppressor genes on lung cancer.

Exosomes in lung cancer metastasis, diagnosis, and immunologically relevant advances.

Lung cancer is a chronic wasting disease with insidious onset and long treatment cycle. Exosomes are specialized extracellular vesicles, at first exosomes were considered as a transporter of cellular metabolic wastes, but recently many studies have identified exosomes which contain a variety of biologically active substances that play a role in the regulation of cellular communication and physiological functions. Exosomes play an important role in the development of lung cancer and can promote metastasis through a variety of mechanisms. However, at the same time, researchers have also discovered that immune cells can also inhibit lung cancer through exosomes. In addition, researchers have discovered that some specific miRNAs in exosomes can be used as markers for early diagnosis of lung cancer. Engineering exosomes may be one of the strategies to enhance the clinical translational application of exosomes in the future, for example, strategies such as modifying exosomes to enhance targeting or utilizing exosomes as carriers for drug delivery have been explored. but more studies are needed to verify the safety and efficacy. This article reviews the latest research on exosomes in the field of lung cancer, from the mechanism of lung cancer development, the functions of immune cell-derived exosomes and tumor-derived exosomes, to the early diagnosis of lung cancer.

Analysis of key genes in the development of lung cancer

Lung cancer is the cancer with the highest incidence rate. Due to the insidious early symptoms, more than 80% of lung cancer patients are diagnosed at an advanced stage. If certain key genes that have a main effect on oncogenic ability can be identified, researchers will be able to use precisely targeted therapies to predict and treat the cancer. In order to identify the key genes that play an important role in the development of lung cancer, this study collected gene expression data respectively from lung cancer patients and paraneoplastic samples, and used statistical modeling methods such as Pearson correlation analysis and significance test to screen out typical genes that have a high degree of variability in cancer and paraneoplastic samples and a high correlation with the survival time of patients. The study obtained 1487 genes that were significantly up-regulated in cancer samples and 447 significantly down-regulated genes. Additionally, these key genes were enriched for pathways relying on the GO and KEGG databases to obtain the common functions of these genes and to explore the biological mechanisms of lung cancer development.

The Importance of the Immune System and Molecular Cell Signaling Pathways in the Pathogenesis and Progression of Lung Cancer.

Lung cancer is a disease that in recent years has become one of the greatest threats to modern society. Every year there are more and more new cases and the percentage of deaths caused by this type of cancer increases. Despite many studies, scientists are still looking for answers regarding the mechanisms of lung cancer development and progression, with particular emphasis on the role of the immune system. The aim of this literature review was to present the importance of disorders of the immune system and the accompanying changes at the level of cell signaling in the pathogenesis of lung cancer. The collected results showed that in the process of immunopathogenesis of almost all subtypes of lung cancer, changes in the tumor microenvironment, deregulation of immune checkpoints and abnormalities in cell signaling pathways are involved, which contribute to the multistage and multifaceted carcinogenesis of this type of cancer. We, therefore, suggest that in future studies, researchers should focus on a detailed analysis of tumor microenvironmental immune checkpoints, and to validate their validity, perform genetic polymorphism analyses in a wide range of patients and healthy individuals to determine the genetic susceptibility to lung cancer development. In addition, further research related to the analysis of the tumor microenvironment; immune system disorders, with a particular emphasis on immunological checkpoints and genetic differences may contribute to the development of new personalized therapies that improve the prognosis of patients.

Improving the Accuracy in Lung Cancer Detection Using NN Classifier

Lung cancer is a leading cause of cancer-related deaths worldwide, with a high mortality rate and a significant economic burden on health care systems. Traditional screening methods, such as X-rays and CT scans, have limitations in terms of accuracy and efficiency, leading to many cases of lung cancer being diagnosed at a later stage, when treatment options are limited. In this paper, we aim to develop a highly accurate and efficient tool for detecting lung cancer using a NN classifier. We first build a large dataset of medical images and patient data for training and evaluating the NN classifier. The dataset includes a variety of imaging modalities, including CT scans, X-rays, and other medical images. We then develop and train a NN classifier for lung cancer detection, using a deep learning technique. The NN classifiers optimized for high accuracy and efficiency, with the goal of achieving earlier and more accurate diagnosis of lung cancer. We evaluate the performance of the NN classifier using a variety of metrics, including sensitivity, specificity, and area under the receiver operating characteristic curve (AUC-ROC). The classifier is tested on a separate test dataset to ensure that it generalizes well to new data. We also compare the performance of the NN classifier to other traditional screening methods, such as X-rays and CT scans, to determine the potential impact of the NN classifier on lung cancer screening. Finally, we use explainable machine learning technique called as GLCM to identify specific features and patterns in medical images that are indicative of lung cancer. This analysis provides insights into other underlying mechanisms of lung cancer development and may lead to new discoveries and treatment options.

BCAT1 promotes lung adenocarcinoma progression through enhanced mitochondrial function and NF-κB pathway activation.

Lung cancer is one of the most prevalent and malignant cancers, among which lung adenocarcinoma (LUAD) accounts for the majority and remains a major cause of cancer-related mortality worldwide (Cui et al., 2019). Despite the growing intensity of research on the pathobiology and progression of lung cancer and the fact that many genes have been identified as potential drivers and targets for therapy (Luo et al., 2019; Zhang et al., 2019), the treatment and prognosis of lung cancer patients have hardly improved. Therefore, this study aimed to investigate the precise mechanism of lung cancer development and explore efficient diagnostic and therapeutic methods for clinical treatment.

Circ_SAR1A regulates the malignant behavior of lung cancer cells via the miR-21-5p/TXNIP axis.

BackgroundLung cancer is one of the most common malignancies globally and a significant component of cancer‐related deaths. The lack of early diagnosis accounts for detecting approximately 75% of cancer patients at an intermediate to an advanced stage, with a low 5‐year survival rate. Therefore, a more comprehensive understanding of the molecular mechanisms of lung cancer development is necessary to find reliable and effective therapeutic and diagnostic biomarkers.Methodscirc_SAR1A, miR‐21‐5p, and TXNIP in lung cancer tissues, animal xenografts, and cell lines were validated by qRT‐PCR and western blotting analyses. RNase R digestion and nuclear/cytoplasm fractionation experiments were utilized to determine the stability and localization of circ_SAR1A in lung cancer cells. The binding between miR‐21‐5p and circ_SAR1A or TXNIP was confirmed by luciferase reporter, RNA pull‐down, Spearman's correlation, and rescue assays. CCK‐8, colony formation, flow cytometry, Transwell, and western blotting were utilized to illustrate the malignant behavior of lung cancer cells.Resultscirc_SAR1A and TXNIP were down‐regulated while miR‐21‐5p was up‐regulated in lung cancer samples and cells. circ_SAR1A was located predominantly in the cytoplasm; it inhibited lung cancer growth in vitro and in vivo by sponging to miR‐21‐5p. miR‐21‐5p silencing suppressed lung cancer malignancy by targeting TXNIP.Conclusionscirc_SAR1A is a critical negative regulator of lung carcinogenesis. circ_SAR1A/miR‐21‐5p/TXNIP attenuation inhibited lung cancer progression, presenting an ideal diagnostic and a potential therapeutic target.

Lung cancer in solid organ transplant recipients

Lung cancer remains the leading cause of cancer mortality worldwide. Solid organ transplant recipients are at risk of developing malignant tumors, including lung cancer, due to long-term use of immunosuppressive drugs. Development of cancer, including lung cancer, in this patient cohort, has a number of peculiarities. Moreover, malignant tumors in these patients are difficult to treat and have a poorer prognosis. This review presents a study of the issues concerning the mechanisms of lung cancer development, screening methods and treatment in solid organ transplant recipients.

MiR-210-3p Promotes Lung Cancer Development and Progression by Modulating USF1 and PCGF3.

PurposeLung cancer represents one of the most frequent solid tumors. Adenocarcinoma is a common type of tumor and a significant threat to individual health globally. MicroRNAs (miRNAs) are recognized as critical governors of gene expression during carcinogenesis, while their effects on lung cancer occurrence and development are required for further investigation. Herein, the functional role of miR-210-3p and its regulation mechanism were characterized in lung cancer.MethodsA total of 50 pairs of tumor and tumor-free lung tissues were surgically resected from lung cancer patients. Dual-luciferase reporter assay and RNA immunoprecipitation assay were performed to examine USF1 binding with miR-210-3p and PCGF3. Cultured human lung cancer cells A549 were assayed for viability, apoptosis, migration, and invasion in vitro by CCK-8 test, flow cytometry, transwell chamber assays, tumorigenesis, and lymph node metastasis in vivo by mouse xenograft experiments.ResultsmiR-210-3p was upregulated in lung cancer tissues. The inhibition of miR-210-3p by specific inhibitor tempered lung cancer development and metastasis in vitro and in vivo. miR-210-3p targeted USF1 and inhibited its expression. USF1 was bound with PCGF3, which increased its transcription. PCGF3-specific knockdown mimicked the effect of miR-210-3p on lung cancer development and metastasis in vitro and in vivo.ConclusionThe current study demonstrated that miR-210-3p facilitates lung cancer development and metastasis by impairing USF1-mediated promotion of PCGF3, which provides a better understanding of the mechanism of lung cancer development and metastasis.

Difference of copy number variation in blood of patients with lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Copy number variation (CNV) in several genetic regions correlate with cancer susceptibility. Hence, this study evaluated the association between CNV and non-small cell lung cancer (NSCLC) in the peripheral blood. Blood samples of 150 patients with NSCLC and 150 normal controls were obtained from a bioresource center (Seoul, Korea). Through an epigenome-wide analysis using the MethylationEPIC BeadChip method, we extracted CNVs by using an SVS8 software-supplied multivariate method. We compared CNV frequencies between the NSCLC and controls, and then performed stratification analyses according to smoking status. We acquired 979 CNVs, with 582 and 967 copy-number gains and losses, respectively. We identified five nominally significant associations (ACOT1, NAA60, GSDMD, HLA-DPA1, and SLC35B3 genes). Among the current smokers, the NSCLC group had more CNV losses and gains at the GSDMD gene in chromosome 8 (P=0.02) and at the ACOT1 gene in chromosome 14 (P=0.03) than the control group. It also had more CNV losses at the NAA60 gene in chromosome 16 (P=0.03) among non-smokers. In the NSCLC group, current smokers had more CNV gains and losses at the ACOT1 gene in chromosome 14 (P=0.003) and at HLA-DPA1 gene in chromosome 6 (P=0.02), respectively, than non-smokers. Five nominally significant associations were found between the NSCLC and CNVs. CNVs are associated with the mechanism of lung cancer development. However, the role of CNVs in lung cancer development needs further investigation.

ARHGAP24 inhibits cell proliferation and cell cycle progression and induces apoptosis of lung cancer via a STAT6-WWP2-p27 axis.

Rho GTPase-activating proteins (RhoGAPs) have been reported to be of great importance in the initiation and development of many different cancers. However, their biological roles and regulatory mechanisms in lung cancer development and progression are poorly defined. Real-time PCR or western blotting analysis was used to detect Rho GTPase-activating protein 24 (ARHGAP24), WWP2, p27, p-STAT6 and STAT6 expression levels as well as the activity of RhoA and Rac1 in lung cancer. Cell proliferation, apoptosis and cell cycle were measured by CCK-8 and flow cytometry analysis. Tumor growth of lung cancer cells was measured using a nude mouse xenograft experiment model in vivo. The correlation between WWP2 and p27 was measured by co-immunoprecipitation and ubiquitination analysis. We found that ARHGAP24 expression was lower in lung cancer tissues collected from the The Cancer Genome Atlas and independent hospital database. Overexpression of ARHGAP24 significantly suppressed cell proliferation and the activity of RhoA and Rac1, induced cell apoptosis and arrested cell cycle at the G0–G1 phase. ARHGAP24 overexpression also inhibited tumor growth in nude mice, whereas knockdown of ARHGAP24 significantly promoted cell proliferation and WWP2 expression and inhibited cell cycle arrest at G1 phase through activating STAT6 signaling. ARHGAP24 overexpression inhibited WWP2 overexpression-induced cell proliferation, cell cycle progression and the decreased p27 expression. Moreover, WWP2 was found interacted with p27, and WWP2 overexpression promoted the ubiquitination of p27. In conclusion, our findings suggest that ARHGAP24 inhibits cell proliferation and cell cycle progression and induces cell apoptosis of lung cancer via a STAT6-WWP2-p27 axis.

Persistence of smoking induced non-small cell lung carcinogenesis by decreasing ERBB pathway-related microRNA expression.

BackgroundTobacco use is responsible for approximately 80–90% of non‐small cell lung cancer cases. A large evidence base has shown that the ERBB pathway is associated with the occurrence of lung cancer. However, the mechanisms of how smoking activates the ERBB pathway have yet to be explained. We hypothesized that microRNAs may induce ERBB pathway activity during the process of lung cancer carcinogenesis.MethodsWe analyzed microRNA array data from the Gene Expression Omnibus and the Kyoto Encyclopedia of Genes and Genomes to determine any associations between genes and smoking in three groups of patients with NSCLC: smokers, former smokers, and non‐smokers.ResultsThe interaction network among miRNAs, including hsa‐mir‐185‐3p, hsa‐mir‐4295, hsa‐mir‐4288, and hsa‐mir‐613, promotes lung cancer development by affecting the ERBB pathway.ConclusionOur findings provide evidence to explain the mechanism of lung cancer development in smokers.

Abstract IA06: Molecular mechanisms of lung cancer development: Between metabolic reprogramming and genomic instability in the field of cancerization

Abstract Airway epithelial cells are prone to assault by risk factors and considered to be the primary cell type involved in the field of cancerization. To investigate risk-associated changes in the bronchial epithelium proteome that may offer new insights into molecular pathogenesis of lung cancer, proteins were identified in the airway epithelial cells of bronchial brushings specimens from risk-stratified individuals by shotgun proteomics. Differential expression of selected proteins was validated by parallel reaction monitoring mass spectrometry in an independent set of individual bronchial brushings. We identified over 300 proteins with a significant trend in expression. Pathway analysis revealed enrichment of carbohydrate metabolic enzymes in high-risk individuals. Glucose consumption and lactate production were increased in human bronchial epithelial BEAS2B cells treated with cigarette smoke condensate for seven months. Increased lipid biosynthetic capacity and net reductive carboxylation were revealed by metabolic flux analyses of [U-13C5] glutamine in this in vitro model, suggesting profound metabolic reprogramming in the airway epithelium of high-risk individuals. These results also pointed towards a fundamental role of glutamine and cysteine metabolism in lung cancer progression. Two amino acid transporters, specifically SLC1A5 and SLC7A11, captured our attention for their high level of expression in lung cancer. These transporters are associated with worse survival in lung cancer. A small-molecular inhibitor of SLC1A5 prevents tumor progression in nude mice, and a glutaminase inhibitor CB-839 exhibits radiosensitization to lung cancer cells, an effect that may be mediated by decreased GSH production. Taken together, these studies provide a rationale for new chemopreventive strategies, selection of patients for surveillance programs, and determining how metabolic reprogramming may contribute genomic instability a requirement to cancer development. Further investigation into how glutamine and cystine metabolism contribute to lung cancer development and progression may lead to novel early-interception strategies in lung cancer. This work is supported by NCI CA186145, CA152662, and DoD W81XWH-11-2-0161. Citation Format: Jamshed Rahman, Xiangming Ji, Chirayu Patel, Jamey Young, Pierre P. Massion. Molecular mechanisms of lung cancer development: Between metabolic reprogramming and genomic instability in the field of cancerization [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA06.

The expression and correlation between chemokine CCL7 and ABCE1 in non-small cell lung cancer.

Lung cancer is a malignant disease, and has the highest incidence and mortality worldwide. Lung cancer is also a popular subject in the field of cancer research. The molecular mechanisms of lung cancer development, invasion and metastasis need to be determined to prolong survival times and improve the quality of life. Recent studies have demonstrated that ATP-binding cassette sub-family E member 1 (ABCE1) is one of the factors that contributes to the development and metastasis of lung cancer, but the specific mechanism of this phenomenon remains unclear. A polymerase chain reaction microarray was used in the present study to screen for chemokine (C-C motif) ligand 7 (CCL7) expression in cell lines that highly expressed ABCE1, and the results showed that CCL7 was highly expressed in H1299 cells (P<0.01). The expression of CCL7 and ABCE1 in lung cancer tissues obtained from 30 patients with non-small cell lung cancer (NSCLC) was higher than that in adjacent normal lung tissues (P<0.01), and a positive correlation between the expression levels of the two genes in NSCLC was observed. These findings indicate that ABCE1 is involved in the development and progression of lung cancer through the CCL7 signaling pathway.

Development of New Molecular EZH2 on Lung Cancer Invasion and Metastasis

肺癌是最常见的恶性肿瘤之一，严重威胁人类生命和健康。筛选合适的靶点是肺癌基因治疗的首要因素。研究EZH2与肺癌发生、发展的分子机制，阐明其信号调控网络，探寻新的治疗靶点和策略，将为筛选临床治疗新靶点提供重要理论支持和实验依据，可以提高肺癌患者生存率、改善生存质量，具有重要的临床应用价值和深远的社会意义。

Molecular mechanisms of lung cancer development at its different stages in nuclear industry workers

to assess mutational events in exons 5, 7, and 8 of the p53 gene and to reveal mutant p53 protein in verified cases of morphologically altered (proliferative and precancerous changes, lung cancer) and histologically unaltered, lung tissues in workers exposed to occupational radiation. The investigation used formalin-fixed paraffin-embedded unaltered and altered lung tissue blocks (FFPBs) obtained from the human radiobiological tissue repository. The shelf-life of FFPBs was 5-31 years. An immunohistochemical technique using mouse antibodies against p53 protein (<<DAKO>>, Denmark), stained with diaminobenzidine (DAB) chromogen, was employed to determine p53 protein. DNA was isolated from lung tissue FFPBs with QIAmp DNA FFPE Tissue Kit, (<<QIAGEN>>, USA). Polymerase chain reaction (PCR) was performed to amplify the p53 gene exons 5, 7, and 8 selected for examination, by applying the sequences of genes and primers, the specificity of which was checked using the online resource (http://www.ncbi.nlm.nih.gov/blast). PCR products were detected by temporal temperature gradient gel-electrophoresis and the Sanger sequencing method. The obtained DNA fragments were analyzed on a sequencer ABI Prism 3100 Genetic Analizer (<<Applied Biosystems>>, USA). Computer-aided DNA analysis was made using the BLAST program. A package of applied Statistica 6.0 programs was employed for statistical data processing. Results. Immunohistochemical analysis showed that mutant p53 protein was absent in the cells of unaltered lung tissue and the number of cells with mutant p53 protein increased in all the patients with proliferative and precancerous changes and lung cancer, suggesting p53 protein dysfunction. The total number of p53 gene mutations in exons 5, 7, and 8, if there were proliferative and precancerous lung tissue changes and lung cancer, were 25, 20, and 40%, respectively. All the found mutations were transversions (the substitution of purine for pyrimidine or, conversely), indicating the action of exogenous mutagens. The results of this investigation have confirmed other investigators' data showing that p53 gene mutations in lung cancer are observed in 40-70% of cases. The differences in the number of cases of altered lung tissue with mutations in the p53 gene (not more than 40%) and in those of p53 protein expression were found in 100%, suggesting the regulation of p53 gene function in the cell at multiple levels.

Mixed large cell neuroendocrine carcinoma and mucosa-associated lymphoid tissue lymphoma of the lung: A case report.

In the present study, a 79-year-old male was referred to Kobe City Medical Center General Hospital due to an abnormal shadow that was revealed on a chest X-ray. The patient possessed a five-year history of consolidation in the right lower lobe, which was diagnosed as chronic aspiration pneumonia and followed up. However, the abnormal shadow adjacent to the pleura gradually increased in size and a novel mass appeared in the right lower lobe that rapidly increased in size. A repeat biopsy revealed a combination of large cell neuroendocrine carcinoma with a clinical tumor-node-metastasis (cTNM) stage of cT2bN2M0 (stage 3A) and mucosa-associated lymphoid tissue lymphoma at Ann Arbor stage 1E. Chemoradiotherapy markedly affected the lesion and the size of the mass was significantly reduced subsequent to four cycles of chemotherapy, which was considered to be a near complete response. The present study reports an extremely rare combination of tumors. The disease course was followed over a period of six years, which included the onset of disease, and the present case may therefore be valuable in clarifying the mechanism of lung cancer development.