Immune cell infiltration is of great significance for the diagnosis and prognosis of cancer. In this study, we collected gene expression data of non-small cell lung cancer (NSCLC) and normal tissues included in TCGA database, obtained the proportion of 22 immune cells by CIBERSORT tool, and then evaluated the infiltration of immune cells. Subsequently, based on the proportion of 22 immune cells, a classification model of NSCLC tissues and normal tissues was constructed using machine learning methods. The AUC, sensitivity and specificity of classification model built by random forest algorithm reached 0.987, 0.98 and 0.84, respectively. In addition, the AUC, sensitivity and specificity of classification model of lung adenocarcinoma and lung squamous carcinoma tissues constructed by random forest method 0.827, 0.75 and 0.77, respectively. Finally, we constructed a prognosis model of NSCLC by combining the immunocyte score composed of 8 strongly correlated features of 22 immunocyte features screened by LASSO regression with clinical features. After evaluation and verification, C-index reached 0.71 and the calibration curves of three years and five years were well fitted in the prognosis model, which could accurately predict the degree of prognostic risk. This study aims to provide a new strategy for the diagnosis and prognosis of NSCLC based on the classification model and prognosis model established by immune cell infiltration.
Algorithms ; Carcinoma, Non-Small-Cell Lung ; diagnosis ; physiopathology ; Humans ; Lung Neoplasms ; diagnosis ; physiopathology ; Machine Learning ; Prognosis

BACKGROUND: Non-small cell lung cancer (NSCLC) is a kind of lung cancer, because its high incidence has been concerned. Therefore, it has great significance to reveal the pathogenesis of NSCLC. As a transcriptional regulatory factor, MATF-A plays an important role in the development of multiple tumors, can regulate the migration process of a variety of tumor cells. HOTAIR is a long non-coding RNA (LncRNA) found in recent years, which expresses abnormally in multiple tumors and is involved in the proliferation and migration of multiple tumors. The aim of this study is to explore the role of MRTF-A through HOTAIR to regulate the proliferation and migration of NSCLC cell A549 cell. METHODS: We constructed the overexpression plasmid and interfering plasmid of MRTF-A, and detected the effect of MRTF-A on the proliferation and migration of A549 cells by CCK8 and wound healing methods respectively. Then, we designed the siRNA of HOTAIR to detect its effect on the proliferation and migration of A549 cells. Through qRT-PCR, we detected the effect of MRTF-A on HOTAIR expression. Finally, we constructed HOTAIR's promoter, and detect the effect of MRTF-A on HOTAIR promoter activity by luciferase reporter gene test. RESULTS: Overexpression of MRTF-A promotes the proliferation and migration of A549 cells, while silent MRTF-A inhibits its proliferation and migration. Next, we found that interfered HOTAIR expression inhibited the proliferation of A549 cells. We found that MRTF-A could influence the expression of HOTAIR and regulate the activity of HOTAIR promoter. CONCLUSIONS MRTF-A regulates the proliferation and migration of A549 cell through HOTAIR.
A549 Cells ; Carcinoma, Non-Small-Cell Lung ; genetics ; metabolism ; physiopathology ; Cell Movement ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Humans ; Promoter Regions, Genetic ; RNA, Long Noncoding ; genetics ; metabolism ; Trans-Activators ; genetics ; metabolism

Lung cancer is the one of the malignant tumor of the highest morbidity and mortality over the world, and non-small cell lung cancer (NSCLC) makes up about 80%. Nowadays, molecular targeted therapy has been the first-line treatment for NSCLC. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are increasingly used in the clinical treatment, but the EGFR-TKIs acquired resistance becomes the bottleneck of continuation of EGFR-TKIs therapy. Epithelial-mesenchymal transition (EMT) is a biological phenomenon in which epithelial cells are transformed into mesenchymal cells. EMT promoted metastasis, invasion of lung cancer and conferred characteristic of stem cell on cancer cells. Meanwhile, EMT is one of an important cause of EGFR-TKIs resistance in NSCLC. The recent studies have found that resistant cells restored the sensitivity to EGFR-TKIs by reversing EMT which suggested that the target of EMT may contribute to inhibit or even reverse the resistance of EGFR-TKIs. Here we make a review about research progress of EMT in EGFR-TKIs resistance in NSCLC.
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Animals ; Antineoplastic Agents ; administration & dosage ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; genetics ; metabolism ; physiopathology ; Drug Resistance, Neoplasm ; Epithelial-Mesenchymal Transition ; drug effects ; ErbB Receptors ; antagonists & inhibitors ; genetics ; metabolism ; Humans ; Lung Neoplasms ; drug therapy ; genetics ; metabolism ; physiopathology ; Protein Kinase Inhibitors ; administration & dosage

BACKGROUND: Lung cancer and chronic obstructive pulmonary disease (COPD) are both common diseases in respiratory system and the leading causes of deaths worldwide. The purpose of this study was to determine whether the severity of COPD affects long-term survival in non-small cell lung cancer (NSCLC) patients after surgical resection. METHODS: A retrospective research was performed on 421 consecutive patients who had undergone lobectomy for NSCLC. Classification of COPD severity was based on guidelines of the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Characteristics among the three subgroups were compared and recurrence-free survivals were analyzed. RESULTS: A total of 172 patients were diagnosed with COPD, 124 as mild (GOLD-1), 46 as moderate(GOLD-2), and 2 as severe (GOLD-3). The frequencies of recurrence were significantly higher in higher COPD grades group (P<0.001). Recurrence-free survival at five years were 78.1%, 70.4%, and 46.4% in Non-COPD, GOLD-1 COPD, and GOLD-2/3 COPD groups, respectively (P<0.001). In univariate analysis, age, gender, smoking history, COPD severity, tumor size, histology and pathological stage were associated with recurrence-free survival. Multivariate analyses showed that older age, male, GOLD-2/3 COPD, and advanced stage were independent risk factors associated with recurrence-free survival. CONCLUSIONS NSCLC patients with COPD are at higher risk for postoperative recurrence, and moderate/severe COPD is an independent unfavorable prognostic factor. The severity of COPD based on pulmonary function test can be a useful indicator to identify patients at high risk for recurrence. Therefore, it can contribute to adequate selection of the appropriate individualized treatment.
Adult ; Aged ; Aged, 80 and over ; Carcinoma, Non-Small-Cell Lung ; complications ; mortality ; physiopathology ; surgery ; Female ; Humans ; Lung Neoplasms ; complications ; mortality ; physiopathology ; surgery ; Male ; Middle Aged ; Multivariate Analysis ; Pulmonary Disease, Chronic Obstructive ; complications ; mortality ; physiopathology ; Respiratory Function Tests ; Retrospective Studies

PURPOSE: To investigate associations between dyspnea and clinical outcomes in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: From 2001 to 2014, we retrospectively reviewed the prospective lung cancer database of St. Paul's Hospital at the Catholic University of Korea. We enrolled patients with NSCLC and evaluated symptoms of dyspnea using modified Medical Research Council (mMRC) scores. Also, we estimated pulmonary functions and analyzed survival data. RESULTS: In total, 457 NSCLC patients were enrolled, and 259 (56.7%) had dyspnea. Among those with dyspnea and whose mMRC scores were available (109 patients had no mMRC score), 85 (56.6%) patients had an mMRC score <2, while 65 (43.3%) had an mMRC score ≥2. Significant decreased pulmonary functions were observed in patients with dyspnea. In multivariate analysis, aging, poor performance status, advanced stage, low forced expiratory volume in 1 second (%), and an mMRC score ≥2 were found to be significant prognostic factors for patient survival. CONCLUSION: Dyspnea could be a significant prognostic factor in patients with NSCLC.
Aged ; Carcinoma, Non-Small-Cell Lung/complications/pathology/*physiopathology ; Dyspnea/*etiology/*physiopathology ; Female ; Forced Expiratory Volume ; Humans ; Lung Neoplasms/complications/pathology/*physiopathology ; Male ; Neoplasm Staging ; Prognosis ; Retrospective Studies ; Severity of Illness Index

Arisaema heterophyllum Blume is one of the three medicinal plants known as traditional Chinese medicine Rhizoma Arisaematis (RA). RA has been popularly used to treat patients with convulsions, inflammation, and cancer for a long time. However, the underlying mechanisms for RA effects are still unclear. The present study was designed to determine the cytotoxicity of agglutinin isolated from Arisema heterophyllum Blume (AHA) and explore the possible mechanisms in human non-small-cell lung cancer A549 cells. AHA with purity up to 95% was isolated and purified from Arisaema heterophyllum Blume using hydrophobic interaction chromatography. AHA dose-dependently inhibited the proliferation of A549 cells and induced G phase cell cycle arrest. AHA induced apoptosis by up-regulating pro-apoptotic Bax, decreasing anti-apoptotic Bcl-2, and activating caspase-9 and caspase-3. In A549 cells treated with AHA, the PI3K/Akt pathway was inhibited. Furthermore, AHA induced increase in the levels of ER stress markers such as phosphorylated eukaryotic initiation factor 2α (p-eIF2α), C/EBP-homologous protein (CHOP), inositol-requiring enzyme 1α (IRE1α), and phosphorylated c-Jun NH-terminal kinase (p-JNK). AHA also induced autophagy in A549 cells. Staining of acidic vesicular organelles (AVOs) and increase in the levels of LC3II and ATG7 were observed in AHA-treated cells. These findings suggested that AHA might be one of the active components with anti-cancer effects in Arisaema heterophyllum Blume. In conclusion, cytotoxicity of AHA on cancer cells might be related to its effects on apoptosis and autophagy through inhibition of PI3K/Akt pathway and induction of ER stress.
A549 Cells ; Agglutinins ; pharmacology ; Apoptosis ; drug effects ; Arisaema ; chemistry ; Autophagy ; drug effects ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; enzymology ; metabolism ; physiopathology ; Cell Line, Tumor ; Drugs, Chinese Herbal ; pharmacology ; Endoplasmic Reticulum Stress ; drug effects ; Humans ; MAP Kinase Signaling System ; drug effects ; Phosphatidylinositol 3-Kinases ; genetics ; metabolism ; Phosphorylation ; drug effects ; Proto-Oncogene Proteins c-akt ; genetics ; metabolism

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD(+), essential for a number of enzymes and regulatory proteins involved in a variety of cellular processes, including deacetylation enzyme SIRT1 which modulates several tumor suppressors such as p53 and FOXO. Herein we report that NQO1 substrates Tanshione IIA (TSA) and β-lapachone (β-lap) induced a rapid depletion of NAD(+) pool but adaptively a significant upregulation of NAMPT. NAMPT inhibition by FK866 at a nontoxic dose significantly enhanced NQO1-targeting agent-induced apoptotic cell death. Compared with TSA or β-lap treatment alone, co-treatment with FK866 induced a more dramatic depletion of NAD(+), repression of SIRT1 activity, and thereby the increased accumulation of acetylated FOXO1 and the activation of apoptotic pathway. In conclusion, the results from the present study support that NAMPT inhibition can synergize with NQO1 activation to induce apoptotic cell death, thereby providing a new rationale for the development of combinative therapeutic drugs in combating non-small lung cancer.
Abietanes ; pharmacology ; Apoptosis ; drug effects ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; enzymology ; genetics ; physiopathology ; Cell Line, Tumor ; Cytokines ; antagonists & inhibitors ; genetics ; metabolism ; Enzyme Inhibitors ; pharmacology ; Humans ; NAD ; metabolism ; NAD(P)H Dehydrogenase (Quinone) ; genetics ; metabolism ; Naphthoquinones ; pharmacology ; Nicotinamide Phosphoribosyltransferase ; antagonists & inhibitors ; genetics ; metabolism

OBJECTIVETo fabricate an innovative scaffold for lung cancer cell culture and establish a three-dimensional lung cancer model in vitro, and to reveal the differences in biological functions of lung cancer cells under the two-dimensional and three-dimensional culture conditions.

METHODSWe chose agarose and alginate as the scaffold materials, and 3D printing technique was applied to construct cell culture scaffold. 95D cells were co-cultured with this scaffold. The differences of cell morphology, proliferation ability, protein expression, etc. in the cells cultured under 2D and 3D cultural conditions were evaluated by light microscopy using HE staining, MTT assay, scanning electron microscopy, and Western blot analysis.

RESULTSCells cultured in 2D wells displayed a spindle and polygonal morphology, whereas those grown in the 3D culture aggregated into spheroids, which invaded, migrated and disseminated into the surrounding scaffold. MTT assay showed that the proliferation rates of the 3D-cultured cells for 2-6 days were significantly lower than, but those cultured for 8-9 days were significantly higher than that of the 2D-cultured cells, indicating that proliferative activity of the cells grown in 2D cultures for 8-9 days was inhibited. In contrast, cells grown on 3D scaffolds still maintained a higher proliferation. The Western blot assay showed that the expression of Cdc42, p53, mTOR were significantly down-regulated in 3D scaffold-cultured group (0.529±0.103, 0.820±0.038 vs. 1.967±0.066), compared with that of the 2D-cultured group (3.063±0.139, 1.738±0.122 vs. 2.472±0.151) (P<0.05 for all), while the expression of MMP-2 was up-regulated in the 3D-cultured cells (1.110±0.029), significantly higher than that of the 2D-cultured cells (0.017±0.001) (P<0.05).

CONCLUSIONSThe cell morphology, proliferation and associated protein expression of lung cancer cells in 3D-culture systems are distinctively different as compared to those of the 2D-cultural cells. 3D-bioprinted agarose-alginate scaffold can better mimic the growth microenvironment of lung cancer in vivo and may provide a promising model for lung cancer research in vitro.

Alginates ; Carcinoma, Non-Small-Cell Lung ; metabolism ; pathology ; physiopathology ; Cell Culture Techniques ; Cell Movement ; Cell Proliferation ; Cells, Cultured ; Coculture Techniques ; Glucuronic Acid ; Hexuronic Acids ; Humans ; Lung Neoplasms ; metabolism ; pathology ; physiopathology ; Neoplasm Invasiveness ; Neoplasm Proteins ; metabolism ; Printing, Three-Dimensional ; Sepharose ; Spheroids, Cellular ; pathology ; Time Factors ; Tissue Scaffolds ; Tumor Microenvironment

PURPOSE: Patients with non-small cell lung cancer (NSCLC) and simultaneously having brain metastases at the initial diagnosis, presenting symptoms related brain metastasis, survived shorter duration and showed poor quality of life. We analyzed our experiences on surgical treatment of brain metastasis in patients with NSCLC. MATERIALS AND METHODS: We performed a single-center, retrospective review of 36 patients with NSCLC and synchronous brain metastases between April 2006 and December 2011. Patients were categorized according to the presence of neurological symptoms and having a brain surgery. As a result, 14 patients did not show neurological symptoms and 22 patients presented neurological symptoms. Symptomatic 22 patients were divided into two groups according to undergoing brain surgery (neurosurgery group; n=11, non-neurosurgery group; n=11). We analyzed overall surgery (OS), intracranial progression-free survival (PFS), and quality of life. RESULTS: Survival analysis showed there was no difference between patients with neurosurgery (OS, 12.1 months) and non-neurosurgery (OS, 10.2 months; p=0.550). Likewise for intracranial PFS, there was no significant difference between patients with neurosurgery (PFS, 6.3 months) and non-neurosurgery (PFS, 5.3 months; p=0.666). Reliable neurological one month follow up by the Medical Research Council neurological function evaluation scale were performed in symptomatic 22 patients. The scale improved in eight (73%) patients in the neurosurgery group, but only in three (27%) patients in the non-neurosurgery group (p=0.0495). CONCLUSION: Patients with NSCLC and synchronous brain metastases, presenting neurological symptoms showed no survival benefit from neurosurgical resection, although quality of life was improved due to early control of neurological symptoms.
Adult ; Aged ; Aged, 80 and over ; Brain Neoplasms/physiopathology/*secondary/*surgery ; Carcinoma, Non-Small-Cell Lung/mortality/*pathology ; Demography ; Disease-Free Survival ; Female ; Follow-Up Studies ; Humans ; Kaplan-Meier Estimate ; Lung Neoplasms/*pathology ; Male ; Middle Aged ; Treatment Outcome

Lung cancer is the leading cause of cancer-related deaths worldwide. Recently, advancements in our ability to identify and study stem cell populations in the lung have helped researchers to elucidate the central role that cells with stem cell-like properties may have in lung tumorigenesis. Much of this research has focused on the use of the airway repair model to study response to injury. In this review, we discuss the primary evidence of the role that cancer stem cells play in lung cancer development. The implications of a stem cell origin of lung cancer are reviewed, and the importance of ongoing research to identify novel therapeutic and prognostic targets is reiterated.
Animals ; Carcinoma, Non-Small-Cell Lung ; pathology ; Cell Transformation, Neoplastic ; Humans ; Lung Injury ; physiopathology ; Lung Neoplasms ; pathology ; Neoplastic Stem Cells ; pathology ; Regeneration