Benign Lung Tissues Research Articles

Microwave dielectric properties of normal, fibroelastotic, and malignant human lung tissue

Technological development of microwave treatment and detection techniques for lung cancer requires accurate and comprehensive knowledge of the microwave dielectric properties of human lung tissue. We characterize the dielectric properties of room temperature human lung tissue from 0.5 to 10 GHz for three lung tissue groups: normal, fibroelastotic, and malignant. We fit a two-pole Debye model to the measured frequency-dependent complex permittivity and calculate the median Debye parameters for the three groups. We find that malignant lung tissue is approximately 10% higher in relative permittivity and conductivity compared to normal lung tissue; this trend matches previously reported normal versus malignant data for other biological tissues. There is little contrast between benign lung tissue with fibroelastosis and malignant lung tissue. We extrapolate our data from room temperature to 37 °C using a temperature-dependence model for animal lung tissue and use the Maxwell-Garnett dielectric mixing model to predict the dielectric properties of inflation-dynamic human lung tissue; both approximations correspond with previously reported dielectric data of bovine and porcine lung tissue.

Lung and colon cancer detection from CT images using Deep Learning

Cancer is a deadly disease that has gained a reputation as a global health concern. Further, lung cancer has been widely reported as the most deadly cancer type globally, while colon cancer comes second. Meanwhile, early detection is one of the primary ways to prevent lung and colon cancer fatalities. To aid the early detection of lung and colon cancer, we propose a computer-aided diagnostic approach that employs a Deep Learning (DL) architecture to enhance the detection of these cancer types from Computed Tomography (CT) images of suspected body parts. Our experimental dataset (LC25000) contains 25000 CT images of benign and malignant lung and colon cancer tissues. We used weights from a pre-trained DL architecture for computer vision, EfficientNet, to build and train a lung and colon cancer detection model. EfficientNet is a Convolutional Neural Network architecture that scales all input dimensions such as depth, width, and resolution at the same time. Our research findings showed detection accuracies of 99.63%, 99.50%, and 99.72% for training, validation, and test sets, respectively.

Lung Cancer Classification in Histopathology Images Using Multiresolution Efficient Nets.

Histopathological images are very effective for investigating the status of various biological structures and diagnosing diseases like cancer. In addition, digital histopathology increases diagnosis precision and provides better image quality and more detail for the pathologist with multiple viewing options and team annotations. As a result of the benefits above, faster treatment is available, increasing therapy success rates and patient recovery and survival chances. However, the present manual examination of these images is tedious and time-consuming for pathologists. Therefore, reliable automated techniques are needed to effectively classify normal and malignant cancer images. This paper applied a deep learning approach, namely, EfficientNet and its variants from B0 to B7. We used different image resolutions for each model, from 224 × 224 pixels to 600 × 600 pixels. We also applied transfer learning and parameter tuning techniques to improve the results and overcome the overfitting problem. We collected the dataset from the Lung and Colon Cancer Histopathological Image LC25000 image dataset. The dataset acquisition consists of 25,000 histopathology images of five classes (lung adenocarcinoma, lung squamous cell carcinoma, benign lung tissue, colon adenocarcinoma, and colon benign tissue). Then, we performed preprocessing on the dataset to remove the noisy images and bring them into a standard format. The model's performance was evaluated in terms of classification accuracy and loss. We have achieved good accuracy results for all variants; however, the results of EfficientNetB2 stand excellent, with an accuracy of 97% for 260 × 260 pixels resolution images.

SHOX2 methylation in Vietnamese patients with lung cancer.

DNA methylation on cytosine in the CpG dinucleotides is one of the most common epigenetic perturbations taking place during cancer initiation, progression, occurrence and resistance therapy. DNA methylation seems to be sufficiently stable epigenetic modification to be utilized as a cancer biomarker in in vitro diagnostic (IVD) settings. Nowadays, the SHOX2 methylation (mSHOX2) is one of the most valuable DNA methylation biomarkers of lung cancer that is the leading cause of cancer death. It is being continuously validated across ethnicities, lifestyles and lifespan. This study focused on characteristics of mSHOX2 in Vietnamese patients with lung cancer since a lack of investigation and evidence of its utility in this country. The probe and primer sets were designed according to the MethyLight method for quantitative assessment of the mSHOX2 in 214 formalin-fixed paraffin-embedded (FFPE) lung tissues and 57 plasma samples. mSHOX2 in FFPE tissues allowed discriminating benign and malignant lung diseases with 60% (95% CI 50.7-68.8%) sensitivity and 90.4% (95% CI 82.6-95.5%) specificity. Importantly, based on mSHOX2 in plasma, lung cancer could be detected with 83.3% (95% CI 65.3-94.4%) sensitivity and 92.6% (95% CI 75.7-99.1%) specificity, respectively. There were insignificant associations between mSHOX2 with age, cancer stage, EGFR mutation and serum CEA, CYFRA21-1 concentrations except for that gender. Our study indicated that mSHOX2 was satisfactory for distinguishing malignant from benign lung tissue and noninvasively detecting lung cancer.

The pathological tissue expression pattern and clinical significance of m6A-regulatory genes in non-small cell lung cancer.

Aberrant expression of m6A-related proteins contributes to the occurrence and progression of non-small cell lung cancer (NSCLC). Current studies mainly focus on single m6A regulatory genes and their underlying mechanisms, and the expression of multiple m6A regulatory proteins in NSCLC remains unclear. Therefore, it is necessary to systematically examine these proteins, particularly in clinical specimens. Bioinformatic analysis was used to determine the expression of m6A regulatory genes and their correlation with common gene mutations, such as TP53, EGFR and KRAS, using The Cancer Genome Atlas (TCGA) and the AE-meta databases. Immunohistochemistry was employed to analyze the protein expression of m6A regulatory proteins in 61 benign lung tissues and 316 NSCLC tissues. Statistical analysis was performed to calculate the correlation between the expression of m6A regulatory proteins and clinicopathological features, survival, and common gene mutations in lung carcinoma patients. Analysis of the mRNA levels of 13 core m6A regulators, using information from TCGA and the AE-meta databases, revealed that YTHDF1 levels were upregulated in NSCLC compared to those in adjacent normal tissues. Immunohistochemical staining showed that the expression of METTL3, ALKBH5, YTHDC2 and YTHDF1 was significantly upregulated in NSCLC tissues. Further analyses demonstrated a positive correlation between differentially expressed m6A regulatory proteins, including METTL3, ALKBH5, YTHDC2 and YTHDF1, and the poor clinicopathological features and survival of NSCLC patients. According to the statistics of NSCLC patients enrolled in the present study, the protein levels of METTL3 in patients with EGFR exon-19 mutation were higher than those in patients with wild-type EGFR. Our results indicate that m6A regulators, including METTL3, ALKBH5, YTHDC2 and YTHDF1, could serve as predictive markers of NSCLC, which will facilitate the early detection and diagnosis of NSCLC.

Homology-Based Image Processing for Automatic Classification of Histopathological Images of Lung Tissue.

Simple SummaryThe purpose of this study was to develop a computer-aided diagnosis (CAD) system for automatic classification of histopathological images of lung tissues. Homology-based image processing (HI) was proposed for CAD. For developing and validating CAD with HI, two datasets of histopathological images of lung tissues were used. The private dataset consists of 94 histopathological images that were obtained for the following five categories: normal, emphysema, atypical adenomatous hyperplasia, lepidic pattern of adenocarcinoma, and invasive adenocarcinoma. The public dataset consists of 15,000 histopathological images that were obtained for the following three categories: lung adenocarcinoma, lung squamous cell carcinoma, and benign lung tissue. For the two datasets, our results show that HI was more useful than conventional texture analysis for the CAD system.The purpose of this study was to develop a computer-aided diagnosis (CAD) system for automatic classification of histopathological images of lung tissues. Two datasets (private and public datasets) were obtained and used for developing and validating CAD. The private dataset consists of 94 histopathological images that were obtained for the following five categories: normal, emphysema, atypical adenomatous hyperplasia, lepidic pattern of adenocarcinoma, and invasive adenocarcinoma. The public dataset consists of 15,000 histopathological images that were obtained for the following three categories: lung adenocarcinoma, lung squamous cell carcinoma, and benign lung tissue. These images were automatically classified using machine learning and two types of image feature extraction: conventional texture analysis (TA) and homology-based image processing (HI). Multiscale analysis was used in the image feature extraction, after which automatic classification was performed using the image features and eight machine learning algorithms. The multicategory accuracy of our CAD system was evaluated in the two datasets. In both the public and private datasets, the CAD system with HI was better than that with TA. It was possible to build an accurate CAD system for lung tissues. HI was more useful for the CAD systems than TA.

ATR-FTIR spectroscopy as adjunct method to the microscopic examination of hematoxylin and eosin-stained tissues in diagnosing lung cancer.

Lung cancer remains the leading cause of cancer-related death worldwide. Since prognosis and treatment outcomes rely on fast and accurate diagnosis, there is a need for more cost-effective, sensitive, and specific method for lung cancer detection. Thus, this study aimed to determine the ability of ATR-FTIR in discriminating malignant from benign lung tissues and evaluate its concordance with H&E staining. Three (3) 5μm-thick sections were cut from formalin fixed paraffin embedded (FFPE) cell or tissue blocks from patients with lung lesions. The outer sections were H&E-stained and sent to two (2) pathologists to confirm the histopathologic diagnosis. The inner section was deparaffinized by standard xylene method and then subjected to ATR-FTIR analysis. Distinct spectral profiles that distinguished (p<0.05) one sample from another, called the “fingerprint region”, were observed in five (5) peak patterns representing the amides, lipids, and nucleic acids. Principal component analysis and hierarchical cluster analysis evidently clustered the benign from malignant tissues. ATR-FTIR showed 97.73% sensitivity, 92.45% specificity, 94.85% accuracy, 91.49% positive predictive value and 98.00% negative predictive value in discriminating benign from malignant lung tissue. Further, strong agreement was observed between histopathologic readings and ATR-FTIR analysis. This study shows the potential of ATR-FTIR spectroscopy as a potential adjunct method to the gold standard, the microscopic examination of hematoxylin and eosin (H&E)-stained tissues, in diagnosing lung cancer.

Ectopic expression of LAG-3 in non-small-cell lung cancer cells and its clinical significance.

BackgroundLymphocyte activation gene 3 (LAG‐3, also known as CD223) is an immune checkpoint molecule expressed on various types of lymphocytes, and it is mainly involved in maintaining immune homeostasis. However, there are currently no data on LAG‐3 expression in non–small‐cell lung cancer cells.MethodsHuman lung cancer cells were cultured using conventional methods. The expression of LAG‐3 was measured by Western blot and flow cytometry. Between April 2018 and May 2019, we collected 52 surgical specimens of stage I‐III non–small‐cell lung cancer (NSCLC). Fourteen samples of benign lung tissue lesions were collected as the control group, and the expression levels of LAG‐3 in the lung cancer cells and tissue samples were measured via immunohistochemistry.ResultsWestern blots showed that LAG‐3 was expressed in lung cancer cell lines. There was significant difference in the LAG‐3 expression levels in the NSCLC cells and benign lung tissue (χ 2 = 13.055, P = .0003). The LAG‐3 expression level was significantly associated with the NSCLC clinical stage, and LAG‐3 expression was significantly higher in stage III patients (P < .05).ConclusionLAG‐3 is expressed in NSCLC tumor cells. Furthermore, LAG‐3 not only is expressed in tumor‐infiltrating lymphocytes in NSCLC patients but also is ectopically expressed in tumor cells and associated with TNM stage.

Elevated Heme Synthesis and Uptake Underpin Intensified Oxidative Metabolism and Tumorigenic Functions in Non–Small Cell Lung Cancer Cells

Tumors of human non-small cell lung cancer (NSCLC) are heterogeneous but exhibit elevated glycolysis and glucose oxidation relative to benign lung tissues. Heme is a central molecule for oxidative metabolism and ATP generation via mitochondrial oxidative phosphorylation (OXPHOS). Here, we showed that levels of heme synthesis and uptake, mitochondrial heme, oxygen-utilizing hemoproteins, oxygen consumption, ATP generation, and key mitochondrial biogenesis regulators were enhanced in NSCLC cells relative to nontumorigenic cells. Likewise, proteins and enzymes relating to heme and mitochondrial functions were upregulated in human NSCLC tissues relative to normal tissues. Engineered heme-sequestering peptides (HSP) reduced heme uptake, intracellular heme levels, and tumorigenic functions of NSCLC cells. Addition of heme largely reversed the effect of HSPs on tumorigenic functions. Furthermore, HSP2 significantly suppressed the growth of human NSCLC xenograft tumors in mice. HSP2-treated tumors exhibited reduced oxygen consumption rates (OCR) and ATP levels. To further verify the importance of heme in promoting tumorigenicity, we generated NSCLC cell lines with increased heme synthesis or uptake by overexpressing either the rate-limiting heme synthesis enzyme ALAS1 or uptake protein SLC48A1, respectively. These cells exhibited enhanced migration and invasion and accelerated tumor growth in mice. Notably, tumors formed by cells with increased heme synthesis or uptake also displayed elevated OCRs and ATP levels. These data show that elevated heme flux and function underlie enhanced OXPHOS and tumorigenicity of NSCLC cells. Targeting heme flux and function offers a potential strategy for developing therapies for lung cancer. SIGNIFICANCE: These findings show that elevated heme availability due to increased heme synthesis and uptake causes intensified oxygen consumption and ATP generation, promoting tumorigenic functions and tumor growth in NSCLC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/10/2511/F1.large.jpg.

Expression and significance of EMMPRIN, MMP-9 and TIMP-1 in non-small cell lung carcinoma tissues of Guangxi Province, China

Background: Although radical operation to treat lung cancer is thought to be an important treatment measure, prognosis of advanced lung cancer is still poor. A reasonable treatment procedure for advanced lung cancer is an issue worthy of investigating nowadays. The further research on the role and the co-relationship of EMMPRIN, MMP-9, TIMP-1 will not only help to approach the mechanisms of the non-small cell lung carcinoma (NSCLC) incidence and development in depth, but also offer help for the gene targeted therapy of NSCLC. This study was to examine the expression and significance of tumor metastasis genes EMMPRIN , MMP-9 , TIMP-1 in Guangxi NSCLC)tissues, cancer adjacent tissues and benign lung tissues. Methods: Reverse transcription polymerase chain reaction (RT-PCR) was used to measure the expression level of EMMPRIN, MMP-9, TIMP-1 in 80 cases of NSCIC, 40 cases of tumor adjacent tissues and 10 cases of benign lesion lung tissues, then we analysed the sequence of PCR products of these gene. Results: The positive expression rate of EMMPRIN, MMP-9 and TIMP-1 in lung cancer cells was higher than in the cancer adjacent tissues (P 0.05). Patients with EMMPRIN or MMP-9 negative expression had a significantly longer OS (P=0.016 and P=0.026) than those with positive expression. Conclusions: In NSCLC, the detected level of EMMPRIN, MMP-9 and TIMP-1 was higher than in cancer adjacent tissue and benign lung tissue, suggesting that they were involved in NSCLC incidence and development; EMMPRIN, MMP-9, TIMP-1 expression can not only serve as the indicator to determine the pathological classification, metastasis and prognosis of NSCLC, but also offer help for targeted gene therapy of NSCLC.

Expression and significance of EMMPRIN, MMP-9 and TIMP-1 in non-small cell lung carcinoma tissues of Guangxi Province, China

Background: Although radical operation to treat lung cancer is thought to be an important treatment measure, prognosis of advanced lung cancer is still poor. A reasonable treatment procedure for advanced lung cancer is an issue worthy of investigating nowadays. The further research on the role and the co-relationship of EMMPRIN, MMP-9, TIMP-1 will not only help to approach the mechanisms of the non-small cell lung carcinoma (NSCLC) incidence and development in depth, but also offer help for the gene targeted therapy of NSCLC. This study was to examine the expression and significance of tumor metastasis genes EMMPRIN, MMP-9, TIMP-1 in Guangxi NSCLC)tissues, cancer adjacent tissues and benign lung tissues.

A novel method for quantification of beam's-eye-view tumor tracking performance.

In-treatment imaging using an electronic portal imaging device (EPID) can be used to confirm patient and tumor positioning. Real-time tumor tracking performance using current digital megavolt (MV) imagers is hindered by poor image quality. Novel EPID designs may help to improve quantum noise response, while also preserving the high spatial resolution of the current clinical detector. Recently investigated EPID design improvements include but are not limited to multi-layer imager (MLI) architecture, thick crystalline and amorphous scintillators, and phosphor pixilation and focusing. The goal of the present study was to provide a method of quantitating improvement in tracking performance as well as to reveal the physical underpinnings of detector design that impact tracking quality. The study employs a generalizable ideal observer methodology for the quantification of tumor tracking performance. The analysis is applied to study both the effect of increasing scintillator thickness on a standard, single-layer imager (SLI) design as well as the effect of MLI architecture on tracking performance. The present study uses the ideal observer signal-to-noise ratio (d') as a surrogate for tracking performance. We employ functions which model clinically relevant tasks and generalized frequency-domain imaging metrics to connect image quality with tumor tracking. A detection task for relevant Cartesian shapes (i.e., spheres and cylinders) was used to quantitate trackability of cases employing fiducial markers. Automated lung tumor tracking algorithms often leverage the differences in benign and malignant lung tissue textures. These types of algorithms (e.g., soft-tissue localization - STiL) were simulated by designing a discrimination task, which quantifies the differentiation of tissue textures, measured experimentally and fit as a power-law in trend (with exponent β) using a cohort of MV images of patient lungs. The modeled MTF and NPS were used to investigate the effect of scintillator thickness and MLI architecture on tumor tracking performance. Quantification of MV images of lung tissue as an inverse power-law with respect to frequency yields exponent values of β=3.11 and 3.29 for benign and malignant tissues, respectively. Tracking performance with and without fiducials was found to be generally limited by quantum noise, a factor dominated by quantum detective efficiency (QDE). For generic SLI construction, increasing the scintillator thickness (gadolinium oxysulfide - GOS) from a standard 290μm to 1720μm reduces noise to about 10%. However, 81% of this reduction is appreciated between 290 and 1000μm. In comparing MLI and SLI detectors of equivalent individual GOS layer thickness, the improvement in noise is equal to the number of layers in the detector (i.e., 4) with almost no difference in MTF. Further, improvement in tracking performance was slightly less than the square-root of the reduction in noise, approximately 84-90%. In comparing an MLI detector with an SLI with a GOS scintillator of equivalent total thickness, improvement in object detectability is approximately 34-39%. We have presented a novel method for quantification of tumor tracking quality and have applied this model to evaluate the performance of SLI and MLI EPID designs. We showed that improved tracking quality is primarily limited by improvements in NPS. When compared to very thick scintillator SLI, employing MLI architecture exhibits the same gains in QDE, but by mitigating the effect of optical Swank noise, results in more dramatic improvements in tracking performance.

Correlation analysis between expression of NF-κB and quartz's deposit in non-small cell lung cancer in Xuanwei, Yunnan province

Objective To evaluate the relationship between quartz's deposit and expression of NF-κB in non-small cell lung cancer (NSCLC) lung tissues in Xuanwei, Yunnan Province, and to clarify the role of quartz in Xuanwei NSCLC's carcinogenic mechanism. Methods As research objects, the lung tissues of NSCLC and lung benign lesions after surgical resection were collected from July 2009 to September 2015 at the Third Affiliated Hospital of Kunming Medical University. Firstly, the transmission electron microscopic (TEM) with energy dispersive X-ray analyzer (EDS) was used for observation of crystalline deposit and local pathological changes. Secondly, expression level of NF-κB had been analysed and a correlation analysis with particle size of SiO2 crystal in the same lung sample was made. Results The occurrence rates of quartz in Xuanwei NSCLC lung tissues were above non-Xuanwei NSCLC and benign lung tissues (P 0.05). The expression level of NF-κB was generally increasing when quartz's size became smaller. Conclusion Quartz's deposit may play a certain role in carcinogenic mechanism of lung cancer in Xuanwei, the smaller the particle size, the greater the cytotoxicity. Key words: Carcinoma, non-small-cell lung; Quartz; NF-kappa B

폐암에서 microRNA 155의 발현 양상과 임상병리학적 의의

폐암은 전세계적으로 높은 발병율과 사망률을 보이는 암종으로 소세포암종과 비소세포암종으로 구분되어지며, 비소세포암이 75-80%를 차지하고 있다. miR-155의 유전자의 과 발현은 갑상선암, 유방암, 대장암, 자궁 경부암, 췌장선암(PDAC), 폐암 등의 고형암에서 관찰된다. 본 연구에서는 한국인 폐암 환자의 조직에서 특이적으로 발현되는 miRNA의 양상을 양성 폐질환자 와 비교 분석하고, 폐암환자의 임상병리학적 특성과의 상관성을 분석하여 miRNA가 암 진단의 생물표지자로서의 가능성을 조사하여 향후 암의 조기 진단 및 치료, 예후 연구에 기초 자료를 제공하고자 하였다. 파라핀 포매 된 비소세포폐암환자 및 양성 폐 질환자의 블록에서 total RN를의 분리하여, 정량 실시간연쇄중합반응을 통해 miR-155의 발현량을 정량 분석을 실시하였으며, miR-155의 발현과 폐암환자의 임상적 특징과의 상관관계를 분석하였다. 폐암 환자군과 양성 폐질환자의 miR-155의 &#x25B3;Ct 값을 분석한 결과 폐암환자군에서 유의하게 높게 발현되었다(p&#x3C;0.001). 병리조직학적 분류에 따라서는 편평상피세포암종에서 선암종에 비해 높게 발현되었다. 분화도에 따라서는 저분화 암에서 고분화암에 비해 유의하게 높게 발현되었다(p=&#x3C;0.001). 또한 miR-155의 과발현은 림프절 전이와도 통계적으로 유의성 나타내었다(p&#x3C;0.05). 생존분석결과 miR-155의 과발현은 폐암환자의 생존률과 유의한 상관관계를 나타내었다(p&#x3C;0.05). 본 연구의 결과로 miR-155의 발현은 폐암의 진행 및 전이에 중요한 역할을 할 것으로 생각되며, 폐암의 조기진단과 예후의 예측을 위하여 보다 다양한 종류의 miRNAs에 대한 연구가 이루어져야 할 것으로 판단된다. Lung cancer is currently the most common malignant disease and the leading cause of mortality in the world and non-small cell lung cancer (NSCLC) accounts for 75-80% of lung cancer cases. miR-155 gene was found to be over expressed in several solid tumors, such as thyroid carcinoma, breast cancer, colon cancer, cervical cancer, pancreatic ductal adenocarcinoma (PDAC) and lung cancer. The aims of this study were to define the expression of miR-155 in lung cancer and its associated clinic-pathologic characteristics. Total RNA was purified from formalin-fixed, paraffin-embedded NSCLC tissues and benign lung tissues. Expression of miR-155 in human lung cancer tissues were evaluated as mean fold changes of miR-155 in cancer tissues compared to benign lung tissues by quantitative real-time reverse transcriptase polymerase chain reaction (real-time qRT-PCR) and associations of miR-155 expression with clinic-pathologic findings of cancer. Compared with the benign control group, miR-155 expression was significantly overexpressed in NSCLCs (p=&#x3C;0.001). miR-155 was more overexpressed in squamous cell carcinoma than in adenocarcinoma. Poorly differentiated tumors showed significantly overexpression of miR-155 than well-differentiated tumors (p=&#x3C;0.001). Overexpression of miR-155 was significantly associated with lymph node metastasis (p=&#x3C;0.05). In survival analysis for all NSCLC patients, high miR-155 expression was significantly correlated with worse overall survival (p=&#x3C;0.05). These results suggested that miR-155 might play an important role in lung cancer progression and metastasis.

ANGPTL4 Correlates with NSCLC Progression and Regulates Epithelial-Mesenchymal Transition via ERK Pathway.

Purpose Lung cancer remains the leading cause of cancer deaths with intricate mechanisms. In the present study, we evaluated the clinical significance and biological role of ANGPTL4 in non-small cell lung cancer (NSCLC), the most common lung cancer subtype. Methods Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used for examining the mRNA level of ANGPTL4 in NSCLC tissues and adjacent non-tumor tissues, NSCLC cell lines, and the immortalized human bronchial epithelial cell line HBE, respectively. A tissue microarray was used for analyzing the relationship between ANGPTL4 expression and the clinicopathological parameters of NSCLC patients. Commercial lentivirus expressing shRNAs was used for silencing ANGPTL4. Cell Counting Kit-8 (CCK-8) was employed for evaluating the cell proliferation ability and transwell with or without matrigel was used for cell migration and invasion assay. Results As the result, ANGPTL4 was over-expressed in NSCLC tissues compared with benign lung tissues. Silencing ANGPTL4 expression strongly inhibited the proliferation, migration, and invasion of A549 and H520 cells, which was in accordance with the increase of epithelial marker E-cadherin and decrease of mesenchymal marker vimentin. By screening the ERK, AKT, EGFR, and STAT3 pathways, we found that cell growth, migration, and invasion arrest induced by loss of ANGPTL4 expression was partially attributable to down-regulation of ERK signaling. Conclusion These results suggested that ANGPTL4 was essential for proliferation and metastasis of lung cancer cells and might serve as a novel target for the treatment of lung cancer.

Practical utility of insulin-like growth factor II mRNA-binding protein 3, glucose transporter 1, and epithelial membrane antigen for distinguishing malignant mesotheliomas from benign mesothelial proliferations.

The differentiation of malignant mesotheliomas and benign mesothelial proliferations is crucial in determining patient care and prognosis. But, this distinction can be extremely difficult, particularly in small biopsies. Recently, insulin-like growth factor II mRNA-binding protein 3 (IMP3) and glucose transporter 1 (GLUT-1) have been reported as specific and sensitive markers in the distinction of mesotheliomas from benign mesothelial proliferations. The purpose of this study is to evaluate the utility of IMP3, GLUT-1, and epithelial membrane antigen (EMA) immunohistochemistry for distinguishing mesotheliomas from benign mesothelial proliferations. Immunoexpression of IMP3, GLUT-1, and EMA was evaluated in 88 malignant mesotheliomas, 35 adenomatoid tumors, and 20 benign lung tissues with reactive mesothelial cells. The sensitivity for IMP3, GLUT-1, and EMA was 37%, 21%, and 41%, respectively. The specificity for IMP3, GLUT-1, and EMA was 100%. When IMP3, GLUT1, and EMA combined, the sensitivity was 66% for IMP3/EMA staining, 53% for GLUT-1/EMA staining, and 45% for IMP3/GLUT-1. Use of IMP3 and EMA together is more helpful to distinguish malignant mesotheliomas from benign mesothelial proliferations than the use of IMP3 or EMA alone.

Prognostic value of dual-specificity phosphatase 6 expression in non-small cell lung cancer.

Dual-specificity phosphatase 6 (DUSP6/MKP-3) is a mitogen-activated protein kinase phosphatase that regulates extracellular signal-regulated kinases (ERKs) activity via feedback mechanisms, with an increasingly recognized role in tumour biology. The aim of this study was to explore the role of DUSP6 expression in the prognosis of human non-small cell lung cancer (NSCLC). DUSP6 expression levels were evaluated by real-time quantitative reverse transcription polymerase chain reaction (PCR) in 60 NSCLC samples from patients who underwent pulmonary resection at 12 de Octubre University Hospital. We performed a statistical analysis to investigate the correlation of DUSP6 expression and the clinical outcomes. We found that 66.7% of the tumour samples show the downregulation of DUSP6 at the messenger RNA (mRNA) levels compared to benign epithelial lung tissues and 55% of them show at least twofold downregulation of DUSP6 gene expression. Patients were classified into three groups according to their DUSP6 expression levels and those with very low levels (at least twofold downregulation) had the worst outcomes. Using the value of twice below the mean value in benign epithelial lung tissue as a cutoff, the overall survival of patients with very low DUSP6 levels was significantly lower than that in the rest of patients (31.9 ± 18.8 months vs. not reached, P = 0.049). This was most pronounced in adenocarcinoma histology and high-stage tumour samples. Our results suggest that DUSP6 gene expression in tumour samples may be a prognostic marker in NSCLC.

Expression of microRNA miR-126 and miR-200c is associated with prognosis in patients with non-small cell lung cancer.

MicroRNAs (miRNAs) are short non-coding RNAs that exert a critical influence on tumorigenesis through post-transcriptional modification and are considered to be potential biomarkers for the diagnosis or prognosis of various cancers. Although several miRNAs have been proposed as relevant biomarkers for non-small cell lung cancer (NSCLC), detailed working mechanisms and validated prognostic significance of these miRNAs remain controversial. In this study, we evaluated expression levels of miRNA-126 (miR-126) and miR-200c in 72 NSCLCs and 30 benign lung tissues by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and analyzed the correlation of miRNA expression with a variety of clinicopathological factors and patient survival. Compared with the benign control group, miR-126 expression was significantly downregulated in NSCLCs (p < 0.001), while miR-200c expression was significantly upregulated in NSCLCs (p < 0.001). The expression of miR-126 was significantly higher in NSCLCs with a tumor size of ≤3 cm than in those with a tumor size of >3 cm (p = 0.026). There were no other significant associations between miRNA expression and clinicopathological features. In univariate survival analysis for all NSCLC patients, high miR-200c expression (p = 0.037), large tumor size (p = 0.026), and lymphovascular invasion (p = 0.012) were significantly correlated with worse overall survival. High miR-126 expression was significantly associated with favorable prognosis only in patients with adenocarcinoma (p = 0.033). In multivariate analysis, miR-200c and tumor size remained as independent prognostic factors. Our results suggest that miR-126 might play tumor-suppressive and miR-200c an oncogenic role, and these miR's are potential prognostic biomarkers for NSCLC.

Monocyte to macrophage differentiation-associated (MMD) targeted by miR-140-5p regulates tumor growth in non-small cell lung cancer

Monocyte to macrophage differentiation-associated (MMD) is identified in macrophages as a gene associated with the differentiation from monocytes to macrophages. Recent microarray analysis for non-small cell lung cancer (NSCLC) suggests that MMD is an important signature associated with relapse and survival among patients with NSCLC. Therefore, we speculate that MMD likely plays a role in lung cancer. In this study, we found that the protein level of MMD was increased in lung cancer compared to benign lung tissues, and knockdown of MMD inhibited the growth of A549 and Lewis lung cancer cells (LLC) in vitro and in vivo. Integrated analysis demonstrated that MMD was a direct functional target of miR-140-5p. Furthermore, we found that miR-140-5p/MMD axis could affect the cell proliferation of lung cancer cells by regulating Erk signaling. Together, our results highlight the significance of miR-140-5p/MMD axis in lung cancer, and miR-140-5p/MMD axis could serve as new molecular targets for the therapy against lung cancer.

Downregulation of BTG3 in non-small cell lung cancer

BTG3 is identified as a tumor suppressor gene in some malignancies. Btg3-deficient mice display a higher incidence of lung cancer. These results suggest that BTG3 plays an important role in lung tumorigenesis, although the underlying mechanisms are unknown. The BTG3 expression was detected using immunohistochemical staining and our results showed that the expression of BTG3 was reduced in lung cancer compared to benign lung tissues. We identified two BTG3 isoforms present in lung cancer: Full-length BTG3 and BTG3b lacking the 44 amino acids. BTG3 was predominantly expressed in benign lung tissues, whereas its expression was generally undetectable in lung cancer and cancer cell lines. Functional analysis revealed that BTG3 but not BTG3b inhibited lung cancer growth. Our results disclosed an important role of BTG3 in lung tumorigenesis.