Major Type Of Lung Cancer Research Articles

Expression of long non-coding RNA SFTA1P and its function in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a major type of lung cancer with high morbidity and mortality. Long non-coding RNAs (lncRNAs) have been reported to be important in development and progression of NSCLC. However, the role of lncRNA SFTA1P remains unclear. This study aims to explore the clinical roles, biological function, and mechanism of SFTA1P in NSCLC. SFTA1P expression was estimated by the quantitative real-time polymerase chain reaction (qRT-PCR) of 90 pairs of tissue samples, the Cancer Genome Atlas (TCGA) database and microarray. After overexpressing SFTA1P, NSCLC cell proliferation, cycle, and apoptosis were detected. We found that the expression of SFTA1P was significantly downregulated in NSCLC tissues with high diagnostic value (AUC = 0.87), which was consistent with the results of TCGA and microarray data. For the analysis of clinical features, the results revealed that SFTA1P expression was closely related to the pathological type (P < 0.01). Furthermore, the cell function results suggested that the overexpression of SFTA1P triggered cell cycle arrest in the S-phase (P < 0.05). From a mechanistic perspective, the results showed that the PI3K-AKT signaling pathway was inhibited after overexpression of SFTA1P in NSCLC. Taken together, this work supported that SFTA1P may play a suppressing role in the tumorigenesis of NSCLC by modulating PI3K-AKT signaling pathway to influence cell cycle, which provides a potential and prospective biomarker for NSCLC.

Identification of a Seven-lncRNA Immune Risk Signature and Construction of a Predictive Nomogram for Lung Adenocarcinoma

Background The incidence of lung cancer is the highest of all cancers, and it has the highest death rate. Lung adenocarcinoma (LUAD) is a major type of lung cancer. This study is aimed at identifying the prognostic value of immune-related long noncoding RNAs (lncRNAs) in LUAD. Materials and Methods Gene expression profiles and the corresponding clinicopathological features of LUAD patients were obtained from The Cancer Genome Atlas (TCGA). The least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was performed on the prognostic immune-related lncRNAs to calculate the risk scores, and a risk signature was constructed. Survival analysis was performed to assess the prognostic value of the risk signature. A nomogram was also constructed based on the clinicopathological features and risk signature. Results A total of 437 LUAD patients with gene expression data and clinicopathological features were obtained in this study, which was considered the combination set. They were randomly and equally divided into a training set and a validation set. Seven immune-related lncRNAs (AC092794.1, AL034397.3, AC069023.1, AP000695.1, AC091057.1, HLA-DQB1-AS1, and HSPC324) were identified and used to construct a risk signature. The patients were divided into the low- and high-risk groups based on the median risk score of -0.04074. Survival analysis suggested that patients in the low-risk group had a longer overall survival (OS) than those in the high-risk group (p = 1.478e − 02). A nomogram was built that could predict the 1-, 3-, and 5-year survival rates of LUAD patients (C-index of the nomogram was 0.755, and the AUCs for the 1-, 3-, and 5-year survivals were 0.826, 0.719, and 0.724, respectively). The validation and combination sets confirmed these results. Conclusion Our study identified seven novel immune-related lncRNAs and generated a risk signature, as well as a nomogram, that could predict the prognosis of LUAD patients.

MiR-519a functions as a tumor suppressor and is negatively associated with poor prognosis of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the major type of lung cancer. MicroRNAs (miRNAs) are currently considered as novel targets and tools in cancer therapy. The aim of this study was to investigate the expression level and functional role of miR-519a in NSCLC, as well as its clinical values. One hundred and two patients with NSCLC were recruited. Quantitative real-time PCR (qRT-PCR) was used for the measurement of the expression level of miR-519a. Kaplan-Meier survival and Cox regression analyses were conducted to explore the prognostic significance of miR-519a in NSCLC. MTT and Transwell assays were used to detect the effect of miR-519a on NSCLC cell proliferation, migration, and invasion. MiR-519a was significantly downregulated in NSCLC tissues, as well as NSCLC cell lines. The expression level of miR-519a was prominently associated with lymph node metastasis and TNM stage. Kaplan-Meier analysis suggested that low miR-519a expression was closely associated with shorter overall survival. Multivariate Cox regression analysis demonstrated that miR-519a expression level and TNM stage were two independent prognostic factors for 5-year overall survival in NSCLC patients. In vitro study, miR-519a significantly inhibited the proliferation, migration, and invasion of NSCLC cells. STAT3 was proved to be the target gene of miR-519a. MiR-519a functions as a tumor suppressor and inhibits tumor progression of NSCLC via targeting STAT3. MiR-519a may act as a prognostic biomarker and therapeutic target for NSCLC.

MiR-874 directly targets AQP3 to inhibit cell proliferation, mobility and EMT in non-small cell lung cancer.

BackgroundNon‐small cell lung cancer (NSCLC) is a major type of lung cancer with high morbidity and high mortality. miR‐874 has been determined to play a role in tumor suppression in several cancers. The purpose of our study was to detect the biological mechanisms of miR‐874 and AQP3 in NSCLC. Methods: CCK‐8 and Transwell assays were utilized to perform cell invasion.Western blot was employed to evaluate the protein expression. Results: The expression of miR‐874 was lower in NSCLC tissues than that of corresponding adjacent nontumor tissues. Downregulation of miR‐874 predicted a poor prognosis in NSCLC. The cell proliferation and mobility were suppressed by overexpression of miR‐874, which were promoted by knockdown of miR‐874 in A549 and H1299 cells. miR‐874 mediated the expression of AQP3 by directly binding to the 3′‐untranslated regions (UTR) of AQP3 mRNA in NSCLC cells. Moreover, miR‐874 inhibited the proliferation and mobility by targeting AQP3 and inhibited the PI3K/AKT signaling pathway in A549 cells. miR‐874 inhibited the growth of NSCLC in vivo. Conclusions: In conclusion, miR‐874 inhibited proliferation and mobility by regulating AQP3 in NSCLC. The newly identified miR‐874/AQP3 axis provides novel insight into the pathogenesis of NSCLC.

Hydroxygenkwanin Suppresses Non-Small Cell Lung Cancer Progression by Enhancing EGFR Degradation.

Epidermal growth factor receptor (EGFR) is frequently overexpressed and mutated in non-small cell lung cancer (NSCLC), which is the major type of lung cancer. The EGFR tyrosine kinase inhibitors (TKIs) are the approved treatment for patients harboring activating mutations in the EGFR kinase. However, most of the patients treated with EGFR-TKIs developed resistance. Therefore, the development of compounds exhibiting unique antitumor activities might help to improve the management of NSCLC patients. The total flavonoids from Daphne genkwa Sieb. et Zucc. have been shown to contain antitumor activity. Here, we have isolated a novel flavonoid hydroxygenkwanin (HGK) that displays selective cytotoxic effects on all of the NSCLC cells tested. In this study, we employed NSCLC cells harboring EGFR mutations and xenograft mouse model to examine the antitumor activity of HGK on TKI-resistant NSCLC cells. The results showed that HGK suppressed cancer cell viability both in vitro and in vivo. Whole-transcriptome analysis suggests that EGFR is a potential upstream regulator that is involved in the gene expression changes affected by HGK. In support of this analysis, we presented evidence that HGK reduced the level of EGFR and inhibited several EGFR-downstream signalings. These results suggest that the antitumor activity of HGK against TKI-resistant NSCLC cells acts by enhancing the degradation of EGFR.

A natural anthraquinone derivative shikonin synergizes with AZD9291 against wtEGFR NSCLC cells through reactive oxygen species-mediated endoplasmic reticulum stress

BackgroundNSCLC is the major type of lung cancer and the survival rates of NSCLC patients remain low. AZD9291 is a third-generation EGFR-TKI and approved to treat NSCLC patients harboring EGFR T790M mutation and common targetable activating EGFR mutations, but it has a limited effect for wtEGFR NSCLC. PurposeThe current study investigated whether shikonin could enhance the antitumor effect of AZD9291 in wtEGFR NSCLC cells. MethodsSRB and colony formation assay were used to detect the proliferation of NSCLC cells, propidium iodide staining was performed to detect the apoptosis, ROS was analyzed using DCFH-DA staining, and western blot was used to detect the expression of indicated proteins. ResultsWe demonstrated that shikonin, a natural ROS inducer, could enhance the antitumor effect of AZD9291 in wtEGFR NSCLC cells. In addition, shikonin increased AZD9291-induced apoptosis accompanying with the generation of ROS and activation of ER stress. Furthermore, ROS inhibition by NAC or GSH reversed the apoptosis induced by shikonin plus AZD9291, and recovered the ER stress activated by combination treatment, indicating that ROS mediated ER stress played a vital role in this combination therapy. Moreover, shikonin increased the anticancer activity of AZD9291 in primary wtEGFR NSCLC cells through ROS-mediated ER stress. ConclusionOur study suggests that combining shikonin with AZD9291 is a promising therapeutic strategy for treating wtEGFR NSCLC patients.

Construction and Validation of a Protein Prognostic Model for Lung Squamous Cell Carcinoma.

Lung squamous cell carcinoma (LUSCC), as the major type of lung cancer, has high morbidity and mortality rates. The prognostic markers for LUSCC are much fewer than lung adenocarcinoma. Besides, protein biomarkers have advantages of economy, accuracy and stability. The aim of this study was to construct a protein prognostic model for LUSCC. The protein expression data of LUSCC were downloaded from The Cancer Protein Atlas (TCPA) database. Clinical data of LUSCC patients were downloaded from The Cancer Genome Atlas (TCGA) database. A total of 237 proteins were identified from 325 cases of LUSCC patients based on the TCPA and TCGA database. According to Kaplan-Meier survival analysis, univariate and multivariate Cox analysis, a prognostic prediction model was established which was consisted of 6 proteins (CHK1_pS345, CHK2, IRS1, PAXILLIN, BRCA2 and BRAF_pS445). After calculating the risk values of each patient according to the coefficient of each protein in the risk model, the LUSCC patients were divided into high risk group and low risk group. The survival analysis demonstrated that there was significant difference between these two groups (p= 4.877e-05). The area under the curve (AUC) value of the receiver operating characteristic (ROC) curve was 0.699, which suggesting that the prognostic risk model could effectively predict the survival of LUSCC patients. Univariate and multivariate analysis indicated that this prognostic model could be used as independent prognosis factors for LUSCC patients. Proteins co-expression analysis showed that there were 21 proteins co-expressed with the proteins in the risk model. In conclusion, our study constructed a protein prognostic model, which could effectively predict the prognosis of LUSCC patients.

Integrative analysis of genetic and epigenetic profiling of lung squamous cell carcinoma (LSCC) patients to identify smoking level relevant biomarkers

BackgroundIncidence and mortality of lung cancer have dramatically decreased during the last decades, yet still approximately 160,000 deaths per year occurred in United States. Smoking intensity, duration, starting age, as well as environmental cofactors including air-pollution, showed strong association with major types of lung cancer. Lung squamous cell carcinoma is a subtype of non-small cell lung cancer, which represents 25% of the cases. Thus, exploring the molecular pathogenic mechanisms of lung squamous cell carcinoma plays crucial roles in lung cancer clinical diagnosis and therapy.ResultsIn this study, we performed integrative analyses on 299 comparative datasets of RNA-seq and methylation data, collected from 513 lung squamous cell carcinoma cases in The Cancer Genome Atlas. The data were divided into high and low smoking groups based on smoking intensity (Numbers of packs per year). We identified 1002 significantly up-regulated genes and 534 significantly down-regulated genes, and explored their cellular functions and signaling pathways by bioconductor packages GOseq and KEGG. Global methylation status was analyzed and visualized in circular plot by CIRCOS. RNA-and methylation data were correlatively analyzed, and 24 unique genes were identified, for further investigation of regional CpG sites’ interactive patterns by bioconductor package coMET. AIRE, PENK, and SLC6A3 were the top 3 genes in the high and low smoking groups with significant differences.ConclusionsGene functions and DNA methylation patterns of these 24 genes are important and useful in disclosing the differences of gene expression and methylation profiling caused by different smoking levels.

Long noncoding RNA PART1 promotes progression of non-small cell lung cancer cells via JAK-STAT signaling pathway.

Non‐small cell lung cancer (NSCLC), the major type of lung cancer, becomes the greatest threat to the life of people. Growing evidence shows prostate androgen‐regulated transcript 1 (PART1) is considered as effective markers for prostate cancer, and has been shown to be associated with poor prognosis of NSCLC. However, the tumorigenic mechanism of PART1 in NSCLC remains to be investigated. In this study, we found that the expression of PART1 was robustly induced in NSCLC tissues and cell lines. Functional studies established that overexpression of PART1 could promote NSCLC cell proliferation, migration, and invasion, while interference of PART1 inhibited NSCLC progression. Our results also identified miR‐635 as a novel target of PART1, whose expression was inhibited by PART1 in NSCLC cell lines. Moreover, gain‐ and loss‐of‐function studies revealed that PART1 could sponge miR‐635 and increase the expression of Janus kinase (JAK) and signal transducer and activator of transcription proteins (STATs). Finally, we deciphered the molecular mechanism by which PART1 contributed to promotion of NSCLC cell progression via phosphorylation and activation of JAK‐STAT signaling pathway. The animal experiment further confirmed that interference of NSCLC could suppress in vivo tumorigenic ability of NSCLC with favorable pharmacological activity via inactivation of JAK‐STAT signaling pathway. In conclusion, our findings clarified the biologic significance of PART1/miR‐635/JAK‐STAT axis in NSCLC progression and provided novel evidence that PART1 may be a new potential therapeutic target for the treatment of NSCLC.

Identification of an immune signature predicting prognosis risk of patients in lung adenocarcinoma

BackgroundLung cancer has become the most common cancer type and caused the most cancer deaths. Lung adenocarcinoma (LUAD) is one of the major type of lung cancer. This study aimed to establish a signature based on immune related genes that can predict patients’ OS for LUAD.MethodsThe expression data of 976 LUAD patients from The Cancer Genome Atlas database (training set) and the Gene Expression Omnibus database (four testing sets) and 1534 immune related genes from the ImmPort database were used for generation and validation of the signature. The glmnet Cox proportional hazards model was used to find the best gene model and construct the signature. To assess the independently prognostic ability of the signature, the Kaplan–Meier survival analysis and Cox’s proportional hazards model were performed.ResultsA gene model consisting of 30 immune related genes with the highest frequency after 1000 iterations was used as our signature. The signature demonstrated robust prognostic ability in both training set and testing set and could serve as an independent predictor for LUAD patients in all datasets except GSE31210. Besides, the signature could predict the overall survival (OS) of LUAD patients in different subgroups. And this signature was strongly associated with important clinicopathological factors like recurrence and TNM stage. More importantly, patients with high risk score presented high tumor mutation burden.ConclusionsThis signature could predict prognosis and reflect the tumor immune microenvironment of LUAD patients, which can promote individualized treatment and provide potential novel targets for immunotherapy.

MiR-218-5p Suppresses the Killing Effect of Natural Killer Cell to Lung Adenocarcinoma by Targeting SHMT1.

PurposeLung adenocarcinoma (LA) is one of the major types of lung cancer. MicroRNAs (miRNAs) play an essential role in regulating responses of natural killer (NK) cells to cancer malignancy. However, the mechanism of miR-218-5p involved in the killing effect of NK cells to LA cells remains poorly understood.Materials and MethodsThe expression of miR-218-5p was examined by quantitative real-time polymerase chain reaction (qRT-PCR). Serine hydroxymethyl transferase 1 (SHMT1) level was detected by qRT-PCR or western blots. Cytokines production of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) were detected by ELISA. The killing effect of NK cells to LA cells was investigated using lactate dehydrogenase cytotoxicity assay kit. The interaction of miR-218-5p and SHMT1 was probed by luciferase activity assay. Xenograft model was established to investigate the killing effect of NK cells in vivo.ResultsmiR-218-5p was enhanced and SHMT1 was inhibited in NK cells of LA patients, whereas stimulation of interleukin-2 (IL-2) reversed their abundances. Addition of miR-218-5p reduced IL-2-induced cytokines expression and cytotoxicity in NK-92 against LA cells. Moreover, SHMT1 was negatively regulated by miR-218-5p and attenuated miR-218-5p-mediated effect on cytotoxicity, IFN-γ and TNF-α secretion in IL-2-activated NK cells. In addition, miR-218-5p exhaustion inhibited tumor growth by promoting killing effect of NK cells.ConclusionmiR-218-5p suppresses the killing effect of NK cells to LA cells by targeting SHMT1, providing a potential target for LA treatment by ameliorating NK cells function.

Abstract 894: Overexpression and extended degradation rate of Axl in acquired gefitinib-resistant non-small cell lung cancer cells

Abstract Non-small cell lung cancer (NSCLC) is a major type of lung cancer which accounts for approximately 80-85% of all lung cancers. Epidermal growth factor receptor (EGFR)- targeted tyrosine kinase inhibitors (TKIs), such as gefitinib have improved the survival of NSCLC patients with activating mutations in EGFR. However, the drug responses are only transient because tumors acquire resistance via secondary mutations in EGFR (T790M) or amplification of other receptor tyrosine kinases (RTKs) including MET or AXL. Therefore, the precise mechanisms of chemoresistance and finding the novel ways of targeting cancer cells are needed to be identified. AXL, a TAM (Tyro3, AXL, Mer) family member, has been studied as a tumorigenesis, chemoresistance, and EMT marker. Also, we found that AXL is overexpressed in EGFR mutated gefitinib-resistant non-small lung cancer cells (PC9-gef) compared to its parent cells (PC9). Moreover, the AXL degradation rate was found to be suppressed. These findings suggest that the modulation of AXL turnover can be a therapeutic target to overcome gefitinib-resistance. In this study, we confirmed the possibilities of overcoming gefitinib-resistance through the down-regulation and turnover acceleration of AXL by employing yuanhadine, an anti-tumor agent derived from Daphne Genkwa. Yuanhuadine was also effectively suppressed the tumor growth in nude mouse xenograft models implanted with PC9 or PC9-gef cells. Therefore, regulation of AXL expression by modulating its degradation rate can be a therapeutic strategy to overcome acquired gefitinib-resistance in NSCLC. Citation Format: Donghwa Kim, Duc-Hiep Bach, Ji-Young Hong, Hyen Joo Park, Sang Kook Lee. Overexpression and extended degradation rate of Axl in acquired gefitinib-resistant non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 894.

MicroRNA-1 overexpression increases chemosensitivity of non-small cell lung cancer cells by inhibiting autophagy related 3-mediated autophagy.

Non-small cell lung cancer (NSCLC) is a major type of lung cancer. Drug resistance is a enormous obstacle for cancer treatment. Copious microRNAs (miRNAs) have been demonstrated to be implicated in drug resistance in NSCLC. In the present study, RT-qPCR assay revealed that microRNA-1 (miR-1) expression was downregulated in DDP resistant NSCLC tissues and cells. Western blot assay presented a remarkable increase of LC3B-II/LC3B-I ratio and a notable decline of p62 level in DDP resistant NSCLC cells, while these effects were weakened by miR-1. GFP-LC3 puncta experiment showed that ectopic expression of miR-1 induced a noticeable downregulation of GFP-LC3 positive cell percentage in DDP resistant NSCLC cells. Bioinformatical analysis and luciferase assay revealed that autophagy related 3 (ATG3) was a target of miR-1. Also, Western blot and RT-qPCR assays manifested that ATG3 was highly expressed in DDP resistant NSCLC tissues and cells. Additionally, miR-1 inhibited ATG3 expression and ATG3 upregulation abolished miR-1-meidated autophagy inhibition in DDP resistant NSCLC cells. Cell Counting Kit-8 (CCK-8) assay showed that the half maximal inhibitory concentration (IC50 ) of cisplatin (DDP) was reduced in miR-1-enforced DDP resistant NSCLC cells, but was restored following the overexpression of ATG3. Flow cytometry experiments further showed that miR-1 overexpression induced a significant upregulation of apoptotic rate and ATG3 restoration weakened miR-1-induced apoptosis in DDP resistant NSCLC cells. Collectively, our study validated that miR-1 overexpression improved DDP sensitivity of NSCLC cells by inhibiting ATG3-mediated autophagy, providing a potential therapeutic target for easing chemoresistance of anti-tumor drugs.

Expression of Bcl-2 is a favorable prognostic biomarker in lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) is the second major type of lung cancer globally. The majority of patients with LUSC are clinically diagnosed at the advanced stages, thus it is urgent to identify suitable prognostic markers for LUSC. B-cell lymphoma 2 (Bcl-2) has been widely studied in non-small cell lung cancer (NSCLC). However, the prognostic role of Bcl-2 in NSCLC remains conflicting and controversial, particularly for LUSC. Although certain studies have been performed to identify the prognostic value of Bcl-2, to the best of our knowledge, no study has investigated the prognostic role of Bcl-2 in LUSC specifically. The present study aimed to comprehensively evaluate the prognostic value of Bcl-2 in LUSC. Microarray data for LUSC were downloaded from public databases, including the Gene Expression Omnibus and The Cancer Genome Atlas. Microarray data of 901 patients with LUSC from 16 data sets were retrieved. The meta-z algorithm was applied and the combined z score was identified as −2.43, suggesting Bcl-2 is a favorable prognostic biomarker. Furthermore, immunohistochemical staining of Bcl-2 expression was performed in a tissue microarray of 72 patients with LUSC and survival analysis demonstrated that patients with high expression Bcl-2 exhibited significantly more improved overall survival rates compared with those with low Bcl-2 expression. Multivariate Cox regression revealed that high expression of Bcl-2 is an independent favorable prognostic factor (hazard ratio, 0.295; confidence interval, 0.097–0.904; P<0.05). Therefore, the results of the present study demonstrated that Bcl-2 is a favorable prognostic biomarker in LUSC.

Heavy metals assessment in Egyptian smokers with lung cancer

Background Smoking and heavy metals are major risk factors and have an important role in development of lung cancer. Purpose The purpose of this study was to investigate the relationship between development of lung cancer and the synergistic effect of smoking and heavy metals in Egyptian smokers. Patients and methods A total of 41 participants enrolled in this study and were subdivided into three groups: smokers with lung cancer (n=11), nonsmokers with lung cancer (n=15), and apparently healthy smokers (n=15). The diagnosis and types of lung cancer based on pathological examination of biopsies taken either by computed tomography-guided, ultrasound-guided, fiberoptic bronchoscopy (FOB), and blind or thoracoscopic pleural biopsy. Serum levels of five heavy metals (zinc, lead, nickel, manganese, chromium) were assayed using inductive plasma spectrometry. Results Squamous cell carcinoma represents the major type of lung cancer (72.7%) among group of smokers with lung cancer; however, adenocarcinoma either primary or metastatic represents the major type (93.4%) among the nonsmoker group, and all investigated heavy metals in this study (zinc, lead, nickel, manganese, chromium) express significantly higher mean value of their serum levels (P=0.005, 0.005, 0.006, Conclusion Squamous cell carcinoma has been strongly associated with higher serum levels of all investigated heavy metals. There is no association between degree of severity of smoking and serum levels of all investigated heavy metals.

Knocking down MiR-15a expression promotes the occurrence and development and induces the EMT of NSCLC cells in vitro.

Non-small cell lung cancer (NSCLC) is a major type of lung cancer, with the highest mortality rate in all cancers. For all stages of NSCLC, the five-year survival is less than fifteen percent. Epithelial-mesenchymal transition (EMT) is a significant process in tumor occurrence and development, in which microRNAs may play an important role. In many cancers, microRNA-15's family member can act as suppressors or oncogenes of tumors; however, the relation between these microRNAs and EMT in lung cancer remains unclear. According to our study, miR-15a expression decreased in tumor tissues compared with than that in adjacent tissue samples. Knocking down miR-15a expression in NSCLC cells inhibited apoptosis and facilitated cell proliferation and invasion, and. Moreover, down-regulating miR-15a decreased the expression of an EMT-associated protein, E-cadherin, while increased those of vimentin, N-cadherin, and slug.

A computational method for the identification of candidate drugs for non-small cell lung cancer.

Lung cancer causes a large number of deaths per year. Until now, a cure for this disease has not been found or developed. Finding an effective drug through traditional experimental methods invariably costs millions of dollars and takes several years. It is imperative that computational methods be developed to integrate several types of existing information to identify candidate drugs for further study, which could reduce the cost and time of development. In this study, we tried to advance this effort by proposing a computational method to identify candidate drugs for non-small cell lung cancer (NSCLC), a major type of lung cancer. The method used three steps: (1) preliminary screening, (2) screening compounds by an association test and a permutation test, (3) screening compounds using an EM clustering algorithm. In the first step, based on the chemical-chemical interaction information reported in STITCH, a well-known database that reports interactions between chemicals and proteins, and approved NSCLC drugs, compounds that can interact with at least one approved NSCLC drug were picked. In the second step, the association test selected compounds that can interact with at least one NSCLC-related chemical and at least one NSCLC-related gene, and subsequently, the permutation test was used to discard nonspecific compounds from the remaining compounds. In the final step, core compounds were selected using a powerful clustering algorithm, the EM algorithm. Six putative compounds, protoporphyrin IX, hematoporphyrin, canertinib, lapatinib, pelitinib, and dacomitinib, were identified by this method. Previously published data show that all of the selected compounds have been reported to possess anti-NSCLC activity, indicating high probabilities of these compounds being novel candidate drugs for NSCLC.

Abstract 3169: SerpinB2 enhances invadopodia-like structure protrusions and is down-regulated in acquired gefitinib-resistant non-small cell lung cancer cells

Abstract Non-small cell lung cancer (NSCLC) is a major type of lung cancer which accounts for approximately 80-85% of all lung cancers. The targeted therapies have significantly improved the survival of advanced NSCLC patients, but the failure of targeted therapy due to the resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, is now considered a major problem. SerpinB2 is a component of the urokinase plasminogen activator (uPA) system and has been recognized as a biomarker for the progression and metastasis of lung cancer. We found that SerpinB2 is down-regulated in gefitinib-resistant (H292-Gef) cells compared to gefitinib-sensitive (H292) cells. The low SerpinB2 levels in H292-Gef cells were also associated with an enhancement in invasiveness and increase in the length of invadopodia-like structures in the cells. The effect on invasiveness and gefitinib sensitivity was confirmed by knockdown and overexpression of SerpinB2. In addition, an antitumor agent yuanhuadine (YD) was used to test the possibility to overcome the resistance through the up-regulation of SerpinB2. YD effectively elevated SerpinB2 levels and suppressed invasive properties in H292-Gef cells. Collectively, these findings demonstrate the prospective role of SerpinB2 as a novel biomarker for acquired gefitinib resistance and a potential target for NSCLC treatment. Acknowledgement This study was funded by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015R1D1A1A02062012). Citation Format: Song Yi Bae, Donghwa Kim, Hyen Joo Park, Woong Sub Byun, Ji-Young Hong, Hye-Jung Lee, Sang Kook Lee. SerpinB2 enhances invadopodia-like structure protrusions and is down-regulated in acquired gefitinib-resistant non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3169. doi:10.1158/1538-7445.AM2017-3169

Comparative beneficiary effects of immunotherapy against chemotherapy in patients with advanced NSCLC: Meta-analysis and systematic review.

Lung cancer is the most commonly diagnosed cancer among men and it is the third ranked in women. There are two major types of lung cancer, namely, small cell lung cancer (SCLC), which accounts for ~20% of the cases, and non-small cell lung cancer (NSCLC), which is the most common. Chemotherapy and chemoradiotherapy have been used as the first-line therapies but suffer from lack of efficacy and also of several toxic adverse effects. Immunotherapeutic approaches including tumor antigen vaccination, monoclonal antibodies targeting checkpoint pathways and also activated immune cells are being developed and have been shown to be effective in treating NSCLC. Despite their promise, efficacy of several immunotherapies has not been consistent. We undertook this meta-analysis study to analyze results from clinical trials that compared efficacy and safety of immunotherapies with placebo or chemotherapy/radiotherapy in improving overall survival (OS) and progression-free survival (PFS) of NSCLC patients. Various databases were searched to identify randomized clinical studies examining the efficacy and safety of antibody- and vaccine-based immunotherapies in NSCLC patients in comparison to chemotherapy or chemoradiotherapy or placebo. Effects on OS and PFS and also adverse events have been compared. In accordance with the selection criteria, a total of 13 studies with 3,513 patients in immunotherapy and 3,072 patients in chemotherapy/placebo, were selected. PFS (odds ratio 1.81, 95% CI 1.36, 2.42; P<0.0001) and OS (P<0.0001) are found to be greatly improved by immunotherapies. Immunotherapy of NSCLC patients was also found to prevent several adverse effects and to improve daily living ability of the patients. The present meta-analysis strongly suggests that immunotherapy improves OS and PFS of patients with NSCLC.

MiR-675 promotes disease progression of non-small cell lung cancer via activating NF-κB signaling pathway.

Non-small cell lung cancer (NSCLC) is a major type of lung cancer significantly affected human life. Current studies have revealed potential role of miR-675 in the etiology of lung cancer. Therefore, in this study, we aimed to investigate the role of miR-675 in NSCLC cell line. We recruited 92 cases of NSCLC patients from July 2009 to February 2011 in the oncology department. Tumor and peripheral tissue was collected for miR-675 expression. NSCLC cell lines with either miR-675 over-expression or low-expression were established. Western blotting and immunofluorescence staining were used for detecting P65 and pP65 expression and translocation in the nuclei. MiR-675 expression was significantly higher in the lung cancer tissue than the peripheral normal tissue (P &lt; 0.001). The gene expression of pP65 was also increased and decreased in cells with over-expression or low-expression of miR-675, respectively (both P &lt; 0.05). Whereas the trend of P65 expression was on the opposite (both P &lt; 0.05), indicating the NF-κB signaling pathway was activated when miR-675 was expressed and vice versa. Immunofluorescence staining showed that more pP65 expression was clustered in the nuclei in miR-675 over-expressed cells, which further demonstrated NF-κB signaling pathway activation. Increased miR-675 expression is associated with NSCLC progression through activation of NF-κB signaling pathway.