Carcinogenesis Of Lung Cancer Research Articles

Non-Small Cell Lung Cancer with Estrogen Receptors and ALK Positivity.

Estrogens are steroid hormones that affect a number of physiological functions in cells; these compounds play an irreplaceable role in the reproductive system. Their effects are mediated by the estrogen receptor (ER), of which there are two subtypes - ERα and ERβ. ERs are expressed in regions outside the reproductive system, including bone, brain, intestine, endothelium, kidney, and lung. Expression of ER by lung cancer (LC) cells was first described in the early 1980s. The experimental literature also describes co-expression of ERβ and an epidermal growth factor activating mutation, and the additive antiproliferative effects of anti-estrogens plus tyrosine kinase inhibitors during treatment of lung adenocarcinoma. However, coincident expression of ER and ALK translocation were not decribed. The 4-year survival for generalized non-small cell lung cancer indicates the possibility that both molecular features (ER and ALK positivity) may be a favorable prognostic biomarker for this tumor. A 69-year-old patient presented with generalized lung adenocarcinoma that was positive for ERb and the ALK-EML4 fusion gene. The tumor was stage IV. Additional examinations excluded malignancy of the gynecological area. The patient was treated with chemotherapy and atyrosine kinase ALK inhibitor. The role of individual ER subtypes in LC carcinogenesis, and the possible therapeutic effects, is unclear. This is the first documented case of co-occurrence of ALK-EML4 and ERβ in LC. Key words non-small cell lung cancer - estrogen receptors - ALK translocation - prognosis - treatment This work was supported by Ministry of Health of the Czech Republic, grant AZV 16-32318A, and by Ministry of Education, Youth and Sports of the Czech Republic, grant NPU I LO1304. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 23. 9. 2018 Accepted: 25. 10. 2018.

Copy Number Analysis of Lung Tumor Progression in Mice

Background & Hypothesis 
 The xeroderma pigmentosum group C (XPC) gene encodes a protein that repairs DNA damage, like that caused by UV light. Its mutation in patients is associated with increased risk of melanoma. In our mouse model, the Xpc gene has a targeted deletion, leading to increased frequency of lung tumors in a mouse strain typically resistant to lung chemical carcinogenesis. We hypothesize that there will be enrichment of specific copy number variations (CNVs) in the genome throughout tumor progression that can distinguish the different stages of carcinogenesis in lung cancer. 
 Project Methods 
 Urethane treatments induced lung tumors in Xpc -/- (ko) mice. Laser capture microscopy was used to isolate tumor, hyperplasia, and normal tissue from lung sections. After DNA extraction, genomic DNA (gDNA) was quantified using Quantifluor assay. Whole genome amplification was completed using Repli-G kit. PCR, copy number analysis, and restriction enzyme digestion were quality control measures for amplified gDNA. Single nucleotide polymorphism (SNP) microarrays will assess CNVs in samples that are successfully amplified. 
 Results 
 DNA was successfully amplified, as confirmed by the Quantifluor assay. PCR, copy number analysis, and restriction enzyme digestion confirmed 3 out of the 4 amplified samples were comparable to matched non-amplified samples, suggesting mouse gDNA was maintained. 
 Potential Impact 
 The mouse model findings can be applied to publically available human genome databases of lung cancer CNVs. Overlapping findings in mice and human CNVs may give insight into novel pathways for effective treatment in lung cancer.

LncRNA LINC00319 accelerates ovarian cancer progression through miR-423-5p/NACC1 pathway

Long noncoding RNA (lncRNA) LINC00319 has been reported to promote carcinogenesis of lung cancer and cutaneous squamous cell carcinoma. However, the role and mechanism of LINC00319 in ovarian cancer progression is unclear. In this study, LINC00319 expression was found to be upregulated in ovarian cancer tissues and cell lines. And our evidence showed that LINC00319 could be a potential prognostic biomarker for patients with ovarian cancer. Cell Counting Kit-8 (CCK-8), colony formation and transwell assays indicated that LINC00319 upregulation promoted proliferation, migration and invasion of ovarian cancer cells. Bioinformatics analysis and luciferase reporter assay revealed that LINC00319 worked as the sponge for miR-423-5p. Furthermore, miR-423-5p directly targeted NACC1. qRT-PCR and western blot results demonstrated that LINC00319 upregulates NACC1 expression through inhibiting miR-423-5p in ovarian cancer cells. Moreover, we observed an inverse expression correlation between miR-423-5p and LINC00319 or between miR-423-5p and NACC1 in ovarian cancer tissues. Finally, rescue assay showed that NACC1 restoration rescued the potentials of proliferation, migration and invasion in LINC00319-depleted ovarian cancer cells. In conclusion, our findings demonstrated that LINC00319 promotes ovarian cancer progression through upregulating NACC1 expression by restraining miR-423-5p.

Integrated analysis of DNA methylation profiling and gene expression profiling identifies novel markers in lung cancer in Xuanwei, China.

BackgroundAberrant DNA methylation occurs frequently in cancer. The aim of this study was to identify novel methylation markers in lung cancer in Xuanwei, China, through integrated genome-wide DNA methylation and gene expression studies.MethodsDifferentially methylated regions (DMRs) and differentially expressed genes (DEGs) were detected on 10 paired lung cancer tissues and noncancerous lung tissues by methylated DNA immunoprecipitation combined with microarray (MeDIP-chip) and gene expression microarray analyses, respectively. Integrated analysis of DMRs and DEGs was performed to screen out candidate methylation-related genes. Both methylation and expression changes of the candidate genes were further validated and analyzed.ResultsCompared with normal lung tissues, lung cancer tissues expressed a total of 6,899 DMRs, including 5,788 hypermethylated regions and 1,111 hypomethylated regions. Integrated analysis of DMRs and DEGs identified 45 tumor-specific candidate genes: 38 genes whose DMRs were hypermethylated and expression was downregulated, and 7 genes whose DMRs were hypomethylated and expression was upregulated. The methylation and expression validation results identified 4 candidate genes (STXBP6, BCL6B, FZD10, and HSPB6) that were significantly hypermethylated and downregulated in most of the tumor tissues compared with the noncancerous lung tissues.ConclusionsThis integrated analysis of genome-wide DNA methylation and gene expression in lung cancer in Xuanwei revealed several genes regulated by promoter methylation that have not been described in lung cancer before. These results provide new insight into the carcinogenesis of lung cancer in Xuanwei and represent promising new diagnostic and therapeutic targets.

Abstract IA35: Immune contexture evolution during lung cancer carcinogenesis and its potential clinical implications

Abstract Immune-checkpoint blockade has shown unprecedented durable clinical responses in patients with various cancer types, including lung cancer, which has created enormous interest among oncologists and immunologists to understand the interactions between cancer and host anticancer immunosurveillance. Tumors grow within an intricate network of epithelial cells, blood and lymphatic vessels, cytokines, and infiltrating immune cells. The location, density, and functional orientation of different immune cell populations constitute the tumor immune contexture that may profoundly impact clinical outcomes of cancer patients. Although most cancers have evaded host immunosurveillance at the time of presentation, an active anticancer immune response within tumor immune contexture, such as the presence of specific T-lymphocyte subsets, the absence of immunosuppressive elements, the localization and homogeneity of the immune infiltrate, specific features of its organization, and so on is often associated with a more favorable prognosis of cancer patients. There is a dynamic interaction between the host immune system and evolving cancer cells, a phenomenon termed immunoediting. Immunoediting is composed of three phases: elimination, equilibrium, and escape. The elimination phase refers to the phase when host immune responses are able to eradicate tumor cells of early carcinogenesis when the cancer cell molecular architectures are relatively simple. With selection and evolution, cancer cells become molecularly more complex and cancer immunoediting enters the next phase, equilibrium, during which tumor cells that have escaped elimination and have a nonimmunogenic phenotype are selected for growth. During this phase, new tumor cell variants emerge with various mutations that further increase overall resistance to immune attack. The last phase of immunoediting is the escape phase when tumor cell variants selected in the equilibrium phase have breached the host immune defenses, with various genetic and epigenetic changes conferring further resistance to immune detection. Emerging data have suggested progressive immunosuppression with lung cancer evolution that may have started at as early as preneoplastic states and continues to evolve with disease progression. These data advocate for immunotherapy of lung cancers at earlier stages. In addition to immunotherapy, chemotherapies, targeted agents, and radiation may also have a profound effect on the local immune contexture and mediate at least part of long-term effects by reinstating immunosurveillance. The presence of a pre-existing or induced immune response is often associated with more favorable prognosis. Future studies are required to depict the comprehensive molecular and immune evolution of lung cancers of different stages, both before and during treatment, to systematically understand the complex interaction between host immune system and cancer and eventually more effectively harness the immune system to combat lung cancers. Citation Format: Jianjun Zhang. Immune contexture evolution during lung cancer carcinogenesis and its potential clinical implications [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 IA35.

Associations of the risk of lung cancer with serum 25-hydroxyvitamin D level and dietary vitamin D intake: A dose-response PRISMA meta-analysis.

The associations of the risk of lung cancer with the vitamin D intake and serum level are controversial. We performed a comprehensive dose-response meta-analysis to evaluate the precise relationships between the above mentioned parameters.We performed a web search of the PubMed, Medline, and Embase databases to identify potential studies that evaluated the relationships between vitamin D intake or serum 25-hydroxyvitamin D (25([OH]D) levels and the risk of lung cancer on December 5, 2017. According to the inclusion and exclusive criteria, 16 studies were included in this meta-analysis. The pooled relative risks (RRs) with 95% confidence intervals (CIs) were used to assess the strength of the associations. A dose-response analysis was conducted to quantitate the relationship between the serum 25(OH)D or vitamin D intake and the risk of lung cancer.The pooled RR (highest level vs lowest level) showed that the serum 25(OH)D level was not associated with the risk of lung cancer (RR = 1.046, 95% CI = 0.945–1.159). A high vitamin D intake was inversely correlated with the lung cancer risk (RR = 0.854, 95% CI = 0.741–0.984). No significant dose-response relationship was observed between the serum 25(OH)D level and the lung cancer risk. The linearity model of the dose-response analysis indicated that with every 100 IU/day increase in vitamin D intake, the risk of lung cancer decreased by 2.4% (RR = 0.976, 95% CI = 0.957–0.995, P = .018).A high vitamin D intake provides limited protection against lung cancer carcinogenesis.

Necessity of Epigenetic Epidemiology Studies on the Carcinogenesis of Lung Cancer in Never Smokers.

Based on epidemiological and genomic characteristics, lung cancer in never smokers (LCNS) is a different disease from lung cancer in smokers. Based on current research, the main risk factor for LCNS may be air pollution. A recent case-control study in Koreans reported that nitrogen dioxide (NO2) may be a risk factor for LCNS. Additionally, a cohort study showed that exposure to NO2 was associated with significant hypomethylation. Thus, epigenetic epidemiology studies are needed in the near future to evaluate the carcinogenesis of LCNS according to chronic exposure to air pollution and/or viral infections.

Erratum: The association between inflammation, the microbiome and urethane-induced pulmonary adenocarcinoma.

[This corrects the article DOI: 10.3892/ol.2018.8167.].

The nuclear transcription factor RelB functions as an oncogene in human lung adenocarcinoma SPC-A1 cells

BackgroundLung cancer is a leading public health issue worldwide. Although therapeutic approaches have improved drastically in the last decades, the prognosis of lung cancer patients remains suboptimal. The canonical nuclear transcription factor kappa B (NF-κB) signalling pathway is critical in the carcinogenesis of lung cancer. The non-canonical NF-κB signalling pathway (represented by RelB) has attracted increasing attention in the pathogenesis of haematological and epithelial malignancies. However, the function of RelB in non-small cell lung cancer (NSCLC) is still unclear. Recently, high expression of RelB has been detected in NSCLC tissues. We have also demonstrated that RelB expression is an independent prognostic factor in NSCLC patients.MethodsThe mRNA and protein expression of RelB in NSCLC tissues were detected by qRT-PCR and IHC assay. The cell growth of SPC-A1 cells was detected in real-time using the x-Celligence system and xenograft tumour assays. The proliferation capability of cells was detected using a CFSE assay. Cell apoptosis was measured using Annexin V/PI staining, cell cycle was analyzed by the cytometry. Cell migration abilities were detected using the x-Celligence system and wound healing assays. The relative amounts of the active and inactive gelatinases MMP-2 and MMP-9 were examined using gelatin zymography experiments. Apoptosis of RelB depletion SPC-A1 cells after ionizing radiation at 8 Gy. The expression of cellular proliferation signal pathway related-proteins were examined by Western blot analysis.ResultsThe expression of RelB increases in NSCLC tissues. High RelB expression was significantly correlated with advanced-metastatic stage in patients with NSCLC. RelB-silencing inhibits cell growth in vitro and in vivo. We found that RelB affected cell proliferation by regulating AKT phosphorylation. RelB silencing attenuates the migration and invasion abilities of SPC-A1 cells and is likely related to the down regulation of MMP-9 activity and Integrin β-1 expression. In addition, RelB modulated radiation-induced survival of NSCLC cells predominantly by regulating Bcl-xL expression.ConclusionsGiven the involvement of RelB in cell proliferation, migration, invasion, and radio-resistance, RelB functions as an oncogene in NSCLC cells. Our data here shed light on unexplored aspects of RelB in NSCLC.

PO-375 Analysis of miRNA expression in non-small cell lung cancer

Introduction MicroRNAs (MiRNAs) can help understanding the carcinogenesis of lung cancer and serve as potential diagnostic biomarkers for differentiating adenocarcinoma (ADC) and squamous cell lung carcinoma (SCC). The aim of the present study is to analyse and compare the expression patterns of miR-21, miR-197, miR-205, miR-375, miR-495 in ADC and SCC samples. Material and methods Fresh frozen tissue samples from 50 non-small cell lung cancer (NSCLC) patients (25ADC, 25SCC) and adjacent normal tissues were examined. The expression of miR-21, miR-197, miR-205, miR-375, miR-495 were evaluated by RT-qPCR. The statistical analysis was performed by SPSSv20. Results and discussions We found overexpression of: miR-21 in 60% (12ADC and 18SCC), miR-205 in 62% (13ADC and 18SCC), miR-197 in 14% (5ADC and 2SCC), miR-375 in 30% (11ADC and 4SCC) and miR-495 in 40% (13ADC and 7SCC) of the samples. The following miRNAs demonstrated decreased expression: miR-21 in 10% (5ADC and 5SCC), miR-205 in 10% (7ADC and 3SCC), miR-197 in 42% (11ADC and 10SCC), miR-375 in 42% (6ADC and 15SCC) and miR-495 in 30% (9ADC and 6SCC) of the tumours. Statistically significant (p ROC analysis was performed for distinguishing ADC from SCC. Only miR-205 (AUC=0,672, p=0,036) and miR-375 (AUC=0,692, p=0,019) showed statistically significant results independently. The combination of these two miRNAs (AUC=0,771; p=0,001) could distinguish between ADC and SCC with 80% sensitivity and 76% specificity. With the same sensitivity and specificity the combination of miR-205 and miR-375 and miR-495 (AUC=0,776; p=0,001) and the combination of miR-205 and miR-197 and miR-375 (AUC=0,774; p=0,001) could also discriminate between ADC and SCC. Conclusion It has been suggested that miR-205 appeared to be a promising diagnostic biomarker for SCC. Our results show that different panels of miRNAs including miR-205, have better potential to discriminate between ADC and SCC. However further analysis of enlarged sample is necessary to ascertain their diagnostic potential in NSCLC. Acknowledgements This work was supported by Grants №D-138/Contract №8554/12.12.2016/MU-Sofia;DUNK01/2/2009/NSF.

Genetically determined height was associated with lung cancer risk in East Asian population.

The association between adult height and risk of lung cancer has been investigated by epidemiology studies, but the results are inconsistent. Mendelian randomization (MR) analyses with individual‐level data from two genome‐wide association studies, including a total of 7127 lung cancer cases and 6818 controls, were carried out to explore whether adult height is causally associated with risk of lung cancer. A weighted genetic risk score (wGRS) was created based on genotypes of 101 known height‐associated genetic variants. Association between the wGRS and risk of lung cancer was analyzed by logistic regression for each study separately. The combined effect was calculated using fixed effect meta‐analysis. MR analyses showed that increased risk of lung cancer (OR = 1.19, 95%CI: 1.05‐1.35, P = 0.006) associated with taller genetically determined height. Compared with individuals in the lowest tertile of the height‐associated wGRS, those in the highest tertile had 1.10‐fold (95% CI: 1.01‐1.20) increased risk of developing lung cancer. Sensitivity analyses excluding BMI‐associated genetic variants demonstrated consistent association. Our study suggested that genetically taller height was associated with increased risk of lung cancer in East Asian population, indicating that increasing height may have a causal role in lung cancer carcinogenesis.

MicroRNA-216b regulated proliferation and invasion of non-small cell lung cancer by targeting SOX9.

Micro (mi)RNAs are small, evolutionarily conserved and endogenous noncoding RNA molecules between 19 and 24 nucleotides in length. The potential roles of miRNAs in the carcinogenesis and progression of non-small cell lung cancer (NSCLC) have been studied previously. In the present study, it was revealed that miRNA-216b (miR-216b) expression was lower in NSCLC tissue and cell lines compared with that in adjacent healthy lung tissue samples and the normal bronchial epithelial 16HBE cell line, respectively. The ectopic expression of miR-216b inhibited the proliferation and invasion of NSCLC cells in vitro. SRY-Box 9 (SOX9) was identified as a direct target of miR-216b in NSCLC. In addition, SOX9 small interfering RNA was able to mimic the effects of miR-216b overexpression on cell proliferation and invasion in NSCLC. Therefore, the data reported in the present study demonstrate that miR-216b is an important tumor suppressor in NSCLC. These data may contribute to the understanding of the molecular mechanism underlying the carcinogenesis and progression of NSCLC, and provide novel therapies for patients with NSCLC.

GATA6-positive lung adenocarcinomas are associated with invasive mucinous adenocarcinoma morphology, hepatocyte nuclear factor 4α expression, and KRAS mutations.

GATA6 is known to play a role in lung development. However, its role in the carcinogenesis of lung cancer is not well studied. The aim of this study was to analyse GATA6 expression in lung adenocarcinomas (LAs) by immunohistochemistry (IHC) in order to define its association with clinicopathological characteristics. IHC analysis of GATA6 was performed with tissue microarray slides containing 348 LAs. The association between GATA6 expression and clinicopathological parameters was evaluated. GATA6 expression in epithelial tumours other than lung cancer was also evaluated. GATA6 expression was found in 47 LAs (13.5%). This occurred more frequently in younger patients (P = 0.005), and was associated with the absence of lymph node metastasis (P =0.024), well-differentiated to moderately differentiated tumours (P < 0.001), the absence of lymphatic invasion (P = 0.020), and the absence of vascular invasion (P = 0.011). GATA6 expression was associated with mucin production (P < 0.001), the invasive mucinous adenocarcinoma subtype (P < 0.001), KRAS mutations (P = 0.026), expression of MUC2 (P < 0.001), CDX2 (P = 0.049), and MUC5AC (P < 0.001), and absence of expression of TTF-1 (P = 0.002). GATA6 expression was also associated with hepatocyte nuclear factor 4α (HNF4α) expression (P < 0.001). GATA6 expression tended to indicate better prognoses, whereas patients with HNF4α expression had significantly worse prognoses (P = 0.033). Of 270 tumours other than lung cancer, 110 expressed GATA6. These findings suggest that GATA6 might interact with HNF4α and contribute to the development of mucinous-type LAs.

Genetic Contribution to Nonsquamous, Non-Small Cell Lung Cancer in Nonsmokers.

Lung carcinogenesis is strongly influenced byenvironmental and heritable factors. The genetic contribution to the different histologic subtypes is unknown. A population-based computerized genealogy resource linked to a statewide cancer registry of lung cancer cases (N= 5408) was analyzed to evaluate the heritable contribution to lung cancer histologic subtype in smokers (n= 1751) and nonsmokers (n= 818). Statistical methods were used to test for significant excess relatedness of lung cancer cases. Significant excess distant relatedness was observed for all lung cancer histologic subgroups analyzed except for the SCLC subset (p= 0.213). When histologic subsets of smokers and nonsmokers with lung cancer were considered, excess relatedness was observed only in nonsmokers with NSCLC (n= 653 [p= 0.026]) and, in particular, in those nonsmokers with the nonsquamous histologic subtype (n= 561 [p= 0.036]). A total of 61 pedigrees demonstrating a significant excess risk of nonsquamous lung cancer in nonsmokers were identified, and an excess of cases in females was observedamong the individuals with these high-risk pedigrees. This analysis supports a genetic predisposition to lung cancer carcinogenesis in nonsmokers with nonsquamous NSCLC.

The function and mechanism of HMGB1 in lung cancer and its potential therapeutic implications.

As a non-histone chromatin-associated protein, high-mobility group box-1 (HMGB1) performs a pivotal function in various human diseases, including autoimmune diseases, neurodegenerative diseases and cancer. Overexpression of HMGB1 has been demonstrated in numerous types of cancer, including breast cancer, colorectal cancer, lung cancer and hepatocellular carcinoma. However, the underlying mechanism of HMGB1 function in lung cancer remains to be elucidated. The present study aimed to analyze, and summarize the role and mechanism of HMGB1 in lung cancer by retrieving available literature regarding HMGB1 in association with lung cancer. It provides comprehensive information on the association of HMGB1 with the carcinogenesis and progression of lung cancer, and discusses the molecular mechanism of these processes. HMGB1 may induce tumorigenesis, metastasis and chemotherapy resistance in lung cancer. Overall, it is evident that HMGB1 serves an important role in the development and progression of lung cancer, and this review warrants further investigation into HMGB1 as a novel target for cancer therapy.

The association between inflammation, the microbiome and urethane-induced pulmonary adenocarcinoma.

Lung cancer is amongst the most common types of cancer throughout the world. The overall 5-year survival rate is ~17%. A number of studies have demonstrated that the microbiome existing within the host may affect the level of inflammation, and consequently contribute to the carcinogenesis of certain types of cancer. To investigate the role of inflammation and the microbiome in the carcinogenesis of lung cancer, an intervention study involving mice, including a control group (C; n=5), a urethane-induced pulmonary adenocarcinoma group (U; n=5) and a prebiotics intervention group (P; n=5) was carried out. This pulmonary adenocarcinoma model was reviewed, and incidences of the disease were identified using histopathology. The levels of the inflammatory cytokines nuclear factor κB (NF-κB), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and IL-6 in the sera samples were measured using an ELISA technique. In addition, high-throughput sequencing of the 16S ribosomal RNA gene segment was used to analyze the species present in the microbiome of the lower airways and intestinal tracts of mice. The results demonstrated that groups P and U exhibited altered histopathology and the development of lung adenocarcinoma tumors, but no differences were observed between the groups. The level of inflammation, determined by measuring the levels of NF-κB, TNF-α, IL-1β and IL-6 inflammatory cytokines, was significantly lower in group P compared with group U (P<0.05), and was significantly higher in group P compared with group C (P<0.05). Overall, the microbiomes of the lower respiratory and intestinal tracts did not change markedly among the 3 groups, in terms of the size of colonies and Shannon diversity indices. However, at a family and operational taxonomic unit (OTU) level, certain microbiota were altered. For example, the abundance of the Clostridiales and Lachnospiraceae families was lower in the lung and intestinal tracts subsequent to urethane-induced treatment compared with in the control group (P<0.05), and the level of abundance of the Clostridiales family increased to similar levels within the control group (P<0.05), when prebiotics were administered. The levels of abundance of the S24-7, Bacteroidales and Firmicutes families were higher in the intestinal tract compared with the control group (P<0.05), and following treatment with prebiotics, the levels of abundance of these families decreased to similar levels observed in the control group (P<0.05). In conclusion, inflammation and the microbiome serve important roles in the carcinogenesis of lung cancer. Additionally, prebiotics may increase the efficacy of lung cancer treatment by modulating levels of inflammation and the composition of the microbiome. The associations between inflammation, the microbiome and lung cancer require attention.

Use of Inhaled Corticosteroids and the Risk of Lung Cancer, the HUNT Study.

Inflammation plays a central role in chronic obstructive pulmonary disease and lung cancer carcinogenesis. Inhaled corticosteroids (ICS) reduce inflammation. This study has investigated whether ICS use is associated with a lower risk of lung cancer. Data from the Nord-Trøndelag Health Study (HUNT2 Survey, 1995-1997) were merged with The Cancer Registry of Norway and Norwegian Cause of Death Registry. From a total of 65,215 participants, those with chronic airway inflammation, defined by FEV1% < 70 and/or chronic cough and expectorate phlegm, were included (N = 4136). Of these, 3041 individuals reported regarding ICS use and were observed for a period of 12years. Cox regression models were used to calculate the risk of lung cancer with a 95% confidence interval (CI) with sex, age, smoking pack years and FEV1% < 70 as known confounders. Among ICS users (N = 1095). we found a higher, but not significant, incidence of lung cancer N = 39 (3.6%), compared to non-users (N = 1946) with N = 65 (3.3%) cases. Age and smoking were associated with a higher risk, while sex and lung function were not. After adjusting for confounders, ICS use did not change the risk of lung cancer, hazard ratio (HR) 0.968, (95% CI, 0.608-1.540), and p value 0.890. ICS use is not associated with a reduced risk of lung cancer in our study population.

Increased KIF15 Expression Predicts a Poor Prognosis in Patients with Lung Adenocarcinoma

Background/Aims: Lung cancer is the leading cause of cancer-related deaths worldwide. The outcome of patients with non-small cell lung cancer remains poor; the 5-year survival rate for stage IV non-small cell lung cancer is only 1.0%. KIF15 is a tetrameric kinesin spindle motor that has been investigated for its regulation of mitosis. While the roles of kinesin motor proteins in the regulation of mitosis and their potentials as therapeutic targets in pancreatic cancer have been described previously, the role of KIF15 in lung cancer development remains unknown. Methods: Paired lung carcinoma specimens and matched adjacent normal tissues were used for protein analysis. Clinical data were obtained from medical records. We first examined KIF15 messenger RNA expression in The Cancer Genome Atlas database, and then determined KIF15 protein levels using immunohistochemistry and western blotting. Differences between the groups were analyzed using repeated measures analysis of variance. Overall survival was analyzed using the Kaplan–Meier method. Cell-cycle and proliferation assays were conducted using A549, NCI-H1299, and NCI-H226 cells. Results: KIF15 was significantly upregulated at both the messenger RNA and protein levels in human lung tumor tissues. In patients with lung adenocarcinoma, KIF15 expression was positively associated with disease stages; high KIF15 expression predicted a poor prognosis. KIF15 knockdown using short hairpin RNA in two human lung adenocarcinoma cell lines induced G1/S phase cell cycle arrest and inhibited cell growth, but there was no effect in human lung squamous cell carcinoma. Conclusion: Our findings show that KIF15 is involved in lung cancer carcinogenesis. KIF15 could therefore serve as a specific prognostic marker for patients with lung adenocarcinoma.

Elucidating the role of microRNA expression as a post-transcriptional mechanism in the carcinogenesis of air pollution-related lung cancer

Elucidating the role of microRNA expression as a post-transcriptional mechanism in the carcinogenesis of air pollution-related lung cancer

MicroRNA-363-3p inhibits cell growth and invasion of non‑small cell lung cancer by targeting HMGA2.

Lung cancer is the second most common cancer and is the leading cause of cancer-related death worldwide. For decades, increasing evidence revealed that microRNAs may contribute to non‑small cell lung cancer (NSCLC) carcinogenesis and progression and could provide novel therapeutic targets for treatments of patients with NSCLC. Accumulated studies indicate that microRNA (miR)‑363‑3p serves important roles in tumorigenesis and tumor development; however, the role of miR‑363‑3p in NSCLC is still unclear. The current study reported that miR‑363‑3p exhibited reduced expression in NSCLC tissues and cell lines. Reduced miR‑363‑3p expression was correlated with tumor node metastasis classification and distant metastasis of NSCLC patients. Notably, miR‑363‑3p re‑expression significantly suppressed cell proliferation and invasion of NSCLC. Furthermore, bioinformatics analysis, luciferase reporter assay, reverse transcription‑quantitative polymerase chain reaction and western blotting indicated that (high mobility group AT-hook 2) HMGA2 was a direct target gene of miR‑363‑3p. HMGA2 was increased in NSCLC tissues and inversely associated with HMGA2 expression. Moreover, HMGA2 underexpression had similar effects to miR‑363‑3p overexpression in NSCLC cells. Thus, the current study suggested that miR‑363‑3p may act as a tumor suppressor in NSCLC and that the miR‑363‑3p could be investigated as a therapeutic target for the patients with this disease.